Статті в журналах: "TGFBR1/2 polymorphisms"

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KAKLAMANI, VIRGINIA G., MAUREEN SADIM, YVONI KOUMANTAKI, PHEDON KAKLAMANIS, and BORIS PASCHE. "Role of Polymorphisms in Adamantiades-Behçet’s Disease." Journal of Rheumatology 35, no. 12 (December 2008): 2376–78. http://dx.doi.org/10.3899/jrheum.080676.

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ObjectiveWe previously showed that Adamantiades-Behçet’s disease (A-BD) is associated with a lower incidence of malignancy compared with the general population. Transforming growth factor-β (TGF-β) has been shown to play a role in cartilage regeneration and is increased in patients with A-BD. We also found 2 functional polymorphisms of the TGF-β pathway, TGFBR1*6A and TGFB1*CC, that are associated with risk of malignancy. We tested whether incidence of these polymorphisms would differ in patients with A-BD compared with healthy controls of similar age and geographic location.MethodsWe performed a case-control study including 139 cases and 128 controls from Greece. Cases and controls were genotyped for TGFBR1*6A and TGFB1*CC.ResultsWe found that cases had lower incidence of TGFBR1*6A compared with controls (11.3% vs 13.3%, respectively). Also, the incidence of TGFB1*CC was lower in cases than controls (24.6% vs 27.0%, respectively). These differences were not statistically significant.ConclusionAlthough there is a suggestion that the lower incidence of TGFBR1*6A in A-BD patients may play a protective role against development of malignancy, larger studies would be needed to fully evaluate the role of TGF-β and its polymorphisms in A-BD.

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Guhlich, Manuel, Laura Hubert, Caroline Patricia Nadine Mergler, Margret Rave-Fraenk, Leif Hendrik Dröge, Martin Leu, Heinz Schmidberger, Stefan Rieken, Andrea Hille, and Markus Anton Schirmer. "Identification of Risk Loci for Radiotoxicity in Prostate Cancer by Comprehensive Genotyping of TGFB1 and TGFBR1." Cancers 13, no. 21 (November 8, 2021): 5585. http://dx.doi.org/10.3390/cancers13215585.

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Genetic variability in transforming growth factor beta pathway (TGFB) was suggested to affect adverse events of radiotherapy. We investigated comprehensive variability in TGFB1 (gene coding for TGFβ1 ligand) and TGFBR1 (TGFβ receptor-1) in relation to radiotoxicity. Prostate cancer patients treated with primary radiotherapy (n = 240) were surveyed for acute and late toxicity. Germline polymorphisms (n = 40) selected to cover the common genetic variability in TGFB1 and TGFBR1 were analyzed in peripheral blood cells. Human lymphoblastoid cell lines (LCLs) were used to evaluate a possible impact of TGFB1 and TGFBR1 genetic polymorphisms to DNA repair capacity following single irradiation with 3 Gy. Upon adjustment for multiplicity testing, rs10512263 in TGFBR1 showed a statistically significant association with acute radiation toxicity. Carriers of the Cytosine (C)-variant allele (n = 35) featured a risk ratio of 2.17 (95%-CI 1.41–3.31) for acute toxicity ≥ °2 compared to Thymine/Thymine (TT)-wild type individuals (n = 205). Reduced DNA repair capacity in the presence of the C-allele of rs10512263 might be a mechanistic explanation as demonstrated in LCLs following irradiation. The risk for late radiotoxicity was increased by carrying at least two risk genotypes at three polymorphic sites, including Leu10Pro in TGFB1. Via comprehensive genotyping of TGFB1 and TGFBR1, promising biomarkers for radiotoxicity in prostate cancer were identified.

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Puchenkova, Olesya A., Vladislav O. Soldatov, Andrei E. Belykh, OlgaYu Bushueva, Gennadii A. Piavchenko, Artem A. Venediktov, Nikolay K. Shakhpazyan, Alexey V. Deykin, Mikhail V. Korokin, and Mikhail V. Pokrovskiy. "Cytokines in Abdominal Aortic Aneurysm: Master Regulators With Clinical Application." Biomarker Insights 17 (January 2022): 117727192210956. http://dx.doi.org/10.1177/11772719221095676.

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Abdominal aortic aneurysm (AAA) is a potentially life-threatening disorder with a mostly asymptomatic course where the abdominal aorta is weakened and bulged. Cytokines play especially important roles (both positive and negative) among the molecular actors of AAA development. All the inflammatory cascades, extracellular matrix degradation and vascular smooth muscle cell apoptosis are driven by cytokines. Previous studies emphasize an altered expression and a changed epigenetic regulation of key cytokines in AAA tissue samples. Such cytokines as IL-6, IL-10, IL-12, IL-17, IL-33, IL-1β, TGF-β, TNF-α, IFN-γ, and CXCL10 seem to be crucial in AAA pathogenesis. Some data obtained in animal studies show a protective function of IL-10, IL-33, and canonical TGF-β signaling, as well as a dual role of IL-4, IFN-γ and CXCL10, while TNF-α, IL-1β, IL-6, IL-12/IL-23, IL-17, CCR2, CXCR2, CXCR4 and the TGF-β noncanonical pathway are believed to aggravate the disease. Altogether data highlight significance of cytokines as informative markers and predictors of AAA. Pathologic serum/plasma concentrations of IL-1β, IL-2, IL-6, TNF-α, IL-10, IL-8, IL-17, IFN-γ, and PDGF have been already found in AAA patients. Some of the changes correlate with the size of aneurysms. Moreover, the risk of AAA is associated with polymorphic variants of genes encoding cytokines and their receptors: CCR2 (rs1799864), CCR5 (Delta-32), IL6 (rs1800796 and rs1800795), IL6R (rs12133641), IL10 (rs1800896), TGFB1 (rs1800469), TGFBR1 (rs1626340), TGFBR2 (rs1036095, rs4522809, rs1078985), and TNFA (rs1800629). Finally, 5 single-nucleotide polymorphisms in gene coding latent TGF-β-binding protein ( LTBP4) and an allelic variant of TGFB3 are related to a significantly slower AAA annual growth rate.

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Puchenkova, Olesya A., Vladislav O. Soldatov, Andrei E. Belykh, OlgaYu Bushueva, Gennadii A. Piavchenko, Artem A. Venediktov, Nikolay K. Shakhpazyan, Alexey V. Deykin, Mikhail V. Korokin, and Mikhail V. Pokrovskiy. "Cytokines in Abdominal Aortic Aneurysm: Master Regulators With Clinical Application." Biomarker Insights 17 (January 2022): 117727192210956. http://dx.doi.org/10.1177/11772719221095676.

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Abdominal aortic aneurysm (AAA) is a potentially life-threatening disorder with a mostly asymptomatic course where the abdominal aorta is weakened and bulged. Cytokines play especially important roles (both positive and negative) among the molecular actors of AAA development. All the inflammatory cascades, extracellular matrix degradation and vascular smooth muscle cell apoptosis are driven by cytokines. Previous studies emphasize an altered expression and a changed epigenetic regulation of key cytokines in AAA tissue samples. Such cytokines as IL-6, IL-10, IL-12, IL-17, IL-33, IL-1β, TGF-β, TNF-α, IFN-γ, and CXCL10 seem to be crucial in AAA pathogenesis. Some data obtained in animal studies show a protective function of IL-10, IL-33, and canonical TGF-β signaling, as well as a dual role of IL-4, IFN-γ and CXCL10, while TNF-α, IL-1β, IL-6, IL-12/IL-23, IL-17, CCR2, CXCR2, CXCR4 and the TGF-β noncanonical pathway are believed to aggravate the disease. Altogether data highlight significance of cytokines as informative markers and predictors of AAA. Pathologic serum/plasma concentrations of IL-1β, IL-2, IL-6, TNF-α, IL-10, IL-8, IL-17, IFN-γ, and PDGF have been already found in AAA patients. Some of the changes correlate with the size of aneurysms. Moreover, the risk of AAA is associated with polymorphic variants of genes encoding cytokines and their receptors: CCR2 (rs1799864), CCR5 (Delta-32), IL6 (rs1800796 and rs1800795), IL6R (rs12133641), IL10 (rs1800896), TGFB1 (rs1800469), TGFBR1 (rs1626340), TGFBR2 (rs1036095, rs4522809, rs1078985), and TNFA (rs1800629). Finally, 5 single-nucleotide polymorphisms in gene coding latent TGF-β-binding protein ( LTBP4) and an allelic variant of TGFB3 are related to a significantly slower AAA annual growth rate.

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Kirschneck, Margarita, Nermien Zbidat, Eva Paddenberg, Caio Luiz Bitencourt Reis, Isabela Ribeiro Madalena, Maria Angélica Hueb de Menezes-Oliveira, César Penazzo Lepri, Peter Proff, Christian Kirschneck, and Erika Calvano Küchler. "Transforming Growth Factor Beta Receptor 2 (TGFBR2) Promoter Region Polymorphisms May Be Involved in Mandibular Retrognathism." BioMed Research International 2022 (June 15, 2022): 1–7. http://dx.doi.org/10.1155/2022/1503052.

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Skeletal malocclusions are common phenotypes in humans and have a strong influence on genetic factors. Transforming growth factor beta (TGFβ) controls numerous functions of the human body, including cell proliferation, differentiation, and migration. Thus, this study is aimed at evaluating whether genetic polymorphisms in TGFB1 and its receptor TGFBR2 are associated with mandibular retrognathism in German children and adolescents. Children and teenagers older than 8 years in the mixed or permanent dentition were included in this study. Patients with syndromes and facial trauma and patients with congenital alterations were excluded. Digital cephalometric tracings were performed using the anatomical landmarks point A, point B, sella (S), and nasion (N). Patients that have a retrognathic mandible ( SNB < 78 °) were selected as case group, and the patients with an orthognathic mandible ( SNB = 78 °– 82°) were selected as the control group. Genomic deoxyribonucleic acid (DNA) from saliva was used to evaluate four genetic polymorphisms in TGFB1 (rs1800469 and rs4803455) and TGBR2 (rs3087465 and rs764522) using real-time PCR. Chi-square or Fisher exact tests were used to compare gender, genotype, and allele distribution among groups. Genotype distribution was calculated in an additive and recessive model. Haplotype analysis was also performed. The established alpha of this study was 5%. A total of 146 patients (age ranging from 8 to 18 years) were included in this epidemiological genetic study. The genetic polymorphism rs3087465 in TGFBR2 was associated with mandibular retrognathism. Carrying the AA genotype in the rs3087465 polymorphism decreased the chance of having mandibular retrognathism ( odds ratio = 0.25 , confidence interval 95 % = 0.06 to 0.94, p = 0.045 ). None of the haplotypes was associated with mandibular retrognathism ( p > 0.05 ). In conclusion, we found that the genetic polymorphism rs3087465 in the promoter region of the TGFBR2 was associated with mandibular retrognathism in Germans.

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Pauly, M., G. Mahon, M. A. Dicato, B. Metzger, and A. Menzel. "Single Nucleotide Polymorphisms (SNP'S) in the P53, SMAD7 and TGFBR1 Genes Associated with Advanced Colorectal Cancer in Caucasian Patients Compared to Healthy Controls." Annals of Oncology 23 (September 2012): ix209. http://dx.doi.org/10.1016/s0923-7534(20)33231-2.

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Kim, Dong Hwan (Dennis), Jina Yun, Jee Hyun Kong, Chul Won Jung, Ahmed Galal, Vikas Gupta, John Kuruvilla, Hans A. Messner та Jeffrey H. Lipton. "Single Nucleotide Polymorphism (SNP) Approach of Multiple Candidate Pathways Predicting the Risk of Acute / Chronic Graft-Versus-Host Disease or Transplant Outcomes Following Allogeneic Hematopoietic Stem Cell Transplantation: Potential Involvement of Nuclear Factor Kappa-B (NFKB), Platelet-Derived Growth Factor (PDGF) and Transforming Growth Factor-Beta (TGF-β) Pathway with Chronic Graft-Versus-Host Disease Graft-Versus-Host Disease." Blood 114, № 22 (20 листопада 2009): 2221. http://dx.doi.org/10.1182/blood.v114.22.2221.2221.

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Abstract Abstract 2221 Poster Board II-198 Background: Acute graft-versus-host disease (GVHD) was known to be involved in the Th1 cytokine activation and alloreactive T-cell cytotoxicity, while the pathogenesis of chronic GVHD is yet revealed fully although in which Th2 cytokine activation or transforming growth factor (TGF) mediated pathway was suggested to be involved. The current study is a hypothesis generating study in order to identify potential predictive surrogate associated with the risk of acute or chronic GVHD in addition with transplant outcomes after allogeneic hematopoietic stem cell transplantation (HSCT). Methods: The current study was performed to identify genetic surrogates predicting the risk of acute / chronic GVHD, relapse free survival, non-relapse mortality and overall survival in 394 pairs transplanted at the Princess Margaret Hospital, Toronto, ON, Canada. In addition, the predictive markers for organ specific incidence of acute / chronic GVHD were also evaluated (i.e. for skin/liver/gut acute GVHD or skin, eye, oral, lung or liver chronic GVHD). Total of 261 single nucleotide polymorphisms (SNPs) in 56 genes were determined for donor/recipients' genotypes using MALDI-TOF based platform, involving in the pathways of 1) cytokines (i.e. IL1A, IL1B and its receptor, IL1R1, IL2 & IL2RA, IL4 & IL4R, IL6 & IL6R, IL8, IL10 & IL10RA, RB, IL12A/BandIL12RB1, IFNG & IFNGR1/2, TNFTI/II/II), 2) NFKB (NFKB1/2/A, NFKBIA/B, IKB, IKK1, IKBKB, RelB), 3) apoptosis (FAS, TRAIL & TRAILR1), 4) endothelium nitric oxide regulation (EDN1, NOS1/2A/3), 5) PDGF (PDGFB/C/D & PDGFRA/B), 6) TGF-β (TGFB1/2 & TGFBR1/2/3, TGFRB1), 7) Toll-like receptor (TLR4/5), 8) NOD2/CARD15 and 9) prostaglandin-endoperoxide synthase (PTGS1/2). The candidate genotypes have been selected by choosing the SNPs in non-synonymous SNPs in exon region with minor allele frequency of > 0.05 to 0.1. Results: Followings are the lists of recipients' and donors' genotypes with p-value<0.05 thus associating with clinical outcomes following allogeneic HSCT: In summary, the risk of chronic GVHD was significantly associated with SNP of the genes involved in the pathway of NFKB, PDGF, TGF-β, and some of cytokines (esp. type II, IL6 & IL4), while that of acute GVHD associates with the genotypes in the pathway of TNF and apoptosis. In addition, survival after allogeneic transplantation was associated with the genotypes in NOS (nitric oxide synthase, endothelial nitric oxide synthesis pathway), IL-2 and TGF pathway. Conclusion: Because of complex nature of GVHD pathogenesis, multiple candidate pathway SNPs has been explored targeting SNPs in the pathway of cytokines, NFKB, apoptosis, endothelium nitric oxide regulation, NOD2/CARD15, PDGF, PTGS1/2, TGF-β and TLR. Different involvements were noted of TGF-β, PDGF or NFKB with chronic GVHD versus TNF and apoptosis-associated SNPs with acute GVHD. Further study will help us to reach more clear conclusion which genotype is the predictor of the risk of GVHD. Disclosures: No relevant conflicts of interest to declare.

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Chen, Ruo-Xi, Wen-Min Lu, Mei-Ping Lu, Mei-Lin Wang, Xin-Jie Zhu, Zhong-Fei Wu, Hui-Qin Tian, Lu-Ping Zhu, Zheng-Dong Zhang та Lei Cheng. "Polymorphisms in MicroRNA Target Sites of TGF-β Signaling Pathway Genes and Susceptibility to Allergic Rhinitis". International Archives of Allergy and Immunology 182, № 5 (2021): 399–407. http://dx.doi.org/10.1159/000511975.

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Background: The polymorphisms inside microRNA target sites locating in the 3′-UTR region may introduce the microRNA-binding changes, which may regulate the gene expression and correlate with the potential diseases. Objectives: We aimed to investigate whether the polymorphisms in microRNA target sites of transforming growth factor beta (TGF-β) signaling pathway genes are associated with the susceptibility of mite-sensitized allergic rhinitis (AR) in a Han Chinese population. Methods: In this case-control study, 454 AR patients and 448 healthy controls were recruited. Three HapMap single-nucleotide polymorphisms (SNPs) were mapped to putative microRNA recognition sites and genotyped by TaqMan allelic discrimination assay. Results: The genotype and allele frequencies of 3 SNPs (rs1590 in TGFBR1; rs1434536 and rs17023107 in BMPR1B) showed lack of significant association with AR. However, in the subgroup analysis, the TG, GG, and TG/GG genotypes of rs1590 exhibited significantly increased risk of AR in the male subgroup (TG: adjusted OR = 1.57, 95% CI = 1.08–2.31; GG: adjusted OR = 1.76, 95% CI = 1.09–2.86; TG/GG: adjusted OR = 1.62, 95% CI = 1.13–2.33). The CT genotypes of rs17023107 might have potential to protect against AR in the patients age of <15 years (adjusted OR = 0.37, 95% CI = 0.14–0.95) and the males (adjusted OR = 0.48, 95% CI = 0.25–0.95). No significant association was found between SNPs and the total serum IgE level. Conclusions: In a Han Chinese population, stratified by age and gender, susceptibility to mite-sensitized AR may be associated with 2 SNPs (rs1590 and rs17023107) in microRNA target sites of TGF-β signaling pathway genes.

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Kim, Dennis Dong Hwan, Hong-Hee Won, Wei Xu, Jieun Uhm, Vikas Gupta, John Kuruvilla, Hans A. Messner, and Jeffrey H. Lipton. "The Risk of Organ Specific Graft-Versus-Host Disease Can Be Predicted by the Multiple Single Nucleotide Polymorphism Based Predictive Models." Blood 120, no. 21 (November 16, 2012): 3056. http://dx.doi.org/10.1182/blood.v120.21.3056.3056.

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Abstract Abstract 3056 Background: The pathogenesis of GVHD is not fully understood. Alloreactive T-lymphocytes are believed to be key mediators of GVHD. However, it is not clear if the pathobiology of GHVD is similar in each target organ GVHD. We aimed to identify predictive single nucleotide polymorphisms (SNP) markers associated with the risk of acute or chronic graft versus host disease (GVHD) as well as organ specific GVHD in 394 transplant recipients and donors. Methods: A total of 259 SNPs were genotyped in 53 genes, and evaluated for the risk of acute/chronic GVHD and organ specific GVHD. Predictive models were generated using both clinical factors and genetic SNP markers confirmed by multivariate analyses. Patients were stratified by quartile (25%) according to their risk score, and the risk of overall and organ specific GVHD were compared among the 3 risk groups (low, intermediate and high risk). C-statistic analysis was also performed to compare the stratification power of the predictive model generated using clinical and genetic factors with a model obtained using only clinical factors. Results: Several SNP markers in the cytokine-, apoptosis-, TGF-¥â or PDGF-mediated pathways were identified as predictive markers of acute/chronic GVHD. The risk of acute GVHD was associated with clinical factors such as HLA disparity and patient age. In addition, recipient FAS genotype (rs2234978), EDN1 genotype (rs4714384), and TGFB genotype (rs1800469), and donor TNFRII genotype (rs3397) were also strong predictive markers for acute GVHD. Significant predictive risk factors forchronic GVHD were the source of stem cells, a previous episode of acute GVHD and the donor IL1R1 genotype (rs3917225). Each organ specific GVHD shared common biologic pathways such as cytokine, TGF-¥â or PDGF-mediated pathways. However, different SNP markers were identified as predictive for individual organ-specific GVHD. Multivariate analyses identified several SNP markers may predict the risk of organ specific acute GVHD in combination with clinical factors. For skin acute GVHD, recipient PDGFD (rs10895534), donor NOS2A (rs3730017), TNFRII (rs3397) and TGFB1 (rs1800469) genotypes were predictive together with clinical factors such as HLA disparity. Donor's genotype for TNFRII (rs3397) was predictive not only for overall acute GVHD but also for skin acute GVHD. No clinical factors were identified for the risk of liver or gut acute GVHD, but several SNP markers were found including recipient PDGFRB (rs2302273), IFNGR1 (rs2234711) and donor PTGS1 (rs10306114), NOS1 (rs9658254), IL1R1 (rs2192752) genotypes for liver acute GVHD and recipient IL4 (rs2243248), donor PDGFD (rs1053861), TGFBR1 (rs420549), IL12A (rs2243115) genotypes for gut acute GVHD. In summary, there are no overlapping SNP markers for the risk prediction of organ specific acute GVHD. For organ specific chronic GVHD, 2 clinical risk factors were predictive including source of stem cells and a preceding history of acute GVHD. In addition, several SNP markers were also identified: recipient PDGFC (rs1425486), donor NFKB1 (rs1805034) and NOS2A (rs3730017) for skin chronic GVHD; recipient IL10RB (rs8178561) and PDGFRB (rs22229562), and donor TGFBR1 (rs868) for eye chronic GVHD; recipient IL12RB1 (rs3746190) and donor FCGR2A (rs1801274) for oral chronic GVHD; and donor IL4R (rs2057768), FAS (rs2234767) and TGFB1 (rs1800469) for lung chronic GVHD. Again, In no overlapping SNP markers were observed for organ-specific chronic GVHD risk. Although this predictive model could not stratify patients according to their risk of overall chronic GVHD (p=0.0763), the predictive models per each organ specific chronic GVHD enabled to stratify the patients according to their risks of each organ specific GVHD (p<0.0001 for skin chronic GVHD, p=0.0033 for eye chronic GVHD, p=0.003 for oral chronic GVHD and p=0.0036 for lung chronic GVHD).Predictive models incorporating clinical and genetic factors improved the stratification power by 11.1% compared to models only including clinical factors. Conclusion: Our study suggests that SNP based approaches can predict the risk of organ-specific GVHD. These SNP markers need to be validated in other series. These SNPs may help focus studies into pathobiology and targeted therapy of GVHD in the future. Disclosures: No relevant conflicts of interest to declare.

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Thorne, Jacob W., Reid Redden, Scott A. Bowdridge, Gabrielle M. Becker, Morgan R. Stegemiller, and Brenda M. Murdoch. "PSV-B-21 Genome-Wide Analysis of Sheep Artificially or Naturally Infected with Gastrointestinal Nematodes." Journal of Animal Science 100, Supplement_3 (September 21, 2022): 307–8. http://dx.doi.org/10.1093/jas/skac247.560.

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Abstract Gastrointestinal nematodes (GIN) are detrimental to the health and productivity of sheep across the world, necessitating genetic selection for improved GIN resistance. In this study, we used genomic analyses across- and within- two important breeds in the United States (US), Rambouillet and Dorper, to investigate physiological mechanisms associated with GIN resistance. Genomic data were evaluated from two experiments where lambs were challenged with GIN, either in a natural environment or artificially. Lambs were genotyped with the Axiom™ Ovine Genotyping Array (50K) with 42,608 single nucleotide polymorphisms (SNP) remaining following quality control for minor allele frequency and variant call rate. In experiment 1, a fecal egg count (FEC) was collected from four- to eight-month-old Dorper and Rambouillet lambs (n=188 total) exposed to GIN on pasture. Using Plink v1.9, a genome-wide association study (GWAS) identified significant SNP (P < 6.0e-5) associated with either an increase or decrease of FEC on chromosomes 1, 2, 3, 4, 12, 15 and 20. In Experiment 2, Rambouillet lambs (n=77) were inoculated with 10,000 Haemonchus contortus L3 larvae and FEC and packed-cell volume (PCV) were recorded. An ensuing GWAS identified significant SNP (P < 2.0e-5) on chromosomes 1, 2, 3, 5, 7, 16, 17 and 23 associated with high and low FEC and SNP on chromosome 10 associated with decreased PCV. Multiple genes were in proximity to the identified SNP, including PIK3 subunits in both experiments. Pathway analysis of reported genes, including PIK3, IMP4, NDST3, MRPL22, HSPA2, TGFA, TGFBR1 and RUNX1 revealed involvement in tissue repair, T-cell differentiation and cytokine signaling in Rambouillet and Dorper sheep more resistant to GIN. Results from this study contribute to the genetic underpinnings of host response to GIN in two important breeds in the US, providing a foundation for future selection of animals more resistant to H. contortus infection.

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Weener, M. E., N. A. Bakunina, J. M. Salmasi, G. V. Poryadin, D. Barh, Yu D. Kuznetsova, and L. M. Balashova. "Genetic testing of ocular manifestations of proliferative syndrome to provide pathophysiology-oriented treatment." Russian Journal of Clinical Ophthalmology 22, no. 1 (2022): 16–22. http://dx.doi.org/10.32364/2311-7729-2022-22-1-16-22.

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Background: uncontrolled cell proliferation of the ocular blood network is one of the leading causes of blindness and low vision worldwide. We summarize relevant published data and our 5-year experience in searching treatment tools for excessive non-productive proliferation. Aim: to describe genetic patterns in patients with ocular blood network proliferation for predicting disease course and selecting adequate treatment. Patients and Methods: 1210 patients with proliferative ocular disorders, retinopathy of prematurity, and diabetes were enrolled. Patients were divided into three groups: (1) monogenic disorders, (2) proliferative vitreoretinopathy and diabetes mellitus, (3) retinopathy of prematurity. Follow-up was 6 to 36 months. Laboratory, genetic, and relevant clinical tests were pursued in all patients. Results: proprietary approach of bioinformatic analysis of whole exome/whole genome sequencing data allows for specifying the proliferative process’s prognosis and severity given clinical and genetic findings. This approach includes the analysis of gene mutations directly or indirectly involved in angiogenesis and key signaling pathways. The analysis of mutation identified in group 2 revealed 509C>T TGFB1 gene polymorphism in two patients and c.3174G>A IGF1R gene polymorphism in three patients. In group 3, the most common VEGFA gene polymorphisms were +13553C>T, -634G>C, +405G>C (rs2010963), and -460C>T (rs833061). Conclusion: specifying the prognosis of the course and severity of proliferative ocular disorders pathogenically-oriented targeted treatment requires specialized genetic testing using an improved data analysis approach. Keywords: proliferative syndrome, diabetes, retinopathy of prematurity, VEGFA, TGFB1, IGF1R, Stickler syndrome, Wagner syndrome, Wolframe syndrome, Marshall syndrome, Norrie disease, Coats disease, retinoschisis. For citation: Weener M.E., Bakunina N.A., Salmasi J.M. et al. Genetic testing of ocular manifestations of proliferative syndrome to provide pathophysiology-oriented treatment. Russian Journal of Clinical Ophthalmology. 2022;22(1):16–22 (in Russ.). DOI: 10.32364/2311-7729- 2022-22-1-16-22.

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Omori, A., C. Stephens, J. Cooc, P. V. Danenberg, K. Danenberg, H. Lenz, and B. Pasche. "Microarray analysis of formalin-fixed paraffin-embedded specimens shows distinct gene expression patterns in tumors containing the transforming growth factor beta receptor 6A polymorphism (TGFBR1*6A)." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 4111. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.4111.

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4111 Introduction: A frequent polymorphism of the type I transforming growth factor beta receptor (TGFBR1) is TGFBR1*6A (6A), which has a deletion of 3 CGC triplets coding for alanine within a 9-alanine (9A) repeat of TGFBR1 exon 1. 6A may act as a tumor susceptibility allele through switching TGF-beta growth inhibitory signals into growth stimulatory signals and also appears to be acquired in some cases by primary colon cancers and their liver metastases. Our aim in this study was to compare the gene expression profiles of colorectal tumors bearing the 6A and the more common 9A genotypes to discover pathways that might be differentially induced by the 6A polymorphism. Methods: 28 colorectal tumors with matched synchronous metastases and 23 non-metastatic colorectal tumors were analyzed for TGFBR1 exon 1 genotype by a PCR-based assay. Nine metastatic and 10 non-metastatic tumors were analyzed by gene expression microarrays. Following microdissection of paraffin-embedded specimens, RNA was isolated, amplified, labeled, and hybridized to Affymetrix U133 Plus 2.0 GeneChips. Results: Among the 28 primary metastatic tumors, 19 were 9A (68%), 8 were 9A/6A heterozygotes (29%) and 1 was a 6A homozygote (3%). There was 100% genotype correspondence with the matched metastases. Among the 23 non-metastatic tumors, 18 were 9A (78%), 3 were heterozygotes (13%) and 2 were 6A/6A (9%). Microarray analysis showed 578 differentially expressed genes in the metastatic tumors and 467 in the non-metastatic tumors between the 6A and 9A genotypes (p<0.01). Significant pathway deregulation between 9A and 6A genotypes included estrogen receptor signaling and histidine metabolism in the non-metastatic tumors and B cell receptor, GM-CSF, SAPK/JNK and IL-4 signaling in the metastatic tumors. Conclusion: Microarray analysis shows differentially expressed genes in the 6A genotype compared to 9A, with different deregulated pathways in metastatic and non-metastatic tumors. This alludes to 6A-specific downstream signaling effects, which may contribute to tumor development and progression. No significant financial relationships to disclose.

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Alves, Ana Paula V. D., Amanda B. Freitas, José Eduardo Levi, Antonio G. Amorim Filho, Lucas A. M. Franco, Mara Sandra Hoshida, Elizabeth G. Patiño, Rossana P. V. Francisco, and Mario Henrique B. Carvalho. "COL1A1, COL4A3, TIMP2 and TGFB1 polymorphisms in cervical insufficiency." Journal of Perinatal Medicine 49, no. 5 (February 8, 2021): 553–58. http://dx.doi.org/10.1515/jpm-2020-0320.

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Abstract Objectives To investigate the association between selected single nucleotide polymorphisms (SNPs) with cervical insufficiency and its relationship with obstetric history. Methods Twenty-eight women with cervical insufficiency (case group) and 29 non-pregnant women (control group) were included. The SNPs sequenced included rs2586490 in collagen type I alpha 1 chain (COL1A1), rs1882435 in collagen type IV alpha 3 chain (COL4A3), rs2277698 in metallopeptidase inhibitor 2 (TIMP2), and rs1800468 in transforming growth factor beta 1 (TGFB1). Results We found a higher frequency of the normal allele in the control group (65.5%) and the homozygous mutated genotype in the case group (64.3%) for rs2586490 in COL1A1 (p=0.023). An unplanned finding in the cervical insufficiency group was a higher gestational age of delivery (median≥38 weeks) in the mutated allele than in the wild-type genotype (median of 28.2 weeks) for rs2857396, which is also in the COL1A1 gene (p=0.011). Conclusions The findings of the present study corroborate the hypothesis that cervical insufficiency has a genetic component and probably involves genes encoding proteins in the extracellular matrix, in addition to inflammatory processes.

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Al-Harbi, Najla M., Sara S. Bin Judia, Krishna N. Mishra, Mohamed M. Shoukri, and Ghazi A. Alsbeih. "Genetic Predisposition to Cervical Cancer and the Association With XRCC1 and TGFB1 Polymorphisms." International Journal of Gynecologic Cancer 27, no. 9 (November 2017): 1949–56. http://dx.doi.org/10.1097/igc.0000000000001103.

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ObjectiveCervical carcinoma (CC), a multifactorial cancer, is assumed to have a host genetic predisposition component that modulates its susceptibility in various populations. We investigated the association between CC risk in Saudi women and 6 single-nucleotide polymorphisms (SNPs) in hypothesis-driven candidate genes.MethodsA total of 545 females were included, comprising 232 CC patients and 313 age-/sex-matched control subjects. Six SNPs (CDKN1A C31A, ATM G1853A, HDM2 T309G, TGFB1 T10C, XRCC1 G399A, and XRCC3 C241T) were genotyped by direct sequencing.ResultsOf the 6 SNPs studied, TGFB1 T10C (odds ratio, 0.74; 95% confidence interval, 0.57–0.94) and XRCC1 G399A (odds ratio, 1.45; 95% confidence interval, 1.11–1.90) displayed different frequencies in cancer patients and control subjects and showed statistically significant association in univariate (P = 0.017, P = 0.005, respectively) analysis. The Cochran-Armitage trend test had confirmed the results (P = 0.027 and P = 0.006, respectively), indicating an ordering in the effect of the risk alleles in CC patients. The 2 SNPs, TGFB1 T10C and XRCC1 G399A, showed also degrees of deviation from Hardy-Weinberg equilibrium in cancer patients (P = 0.001 and P = 0.083, respectively) but not in the control subjects. Furthermore, correction for multiple testing using multivariate logistic regression to assess the joint effect of all SNPs has sustained significant statistical association (P = 0.025 and P = 0.009, respectively).ConclusionsTGFB1 T10C and XRCC1 G399A SNPs were associated with CC risk in univariate and multivariate analysis and displayed allele-dosage effects and coselection in cancer patients. Patients harboring the majority allele TGFB1 T10 (Leu) or the variant allele XRCC1 399A (Gln) have approximately 1.5-fold increased risk to develop CC. Host SNPs genotyping may provide relevant biomarkers for CC risk assessment in personalized preventive medicine.

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Zakrzewski, Piotr K., Ewa Forma, Adam I. Cygankiewicz, Magdalena Bryś, Katarzyna Wójcik-Krowiranda, Andrzej Bieńkiewicz, Andrzej Semczuk, and Wanda M. Krajewska. "Betaglycan Gene (TGFBR3) Polymorphism Is Associated with Increased Risk of Endometrial Cancer." Journal of Clinical Medicine 9, no. 10 (September 24, 2020): 3082. http://dx.doi.org/10.3390/jcm9103082.

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We investigated single nucleotide polymorphism (SNP) of the betaglycan gene (TGFBR3) encoding the TGFβ co-receptor in endometrial cancer (EC) and its association with betaglycan expression. The study group included 153 women diagnosed with EC and 248 cancer-free controls. SNP genotyping and gene expression were analyzed using TaqMan probes. Three out of the eight SNPs tested, i.e., rs12566180 (CT; OR = 2.22; 95% CI = 1.15–4.30; p = 0.0177), rs6680463 (GC; OR = 2.34; 95% CI = 1.20–4.53; p = 0.0120) and rs2296621 (TT; OR = 6.40; 95% CI = 1.18–34.84; p = 0.0317) were found to be significantly associated with increased risk of EC (adjusted to age, body mass index, menarche and parity). Among the analyzed SNPs, only rs2296621 demonstrated the impact on the increased cancer aggressiveness evaluated by the WHO grading system (G3 vs. G1/2, GT—OR = 4.04; 95% CI = 1.56–10.51; p = 0.0026; T—OR = 2.38; 95% CI = 1.16–4.85; p = 0.0151). Linkage disequilibrium (LD) analysis revealed high LD (r2 ≥ 0.8) in two haploblocks, constructed by rs2770186/rs12141128 and rs12566180/rs6680463, respectively. In the case of C/C haplotype (OR = 4.82; 95% CI = 1.54–15.07; p = 0.0116—Bonferroni corrected) and T/G haplotype (OR = 3.25; 95% CI = 1.29–8.15; p = 0.0328—Bonferroni corrected) in haploblock rs12566180/rs6680463, significantly higher frequency was observed in patients with EC as compared to the control group. The genotype-phenotype studies showed that SNPs of the TGFBR3 gene associated with an increased risk of EC, i.e., rs12566180 and rs2296621 may affect betaglycan expression at the transcriptomic level (rs12566180—CC vs. TT, p < 0.01; rs2296621—GG vs. TT, p < 0.001, GT vs. TT, p < 0.05). Functional consequences of evaluated TGFBR3 gene SNPs were supported by RegulomeDB search. In conclusion, polymorphism of the TGFBR3 gene may be associated with an increased EC occurrence, as well as may be the molecular mechanism responsible for observed betaglycan down-regulation in EC patients.

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Flanagan, Jonathan M., Denise M. Frohlich, Thad A. Howard, William H. Schultz, Catherine Driscoll, Ramamoorthy Nagasubramanian, Nicole A. Mortier, et al. "Genetic predictors for stroke in children with sickle cell anemia." Blood 117, no. 24 (June 16, 2011): 6681–84. http://dx.doi.org/10.1182/blood-2011-01-332205.

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Abstract Stroke is a devastating complication of sickle cell anemia (SCA), affecting 5% to 10% of patients before adulthood. Several candidate genetic polymorphisms have been proposed to affect stroke risk, but few have been validated, mainly because previous studies were hampered by relatively small sample sizes and the absence of additional patient cohorts for validation testing. To verify the accuracy of proposed genetic modifiers influencing stroke risk in SCA, we performed genotyping for 38 published single nucleotide polymorphisms (SNPs), as well as α-thalassemia, G6PD A− variant deficiency, and β-globin haplotype in 2 cohorts of children with well-defined stroke phenotypes (130 stroke, 103 nonstroke). Five polymorphisms had significant influence (P < .05): SNPs in the ANXA2, TGFBR3, and TEK genes were associated with increased stroke risk, whereas α-thalassemia and a SNP in the ADCY9 gene were linked with decreased stroke risk. Further investigation at these genetic regions may help define mutations that confer stroke risk or protection in children with SCA.

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Lee, Eunyoung, Yun-Gyoo Lee, Inho Kim, Ji-Hyun Kwon, Dong-Yeop Shin, Ji-Yeon Bae, Sung-Soo Yoon, et al. "Impact of Cytokine Gene Polymorphisms on Risk and Treatment Outcomes of Aplastic Anemia." Blood 118, no. 21 (November 18, 2011): 4369. http://dx.doi.org/10.1182/blood.v118.21.4369.4369.

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Abstract Abstract 4369 Immunosuppressive therapy (IST) is one of the main treatment modalities for acquired aplastic anemia (AA). Approximately 70% of AA patients have been known to achieve clinical improvements with IST consisting of antithymocyte globulin (ATG) and cyclosporine. This remarkably high response rate supports us to tell the immunogenic pathophysiology of AA. Autoreactive cytotoxic T cells play a key role in this immunogenic pathogenesis of AA by working with myelosuppressive cytokines like interferon-gamma (IFN-γ), tumor necrosis factor alpha (TNFα), and transforming growth factor beta (TGFβ), which induce apoptosis in hematopoietic stem cells, partially through the Fas-dependent pathway. The purpose of this study is to find out which single nucleotide polymorphisms (SNPs) in cytokine genes were relevant to the risk of AA and whether the relevant SNPs were associated with response to IST in AA patients. Between January 2000 and December 2008 84 patients were screened and 80 patients confirmed as having acquired AA by bone marrow biopsy, and 84 age- and sex-matched healthy controls were analyzed consecutively. We genotyped the polymorphisms in three cytokine genes (IFNG, TNF, and TGFB1) and FAS gene, which are known to be involved in T cell-mediated marrow destruction. We assessed the association between polymorphisms in those selected genes and risk for AA, and the association between those polymorphisms and response to IST in three genetic models (dominant, recessive, and additive). The IFNG -2353 T allele (dominant model, OR=0.43, p=.012) and TCA haplotype (dominant model, OR=0.50, p=.038) were significantly associated with the development of AA. In addition, this relevant IFNG -2353 T allele and TCA haplotype were related to the response of IST (dominant model, OR=0.076, p=.034). The presence of the minor T allele was protective and related to a 2.3-fold reduction in the risk for AA (p=.012), and the presence of the IFNG TCA haplotype was related to a 2-fold reduced risk for AA (p=.038). Concerning TGFB1, although its polymorphisms are not related to AA susceptibility, P10L T allele (recessive model, OR=0.18, p=.038) and CT haplotype (dominant model, OR=5.68, p=.038) were associated with response to IST. The T allele was related to a 4.3-fold reduced response to IST at 3 months (p=.038) and the presence of the CT haplotype was favorable to IST and was related to a 5.7-fold higher response at 3 months compared with the response in patients without the CT haplotype (p=.038). This exploratory study concurred with prior studies indicating that polymorphisms in IFNG are related to AA susceptibility. In addition, it was found that polymorphisms in IFNG and TGFB1 are associated with response to IST. AA patients with intracellular IFN-γ expression in peripheral lymphocytes showed almost 3-fold higher response to IST than patients without IFN-γ-expressing lymphocytes (p<0.0001) and this finding puts weight on the immunogenic association of responsiveness. Regarding TGFβ, the functionality of polymorphisms and in TGFB1 has rarely been reported. However, the significant relationship between TGFB1 polymorphisms and therapeutic response to IST in our study suggests their late effects on marrow suppression. Our results may help explain the variability of response to IST in AA and suggests that patients with a high probability of response might be treated first with IST rather than conventional marrow transplantation.Table 1.Factors relevant to response to ISTFactorCorrected for Patient CharacteristicsUncorrected DataGenotypeOR (95% CI)POR (95% CI)PResponse at 3-month after IST (n=43) Age1.00 (0.96–1.05).841.02 (0.98–1.06).46 Sex (male vs female)1.13 (0.26–4.84).871.26 (0.37–4.23).71 Severity (severe vs non-severe)1.03 (0.23–4.53).0971.63 (0.48–5.47).43 TGFB P10L C/TTT vs CT + CC0.18 (0.03–0.90).0380.23 (0.06–0.95).043 TGFB haplotypeCT-CT + CT-other vs Other-other5.68 (1.11–29.15).0384.28 (1.05–17.42).043Response at 6-month after IST (n=43) Age1.00 (0.95–1.05).911.02 (0.97–1.06).45 Sex (male vs female)0.38 (0.072–2.01).250.60 (0.16–2.21).44 Severity (severe vs non-severe)2.53 (0.47–13.62).282.22 (0.59–8.26).24 IFNG -2353 A/TTT+AT vs AA0.076 (0.007–0.82).0340.40 (0.10–1.56).19 IFNG haplotypeTCA-TCA + TCA-other vs Other-other0.076 (0.007–0.82).0340.40 (0.10–1.56).19 TGFB haplotypeTC-TC vs TC-other + Other-other0.22 (0.05–0.90).0360.19 (0.03–1.09).063 Disclosures: No relevant conflicts of interest to declare.

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Gritsenko, O. V., G. A. Chumakova, O. V. Gruzdeva, A. V. Ponasenko, and O. L. Barbarash. "Profibrotic genetic polymorphisms as possible risk factors for the development of diastolic dysfunction in patients with epicardial adiposity." Russian Journal of Cardiology 27, no. 10 (September 5, 2022): 5208. http://dx.doi.org/10.15829/1560-4071-2022-5208.

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Aim. To determine the associations of variable sites of fibrogenesis genes with the risk of left ventricular (LV) diastolic dysfunction (DD) in patients with epicardial adiposity (EA).Material and methods. The study included 101 men with general obesity (Altai Territory) without cardiovascular diseases, diabetes and documented LVDD, of which, after determining the epicardial fat thickness (EFT), 2 groups were formed: group 1 — with EA (EA+), EFT ≥7 mm or more (n=70); group 2 — without EA (EA-), EFT <7 mm (n=31). The control group was formed from Kemerovo region residents of the corresponding sex and age and without a history of cardiovascular diseases and general obesity. Polymorphisms of the MMP9 rs17576, TGFB1 rs1800469, MMP3 rs6796620, MMP3 rs626750, MMP1 rs514921, LOC101927143 rs4290029, TIMP2 rs2277698 genes were determined in all patients using the polymerase chain reaction. After 4,7±0,3 years, all patients with general obesity underwent repeated echocardiography to assess LVDD.Results. We found that in the group with EA for rs626750 MMP3, the carriage of the homozygous T allele is 2 times more common (recessive inheritance, p=0,0022). After 4,7±0,3 years, LVDD was registered in 18 patients in the EA+ group and in 2 patients in the EA- group. When analyzing inheritance patterns, as well as comparing genotypes in groups of patients with EA with developed LVDD (n=20) and without LVDD (n=78), we found that patients with EA and LVDD are 3,4 times more likely to be a carrier of the homozygous T allele (recessive inheritance, p=0,02) for rs1800469 TGFB1.Conclusion. In patients with EA and LVDD, the carriage of the T rs1800469 TGFB1 allele is more common, which probably contributes to cardiac fibrosis and LVDD according to a recessive inheritance.

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Gonçalves Junior, Roberto, Aristides da Rosa Pinheiro, José Jorge Schoichet, Carlos Henrique Ramirez Nunes, Rackel Gonçalves, Leticia Ladeira Bonato, Valquiria Quinelato, et al. "MMP13, TIMP2 and TGFB3 Gene Polymorphisms in Brazilian Chronic Periodontitis and Periimplantitis Subjects." Brazilian Dental Journal 27, no. 2 (April 2016): 128–34. http://dx.doi.org/10.1590/0103-6440201600601.

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Abstract Subjects susceptible to chronic periodontitis (CP) show a high risk for the development of peiimplantitis (PI). Both diseases are multifactorial, presenting similarities in their pathophysiology and polygenic profile. MMP-13 (matrix metalloproteinases 13/ collagenase 3) is a collagenolytic enzyme, which expression is induced by TGF beta 3 (transforming growth factor type 3) in human gingival fibroblasts and inhibited by TIMP-2 (tissue inhibitor of metalloproteinase type 2). The aim of this study was to investigate the occurrence of peiimplantitis (PI) in subjects with history of chronic periodontitis (CP) and polymorphisms frequency in MMP13, TIMP2 and TGFB3 genes. One hundred and sixty-three volunteers received dental implant placement were submitted to oral and radiographic examination in order to identify past history of CP or presence of PI. Volunteers were divided into 4 groups: Control (without PI and CP, n=72), CP (with CP and without PI, n=28), PI (with PI and without CP, n=28) and diseased (with CP and PI, n=35). The chi-square test correlated genotypes in specific regions of MMP13 (rs2252070), TIMP2 (rs7501477) and TGFB3 (rs2268626) genes, considering the interaction between CP and PI. The results showed that volunteers with CP had 3.2 times more susceptibility to develop PI (p=0.0004) compared to those without CP. No significant association was observed in MMP13, TIMP2 and TGFB3 genes with CP or PI. CP is a risk factor to develop PI, however, there is no association of both diseases with polymorphisms in the MMP13, TIMP2 and TGFB3 genes.

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Berro, Mariano, Virginia Palau, Maria Marta Rivas, Maria Cecilia Foncuberta, Adriana Vitriu, Guillermina Remaggi, Gregorio Jaimovich, et al. "TGFB1 Functional Polymorphisms in Sibling HSCT. "Tto be or Not Tto be"." Blood 126, no. 23 (December 3, 2015): 4275. http://dx.doi.org/10.1182/blood.v126.23.4275.4275.

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Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) using sibling donors is a life-saving intervention for patients with hematological malignancies. It is recognized that numerous genetic factors in both patient and donor play a role in the outcome of the procedure. TGF beta 1 is a member of a highly pleiotrophic family of growth factors involved in the regulation of numerous immunomodulatory processes. Several functional polymorphisms have been identified in TGF-B1 gene, such as a single nucleotide polymorphism (SNP) at codon 10 of exon 1. We have previously published significant impact of this SNP on unrelated donor (UD) transplant outcome, predominantly on Non Relapse Mortality (NRM) and acute Graft-vs.-Host-Disease (aGVHD). To date there are no published data in large sibling donor HSCT cohorts looking at survival outcomes. We have hypothesized that TGF-B1 SNP may influence the outcome of sibling donor HSCT similarly to UD. Preliminary data were presented at ASH meeting 2014. Two hundred and seventeen patient/donor pairs who underwent a sibling donor HSCT in our centers were genotyped for the presence of a SNP at codon 10 (rs1982073) by an allele-specific PCR. Transplants took place between January 2000 and January 2015 and the median follow up time was 4.4 years. Median age was 33 years and 58% were male. The prevalent diagnoses were acute myeloid leukemia 64 (29%), acute lymphoid leukemia 49 (23%), lymphoproliferative disorders 28 (13%), myelodysplastic syndrome 26 (12%) and myeloproliferative neoplasm 20 (9%). Early stage of the disease was determined in 42%. Myeloablative conditioning regimens were used in 58% of transplants; the source was PBSC in 90% of the patients. The patients' observed SNP frequencies were TT 23%, TC 55% and CC 22%, and for the donors were 26%, 53% and 21% respectively. No significant impacts were observed in the full cohort analysis. When we analyzed the myeloablative cohort, significant differences were founded. Similarly to what we observed in UD, codon 10 CC patients had a significant increase in 1 year treatment related mortality (32% vs. 9%, p=0.01) and Non Relapse Mortality (NRM) (1-3 years CC 31-31% vs. TC/TT 8-13%, Gray's test p=0.04) (figure 1). A very interesting finding was in donor's genotype. Codon 10 TT donor's receptors experienced a significant increase in aGVHD (72% vs. 49%, p=0.03), with 56% of this grades 2-4. Interestingly this group had no protection in terms of relapse, but the opposite, although not significant (1-3 years TT 36-40% vs. TC 17-34% vs. CC 9-13%, Gray's test p=0.1). Finally TT donors had a significant decrease in Overall Survival (OS) compared to other genotypes (1-3 years TT 69-50% vs. TC/CC 77-69%, log-rank p=0.04) (figure 2). No differences were observed in donor genotype in terms of NRM. Besides confirming that as in UD, patient codon 10 CC had an increase in NRM, we conclude that in sibling donor-myeloablative HSCT codon 10 TT donors might be associated with an increase in aGVHD with no protection in relapse and a significant decrease in OS. These results should be confirmed in larger series. Identification of these SNPs pre-transplant will allow for transplant conditioning and immunosuppression regimens to be tailored to the individual patient, as well as assisting in the most appropriate choice of donor. Disclosures No relevant conflicts of interest to declare.

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Berro, Mariano, Louise Cooke, Neema P. Mayor, Gustavo Kusminsky, Steven G. E. Marsh, J. Alejandro Madrigal, and Bronwen E. Shaw. "TGFB1 Functional Polymorphisms: Impact on Outcome in Allogeneic Unrelated Donor Haematopoietic Stem Cell Transplantation." Blood 112, no. 11 (November 16, 2008): 3011. http://dx.doi.org/10.1182/blood.v112.11.3011.3011.

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Abstract Allogeneic haematopoietic stem cell transplantation (HSCT) using volunteer unrelated donors (UD) is a life-saving intervention for patients with haematological malignancies. It is recognised that numerous genetic factors in both patient and donor play a role in outcome. TGF beta 1 is a member of a highly pleiotrophic family of growth factors involved in the regulation of numerous immunomodulatory processes and may play a role in carcinogenesis. Several functional polymorphisms have been identified, such as a single nucleotide polymorphism (SNP) at codon 10 (c.29T>C, p.L10P) of exon 1. Conflicting data has been published regarding the impact of the SNP on plasma levels and its role in sibling HSCT. To date there are no published data in UD HSCT. We hypothesised that this polymorphism may influence the outcome of UD HSCT by modulating the immune response. We genotyped, for the presence of a SNP at codon 10, a large group of patient/donor pairs (314) who underwent an UD HSCT using a donor provided by the Anthony Nolan Trust, in a UK transplant centre. The transplant took place between 1997 and 2006 and the median follow up time was 5.8 years (0.8–10.18 years). The diagnoses were chronic myeloid leukaemia 69 (21%), acute lymphoid leukaemia 76 (24%), acute myeloid leukaemia 76 (24%), myelodysplasic syndrome 25 (8%), lymphoproliferatives disorders 37 (11.8%) and others 31 (9.9%). Myeloablative conditioning regimens were used in 69.9% of transplants; T-cell depletion was included in 86.9% of conditioning protocols. Sixty eight percent of the transplants were full matched (10/10), and 12.7% were 12/12. The patients’ observed SNP frequencies were TC 55.7%, TT 32% and CC 12.1%, and for the donor were 51%, 34.7% and 14.3% respectively. There were no significant effects of the presence of a SNP in either the patient or donor groups alone. However, when we analysed the impact of the total number of SNPs present in the pair, we found that multiple SNPs (3–4 SNPs vs 2 or less) were associated with a significantly decreased overall survival (OS) (5 years: 30% vs 42%, log-rank p=0.04), disease free survival (DFS) (5 years: 17% vs 25%, log-rank p=0.02) and a higher treatment related mortality (1 and 3 years: 42% and 45% vs 25% and 30%, respectively, log-rank p=0.03). In multivariate analysis there was a trend to improved OS in the pairs with fewer SNPs (HR: 0.7; 95% CI 0.4,1.0; p=0.07). We speculated that the impact of the donor genotype might differ depending on the patient genotype. In patients with a wild type genotype, the donor genotype did not impact significantly on outcome. Conversely, the patients with a SNP at codon 10 (TC or CC), had significantly better DFS when using a donor with a wild type genotype compared to those with a SNP present (5 years: 34% vs 21%; log-rank p= 0.04). In conclusion, we have shown for the first time in a large number of UD HSCT pairs that increased numbers of SNPs in the TGFB1 gene at codon 10 in patients and donors are associated with a worse outcome following UD HSCT. While an exact functional mechanism remains unclear, these data emphasise the importance of pursuing functional analyses of TGF beta in this setting. In addition, identification of these SNPs pre-transplant will allow for transplant conditioning and immunosuppression regimens to be tailored to the individual patient, as well as assisting in the most appropriate choice of donor.

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Li, Xiang-Ting, Chang-Qing Shen, Rui Zhang, Ji-Kui Shi, Zong-Hong Li, Hong-Yu Liu, Bo Sun, Kai Wang, and Li-Ru Yan. "Association of TGFBR2 rs6785358 Polymorphism with Increased Risk of Congenital Ventricular Septal Defect in a Chinese Population." Pediatric Cardiology 36, no. 7 (May 30, 2015): 1476–82. http://dx.doi.org/10.1007/s00246-015-1189-2.

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Driscoll, M. Catherine, Joseph Devaney, Heather Gordish, Caterina Minniti, and Eric P. Hoffman. "Genetic Modifiers of Cerebrovascular Large Vessel Stenosis in Sickle Cell Anemia." Blood 104, no. 11 (November 16, 2004): 1658. http://dx.doi.org/10.1182/blood.v104.11.1658.1658.

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Abstract Cerebrovascular disease is a common complication in sickle cell anemia (SCA) with overt stroke occuring in 10% of patients and silent stroke in 24% of patients by age 20 years. Etiologies of overt stroke in SCA are heterogenous and include stenosis of large arteries, hemorrhage, hypertensive and hypoxic encephalopathy. Candidate genes identified as possible modifiers of overt stroke in SCA include adenylate cyclase 9 (ADCY9, rs731471 intron C/T), endothelin-converting enzyme (ECE-1, rs212527, intron A/G), Klotho (KL, rs480780, intron C/A), plasminogen activator inhibitor-1 (PAI-1, rs1799768, − 675 4/5,), transforming growth factor beta receptor 3 (TGFBR3, rs284157, intron G/A), tumor necrosis factor alpha (TNF, rs1800629,-308 G/A), and interlukin 4 receptor (IL4R, rs1805015, 503S/P). We examined the association of these candidate genes in a cohort of patients with SCA and stenosis of large cerebral vessels who are followed at a single institution. Patients with stenosis (n = 42, male = 22) were identified as having overt stroke (n = 29) or positive transcranial Doppler (TCD) (n = 13). The mean age at time of stroke or (+) TCD was 7.8 years. All had large vessel stenosis on magnetic resonance angiogram imaging (MRA). A control group of patients with SCA and normal TCD were identified (n = 71, males = 46, mean age = 14.8 years).This control group has passed through the peak years of stroke risk, ages 2–10 years. Single nucleotide polymorphisms (SNPs) were genotypic using novel Taqman assays. Genotypic associations were determined using logistic regression analysis with odds ratios (OR), 95% confidence intervals, and p-values reported. Among the candidate genes only ADYC9 (OR = 2.75, CI 1.2–6.3, p = 0.017) and TGFBR3 (OR = 2.33, CI 1.0–5.3, p = 0.043) had significant association with stenosis of large vessels in SCA. ADYC9 is a membrane-associated enzyme that catalyzes cAMP formation, which is critical for neuronal signaling and survival. TGFBR3 has a role in cardiac endothelial cell transformation to mesenchyme. Genotypic studies of a complex trait such as stroke in SCA will eventually lead to early diagnosis and new or early interventions. However, such genetic studies require clear definitions of phenotypic subtypes based on neuroimaging studies, including MRA.

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Mooney, Rachel E., Gerry J. Linden, Lewis Winning, Katie Linden, Frank Kee, Pascal P. McKeown, Jayne V. Woodside, Christopher C. Patterson, and Gareth J. McKay. "Association of TGFB1 rs1800469 and BCMO1 rs6564851 with coronary heart disease and IL1B rs16944 with all-cause mortality in men from the Northern Ireland PRIME study." PLOS ONE 17, no. 8 (August 22, 2022): e0273333. http://dx.doi.org/10.1371/journal.pone.0273333.

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Background Historically, high levels of morbidity and mortality have been associated with cardiovascular disease in the Northern Ireland population. Previously reported associations between single nucleotide polymorphisms (SNPs) and cardiovascular disease within other populations have not always been consistent. Objective To investigate associations between 33 SNPs with fatal or non-fatal incident coronary heart disease (CHD) events and all-cause mortality in the Northern Irish participants of the Prospective Epidemiological Study of Myocardial Infarction (PRIME). Method Phase 2 of the PRIME study prospectively evaluated 2,010 men aged 58–74 years in Northern Ireland for more than 10 years for incident CHD events (myocardial infarction, percutaneous coronary intervention, coronary artery bypass, and cardiac death) and more than 15 years for all-cause mortality. SNPs previously reported in association with cardiovascular outcomes were evaluated against incident CHD events and all-cause mortality using Cox’s proportional hazards models adjusted for established cardiovascular disease risk factors. Results During the follow-up period, 177 incident CHD events were recorded, and 821 men died. Both BCMO1 rs6564851 (Hazard ratio [HR] = 0.76; 95% confidence intervals [CI]: 0.60–0.96; P = 0.02) and TGFB1 rs1800469 (HR = 1.30; CI: 1.02–1.65; P = 0.04) were significantly associated with incident CHD events in adjusted models. Only IL1B rs16944 was significantly associated with all-cause mortality (HR = 1.18; CI: 1.05–1.33; P = 0.005). No associations remained significant following Bonferonni correction for multiple testing. Conclusion We report a novel association between BCMO1 rs6564851 and risk of incident CHD events. In addition, TGFB1 rs1800469 and IL1B rs16944 were associated with the risk of incident CHD events and all-cause mortality outcomes respectively, supporting previously reported associations.

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Yuan, Xianglin, Zhongxing Liao, Zhensheng Liu, Li-E. Wang, Susan L. Tucker, Li Mao, Xin Shelley Wang та ін. "Single Nucleotide Polymorphism at rs1982073:T869C of the TGFβ1 Gene Is Associated With the Risk of Radiation Pneumonitis in Patients With Non–Small-Cell Lung Cancer Treated With Definitive Radiotherapy". Journal of Clinical Oncology 27, № 20 (10 липня 2009): 3370–78. http://dx.doi.org/10.1200/jco.2008.20.6763.

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Purpose In search of reliable biologic markers to predict the risk of normal tissue damage by radio(chemo)therapy before treatment, we investigated the association between single nucleotide polymorphisms (SNPs) in the transforming growth factor 1 (TGFβ1) gene and risk of radiation pneumonitis (RP) in patients with non–small-cell lung cancer (NSCLC). Patients and Methods Using 164 available genomic DNA samples from patients with NSCLC treated with definitive radio(chemo)therapy, we genotyped three SNPs of the TGFβ1 gene (rs1800469:C-509T, rs1800471:G915C, and rs1982073:T869C) by polymerase chain reaction restriction fragment length polymorphism method. We used Kaplan-Meier cumulative probability to assess the risk of grade ≥ 3 RP and Cox proportional hazards analyses to evaluate the effect of TGFβ1 genotypes on such risk. Results There were 90 men and 74 women in the study, with median age of 63 years. Radiation doses ranging from 60 to 70 Gy (median = 63 Gy) in 30 to 58 fractions were given to 158 patients (96.3%) and platinum-based chemotherapy to 147 (89.6%). Grade ≥ 2 and grade ≥ 3 RP were observed in 74 (45.1%) and 36 patients (22.0%), respectively. Multivariate analysis found CT/CC genotypes of TGFβ1 rs1982073:T869C to be associated with a statistically significantly lower risk of RP grades ≥ 2 (hazard ratio [HR] = 0.489; 95% CI, 0.227 to 0.861; P = .013) and grades ≥ 3 (HR = 0.390; 95% CI, 0.197 to .774; P = 0.007), respectively, compared with the TT genotype, after adjustment for Karnofsky performance status, smoking status, pulmonary function, and dosimetric parameters. Conclusion Our results showed that CT/CC genotypes of TGFβ1 rs1982073:T869C gene were associated with lower risk of RP in patients with NSCLC treated with definitive radio(chemo)therapy and thus may serve as a reliable predictor of RP.

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Flanagan, Jonathan Michael, Thad A. Howard, Denise M. Frohlich, William Herbert Schultz, Catherine Driscoll, Ramamoorthy Nagasubramanian, Nicole A. Mortier, et al. "Validation of Genetic Predictors for Stroke In Children with Sickle Cell Anemia." Blood 116, no. 21 (November 19, 2010): 2639. http://dx.doi.org/10.1182/blood.v116.21.2639.2639.

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Abstract Abstract 2639 Introduction: Stroke is perhaps the most catastrophic complication of sickle cell anemia (SCA), occurring in 11% of patients with SCA before 20 years of age. There is a definite need for biomarkers that could predict which children with SCA are at greatest risk for developing these irreversible cerebrovascular events. Many candidate genetic polymorphisms have been proposed to affect stroke risk but few have been validated, mainly due to the lack of additional patient cohorts. To validate the accuracy of published genetic modifiers, we genotyped polymorphisms in two large prospective cohorts. Methods: Pediatric patients with SCA and documented primary stroke (n=134, average age at stroke = 5.8 ± 2.8 years) were recruited through the Stroke With Transfusions Changing to Hydroxyurea (SWiTCH, NCT00122980) study. As a control non-stroke group, pediatric SCA patients (n=104, average age = 10.2 ± 3.5 years) enrolled in the Hydroxyurea Study of Long-Term Effects (HUSTLE, NCT00305175) were analyzed. All participants in the HUSTLE cohort were over 5 years old and without previous clinical stroke prior to beginning hydroxyurea treatment. We genotyped 38 single nucleotide polymorphisms (SNP's) with published associations for stroke risk, along with α-thalassemia trait, G6PD deficiency and the β-globin haplotype of each patient. Results: Only 5 of the 38 candidate SNPs were associated with stroke risk (Table 1). As previously reported the presence of α-thalassemia trait was also associated with stroke risk (p=0.009). In contrast, G6PD deficiency was not associated with stroke risk. The classical β-globin gene haplotypes were determined for all 238 subjects, resulting in alleles primarily representing the four classical African haplotypes including Benin (57.6%), Central African Republic (21.8%), Senegal (9.2%) and Cameroon (3.2%), as well as atypical haplotypes (8.2%). None of the classical β-globin haplotypes were associated with stroke. However, fine-mapping of the β-globin gene locus identified recombination events within the Aγ-globin gene region, which were significantly over-represented in the stroke versus non-stroke cohorts (n=26.5% vs. n=12.5%, p=0.0001). In particular, one haplotype we term BEN-Memphis has the classical Benin background haplotype but also has recombination between the promoter and intron 2 of the Aγ-globin gene. There were significantly more stroke subjects with this novel BEN-Memphis haplotype (n=9.3% vs. n=0.5%, p<0.001). Conclusions: Our results confirm α-thalassemia trait is significantly protective against stroke in SCA. Fine-mapping of the β-globin gene locus identified novel recombinations within the β-globin gene locus that were associated with stroke risk. These variant haplotypes may be associated with altered γ- or β-globin gene expression. Of the other previously reported polymorphisms, only 5 of 38 SNPs were significantly associated with stroke risk (Table 1). These findings highlight the dangers of accepting non-validated genetic modifiers. The ADCY9 gene is highly expressed in the brain and is critical for neuronal signaling (Hacker BM et al., Genomics 1998). The TEK gene is an endothelial cell expressed tyrosine kinase that is crucial for prevention and recovery from stroke events (Bai Y et al., Neuroscience 2009). The ANXA2 gene has been proposed to affect the hypercoaguable state of SCA (Ling Q et al., J Clin Invest 2004). Finally, mutations in TGFBR3 have been linked with cerebrovascular disease (Santiago-Sim T et al., Stroke 2009). Further investigations at these genetic regions may help define the specific mutations that confer stroke risk or protection in children with SCA. The minor allele frequency (MAF) is given for each SNP. Significance between the control (HUSTLE, n=104) and stroke (SWiTCH, n=134) groups was tested using the Cochran-Armitage test. The HbA2 polymorphism is the Δ3.7kb α-thalassemia single gene deletion. Disclosure: Off Label Use: The off-label drug use of hydroxyurea to treat clinical complications of sickle cell anemia in children will be discussed.

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Onyeneho, Karyn. "Genetic Determinants of Type 2 Diabetes Mellitus in Adults of African Ancestry: Identification of the Associated Factors." Current Developments in Nutrition 6, Supplement_1 (June 2022): 1121. http://dx.doi.org/10.1093/cdn/nzac078.015.

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Abstract Objectives H1: ADCYAP1R1, BDNF, CD36, HDAC4, NOS3, PON1, TCF7L2, TGFB1 were predominant in adults of African ancestry with or without T2DM. H2: There is a relationship between HBA1C, TG, LDL, FG, FI and genetic associations among adults of African ancestry and the following: H2a: ACGT risk alleles H2b: Chromosomal regions 2, 7, 10, 11, 19 H2c: Sequence variant impacts: intergenic, intron, missense, and synonymous H2d: Minor allele frequencies < .05 H2e: Lead reference SNPs H2f: Variant coordinates H3: ALDH1A1, B3GALT2, C8orf37, CASP16, CCSAP, CDKN2B, CHRNA5, CRNN, CYP7B1, FAT4, FOXP1, GPC6, GRM4, LMCD1, MMP19, MYOM2, NOL11, PHF8, RP11-180C1.1, SLC45A1, SLC9A8, TLE1, ZPLD1 were predominant in adults of African ancestry with peripheral vascular disease in T2DM. Methods Quantitative assessment of secondary data in the Type 2 Diabetes Knowledge Portal comprising nutritional phenotypic traits (peripheral vascular disease, hemoglobin A1C, triglycerides, low-density lipoprotein, fasting glucose, fasting insulin) and genetic associations risk allele, minor allele frequencies, reference single nucleotide polymorphisms, candidate genes, chromosomal regions, variant coordinates, and sequence variation impacts) related to Type 2 Diabetes Mellitus (T2DM) among adults of African ancestry with or without Type 2 Diabetes Mellitus to understand T2DM hereditary disease risk. Results H1 Results: χ2 (126, n = 5,877) = 1228.713, p < .001 H2a Results: χ2 (20, n = 62) = 43.052, p = .002 H2b Results: χ2 (20, n = 62) = 106.969, p < .001 H2c Results: χ2 (15, n = 62) = 60.470, p < .001 H2d Results: χ2 (228, n = 60) = 210.000, p = .798 H2e Results: χ2 (240, n = 61) = 269.118, p = .095 H2f Results: χ2 (245, n = 62) = 273.529, p = .102 H3 Results: χ2 (264, n = 23) = 276.000, p = .293 Conclusions Hereditary disease risks for Type 2 Diabetes nutritional phenotypes and genetic associations are distinct in adults of African ancestry with or without Type 2 Diabetes Mellitus diagnosis. Funding Sources Howard University.

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Park, Eunkyung, Song Joo Yang, Inho Kim, Eun Hyung Jeon, and Seonyang Park. "Genome-Wide Association Study for Determinants of Acute Graft Vs Host Disease (aGVHD) After Allogeneic Hematopoietic Stem Cell Transplantation: Development of 7 SNP Model Predicting aGVHD." Blood 118, no. 21 (November 18, 2011): 1010. http://dx.doi.org/10.1182/blood.v118.21.1010.1010.

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Abstract Abstract 1010 Background: Numerous studies have been reported non-HLA genetic associations with acute graft vs host disease (aGVHD) developing after allogeneic hematopoietic stem cell transplantation (allo-HSCT). So far, however, relatively few genes have been examined in each cohort. Meanwhile, aGVHD represents one of the most attractive targets to study the effect of normally silent genetic polymorphisms. We intended to elucidate genetic determinants predicting aGVHD in patients undergoing allo-HSCT by genome-wide screening of genetic polymorphisms, and develop a SNP model to predict development of aGVHD. Methods: Genetic polymorphisms predicting development of aGVHD were determined through successive 5 stages in a total of 429 patients who underwent allo-HSCT. Firstly, we screened genomic determinants predicting aGVHD using 109K SNP chip (Sentrix Human-1 GT Bead Chip, Illumina) in 15 patients (7 patients with aGVHD and 8 without aGVHD). At stage 2 and 3, low-density Immumina chips comprising 768 candidate SNPs and 96 SNPs, respectively, were manufactured and tested in independent cohorts of 91 patients (34 patients with aGVHD and 57 without aGVHD) and 84 patients (35 patients with aGVHD and 49 without aGVHD), respectively. At stage 4, 76 SNP chips comprising 33 SNPs discovered from the previous studies and also 43 SNPs reported to be associated with aGVHD in the literature were manufactured and evaluated in 36 patients (13 patients with aGVHD and 23 without aGVHD) undergoing allo-HSCT. Finally, 7 SNPs were chosen and validated in an independent cohort of 203 patients (50 patients with aGVHD and 153 without aGVHD) using TaqMan assay. Results: At stage 1, 955 SNPs were identified to be significantly associated with development of aGVHD by whole genome assay. At stage 2, candidate genetic determinants were narrowed down to 74 SNPs. Through stage 3 and 4, 7 SNPs including the two selected from the literature review (transforming growth factor beta receptor II (TGFBR2) and interleukin-18) were finally determined as predictive markers for aGVHD. The 7 SNP model was found to be effective in predicting the development of aGVHD after allo-HSCT. When decision tree model was applied, the sensitivity, specificity, accuracy, and area under ROC (AUR) of the 7 SNP model to predict aGVHD were 80.5%, 80.4%, 80.4% and 91.6%, respectively. Conclusion: A genome-wide association study approach was successful in elucidation of genetic determinants associated with development of aGVHD in patients undergoing allo-HSCT. The 7 SNP model was effective in predicting the development of aGVHD after allo-HSCT. Disclosures: No relevant conflicts of interest to declare.

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Chen, Rong-Fu, Lin Wang, Jiin-Tsuey Cheng, Hau Chuang, Jen-Chieh Chang, Jien-Wei Liu, I.-Chun Lin та Kuender D. Yang. "Combination of CTLA-4 and TGFβ1 gene polymorphisms associated with dengue hemorrhagic fever and virus load in a dengue-2 outbreak". Clinical Immunology 131, № 3 (червень 2009): 404–9. http://dx.doi.org/10.1016/j.clim.2009.01.015.

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Sebastiani, Paola, Ling Wang, Thomas Perls, Dellara F. Terry, Monty Montano, Clinton T. Baldwin, and Martin H. Steinberg. "A Repertoire of Genes Modifying the Risk of Death in Sickle Cell Anemia." Blood 110, no. 11 (November 16, 2007): 150. http://dx.doi.org/10.1182/blood.v110.11.150.150.

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Abstract Phenotypic heterogeneity is a well known characteristic of sickle cell anemia. Patients have different rates of hemolysis-related complications, like pulmonary hypertension, priapism and leg ulceration, and viscosity/vasoocclusion-related complications, like painful episodes, acute chest syndrome and osteonecrosis; they also have variation in levels of HbF and hematocrit. To integrate individual disease variables into a global measure of severity, we developed a Bayesian network model that described the complex associations of 25 clinical and laboratory variables, deriving a score that we used to define disease severity (0, least severe to 1, most severe) as the risk of death within 5 years (Sebastiani et al, Blood 2007). This initial network, validated in 2 unrelated patient populations, did not incorporate the genetic heterogeneity that is likely to modulate its components. Accordingly, we studied the association of single nucleotide polymorphisms (964 SNPs) in candidate genes (315 genes) using a Bayesian beta regression model of the severity score in 741 HBB glu6val homozygotes, aged more than 18 years. Forty-three SNPs in about 25 genes were associated with disease severity. Some associated SNPs tag genes that affect nitric oxide and oxidative biology and the endothelium, such as NOS1, ASS, KL, HMOX1, ECE1, KDR, FLT1. Homozygosity for an intronic SNP in ECE1 is associated with a increase of severity (OR=3.5). As expected, some associations were consistent with our previous findings. For example, the same SNP in ECE1 and TGFBR3, that was highly predictive of severity, was also strongly associated with sickle cell stroke (Sebastiani et al, Nature Genet 2005). Also, the association with severity of genes in the TGF-beta signaling pathway, including BMP6 and TGFBR3, were also associated with individual disease complications. Other associated genes play a less obvious role in the pathobiology of disease, e.g., HAO2, but are very strongly associated with the phenotype of severity (probability of a chance association, for HAO2, 10−6). Several of the genes associated with severity, including KL, PRKCA, FLT1 and MET have been related to aging, as suggested by gene expression profiling and studies in model organisms for aging. In genome-wide studies of the genetic basis of exceptional longevity, we found associations with some of the same genes that were associated with severity in sickle cell anemia. Perhaps increased oxidative stress, and the relentless progression of vasculopathy in sickle cell anemia, cause accelerated tissue damage that is modulated by a set of genes similar to those involved in the normal aging process. We suggest that the disease severity score can be used as a phenotype integrating many features of the disease, for genetic association studies. As we add the results of unbiased genome-wide association studies to capture polymorphisms not included in candidate gene studies, we can develop a predictive network with even greater reliability than one using only clinical and laboratory variables. Such networks might also identify pathways that could be targeted to alter the course of disease.

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Laky, Karen, Jessica Kinard, Anthony Guerrerio та Pamela Frischmeyer-Guerrerio. "Altered TGFβ signaling in non-hematopoietic cells leads to eosinophilic esophagitis." Journal of Immunology 200, № 1_Supplement (1 травня 2018): 104.11. http://dx.doi.org/10.4049/jimmunol.200.supp.104.11.

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Abstract Eosinophilic esophagitis (EoE) is a chronic immune-mediated disease characterized by esophageal inflammation and dysfunction. Among the top ten single nucleotide polymorphisms (SNPs) that are associated with EoE susceptibility, approximately one third are in genes that encode proteins involved in transforming growth factor beta (TGFβ) signaling. Patients and mice heterozygous for a mutation in the kinase domain of TGFβR1 (TGFBR1M318R+/−) exhibit cardiovascular, skeletal, pulmonary, and immune manifestations of Loeys-Dietz Syndrome (LDS). Immune manifestations of LDS include elevated serum IgE against food antigens and an increased likelihood of developing EoE that is characterized by esophageal dilation, food impaction, basal cell hyperplasia, and an inflammatory infiltrate composed of eosinophils, mast cells, T cells, type 2 innate lymphoid cells (ILC2), and antigen presenting cells. How altered TGFβ signaling leads to EoE is unknown. We made bone marrow chimeras to determine which cells are responsible for the development of EOE. We found that altered TGFβ signaling in radio-resistant non-hematopoietic cells was both necessary and sufficient to cause EoE. Moreover, the development of EoE was not predicated on altered TGFβ signaling in the hematopoietic effector cells. Using RNASeq and immuno-histochemistry analyses we show that altered TGFβ signaling in esophageal epithelial cells results in the expression of cytokines, chemokines, and adhesion molecules that facilitate the recruitment, activation, and accumulation of eosinophils, mast cells, T cells, and ILC2. Targeting these inflammatory mediators in vivo should have therapeutic potential for patients suffering with EoE.

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Schipp, Cyrill, Arndt Borkhardt, Polina Stepensky, and Ute Fischer. "Identifying Possible Candidate Factors Influencing the Penetrance of Heterozygous NFKB1 Loss of Function Mutations By Whole Exome Sequencing." Blood 128, no. 22 (December 2, 2016): 3706. http://dx.doi.org/10.1182/blood.v128.22.3706.3706.

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Abstract Introduction The NFκB signaling pathway is a master regulator of immune and inflammatory responses. Recently we and other groups reported heterozygous NFKB1 loss-of-function mutations in patients with combined variable immunodeficiency (CVID) characterized by recurrent infections, autoimmunity and immunoglobulin deficiency. Pedigree analysis revealed incomplete penetrance of the disease causing mutation in 5 of the 6 analyzed families. While patients showed a severe phenotype including hypogammaglobulinemia, chronic infections and cytopenias, other carriers of the same mutation were unaffected except for slightly perturbed immunoglobulin levels indicating the existence of other factors influencing the penetrance of these mutations. Methods To identify genetic factors associated with complete penetrance of dominant NFKB1 mutations, whole exome sequencing was carried out using DNA extracted from blood samples derived from two patients and their families. Sequencing data of two patients and X unaffected carriers of the same NFKB1 mutations (p.R157X and p.I47fsX2) were then screened in silico for single nucleotide variations, small insertions and deletions present in modulators of immune responses in general and the NFκB pathway in particular, employing lists generated based on publicly available data on gene interactions (including e.g. data of the KEGG, and STRING databases). Results We detected no deleterious mutations in known modifier genes such as IL10, IL1B, IL6, CCR5, CCL5, RANTES, TGFB1 and others. But strikingly both patients harbored two polymorphisms (g.797C>A, Gly54Asp, Gly57Glu) in the Mannose Binding Lectin 2 (MBL2) gene that were previously reported as disease causing mutations in patients with primary immunodeficiency. These polymorphisms lead to reduced MBL2 expression and are linked with high susceptibility to infections. We hypothesize that low MBL2 expression in an NFKB1 haploinsufficient background may promote disease penetrance or increase the predisposition to infections. Conclusion Our combined next-generation sequencing and bioinformatics analyses approach identified MBL2 as an interesting candidate factor whose deficient expression may influence the penetrance of NFKB1 loss-of-function mutations. Further analysis of greater cohorts is needed to reinforce the role of MBL2 in the pathogenesis of NFKB1 haploinsufficiency. Disclosures No relevant conflicts of interest to declare.

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Martinez-Castaldi, Carolina, Vikki G. Nolan, Clinton T. Baldwin, Lindsay A. Farrer, Martin H. Steinberg та Elizabeth S. Klings. "Association of Genetic Polymorphisms in the TGF-β Pathway with the Acute Chest Syndrome of Sickle Cell Anemia." Blood 110, № 11 (16 листопада 2007): 2247. http://dx.doi.org/10.1182/blood.v110.11.2247.2247.

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Abstract Acute chest syndrome (ACS), a leading cause of morbidity and mortality in sickle cell anemia (HbSS), is thought to be multi-factorial in etiology. Prior small studies have implicated genes related to endothelial dysfunction in this process. We performed a candidate gene analysis on 1442 subjects with HbSS, with or without coincident α-thalassemia, enrolled in the Cooperative Study of Sickle Cell Disease, to identify genes associated with an increased risk of ACS. The etiology and clinical course of ACS for patients younger than 4 years is thought to be different from that in older ages. To account for inherent differences in ACS between adults and young children we divided the population conservatively into Group 1: pediatric (aged < 5 years) and Group 2: older children and adults (aged > 5 years). All subjects underwent a complete history, including medical record review, and were followed for approximately 5 years. ACS was defined as a new infiltrate on chest x-ray or pleuritic chest pain with a positive radionuclide lung scan. Controls had no history of ACS. Genotyping of haplotype tagging single nucleotide polymorphisms (htSNPs) of candidate genes was carried out on the Sequenom mass spectrometry SNP genotyping system or the ABI SNPlex system. We tested 847 SNPs in 354 candidate genes, including inflammatory mediators, modulators of nitric oxide (NO) biology, vasoregulatory molecules, cellular adhesion molecules and genes involved in the TGF-β signaling pathway. Time to first ACS event was analyzed using Cox proportional-hazards regression. Analyses were adjusted for age at entry, gender and baseline leukocyte count. Additional adjustments for reticulocyte and platelet count were made in Group 2. Correction for multiple testing was performed using the false discovery method based on the Benjamini and Hochberg algorithm. There were 170 ACS cases and 884 controls in Group 1, and 388 cases and 819 controls in Group 2. Two SNPs were significantly associated with ACS in both groups. In both populations, the most significant SNP was rs284157 located in TGFBR3 (transforming growth factor, beta receptor III) (Group 1: p=5.53 × 10–7, Group 2: p=6.40 × 10–38). The second most significantly associated SNP in both groups (rs736839) is in an unknown gene but is in linkage disequilibrium with the gene SMAD7, also of the TGF-β pathway (Group 1: p= 0.000792, Group 2: p=3.8 × 10–6). In Group 1 there were 2 additional SNPs significantly associated with ACS, both in PIK3CG (rs1526083, located at an intron/exon boundary, p= 0.0004 and rs12536620, p= 0.00007). This gene is a member of the PI3/PI4-kinase family and is involved in cell-cell adhesion. Six additional SNPs were associated with ACS in Group 2: rs2068991 in SMAD1 (p= 3.18 × 10–8), two SNPs in KLOTHO (KL), which plays a role in NO production (rs2149860, p=6.24 × 10-5 and rs656525, p=0.001138) and one each in the genes NRCAM, SMAD3 and STARD13, the latter of which is very near KL. In conclusion, 10 SNPs in 8 genes were significantly associated with development of ACS. Several of these genes are involved in the TGF-β signaling pathway, which has been implicated in other complications of sickle cell anemia. Confirmation of these results in other populations and further studies of these genes will likely lead to a greater understanding of the mechanisms involved in the development of ACS.

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Krela-Kaźmierczak, I., M. Michalak, A. Wawrzyniak, A. Szymczak, P. Eder, L. Łykowska-Szuber, M. Kaczmarek-Ryś, et al. "The c.29T>C polymorphism of the transforming growth factor beta-1 (TGFB1) gene, bone mineral density and the occurrence of low-energy fractures in patients with inflammatory bowel disease." Molecular Biology Reports 44, no. 6 (October 9, 2017): 455–61. http://dx.doi.org/10.1007/s11033-017-4131-2.

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Saidakramovich, Khasanov Ulugbek, and Sharipov Sanjar Salomovich*. "Analysis of Associative Relationship of Allelic and Genotypical Variants of Polymorphism Rs 2010963 of the VEGFA Gene with Formation and Development of Ronchopathy." International Journal of Advanced Dental Sciences and Technology 1, no. 2 (August 10, 2021): 1–5. http://dx.doi.org/10.35940/ijadst.b1002.081221.

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It is interesting to note that the adverse effect of this genotype was observed exclusively in patients with ronchopathy, while in patients with ronchopathy, the frequency of this genotype did not differ in comparison with the control group, i.e. there is a significant tendency to an increase in the genotype with an increase in the severity of the pathology. Material and methods. To solve the set tasks, 208 patients with various diseases of the upper respiratory tract, with nasal breathing disorders, causing ronchopathy, who were hospitalized in the ENT department of the multidisciplinary clinic of the Tashkent Medical Academy for 2015 to 2021, were examined. The control group consisted of 50 apparently healthy people who agreed to participate in the study (students, masters, clinical residents). Among the sick men there were 144 (73%), women - 64 (27%). The age of the patients ranged from 18 to 70 years, averaging 44.5 ± 6.8 years. Molecular genetic studies were carried out in the Department of Molecular Medicine and Cell Technologies of the RSNPMC Hematology. This part of the work consisted of several stages: 1. Blood sampling. 2. Isolation of DNA from peripheral blood lymphocytes. 3. Carrying out PCR. 4. Conducting electrophoresis and visualizing the results (if necessary). The analysis of the TGFb1 gene polymorphism associations was carried out using a case-control model (casecontrol, comparison of two samples). The sample "case" was formed from 104 patients with ronchopathy. Conclusion. Since this work is one of the few works on the study of the relationship between rs 2010963 of the VEGFA gene and the risk of developing ronchopathy, our data may become the subject of further discussions.

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Saidakramovich, Khasanov Ulugbek, and Sharipov Sanjar Salomovich. "Analysis of Associative Relationship of Allelic and Genotypical Variants of Polymorphism Rs 2010963 of the VEGFA Gene with Formation and Development of Ronchopathy." International Journal of Advanced Dental Sciences and Technology 1, no. 2 (August 10, 2021): 1–5. http://dx.doi.org/10.54105/ijadst.b1002.081221.

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It is interesting to note that the adverse effect of this genotype was observed exclusively in patients with ronchopathy, while in patients with ronchopathy, the frequency of this genotype did not differ in comparison with the control group, i.e. there is a significant tendency to an increase in the genotype with an increase in the severity of the pathology. Material and methods. To solve the set tasks, 208 patients with various diseases of the upper respiratory tract, with nasal breathing disorders, causing ronchopathy, who were hospitalized in the ENT department of the multidisciplinary clinic of the Tashkent Medical Academy for 2015 to 2021, were examined. The control group consisted of 50 apparently healthy people who agreed to participate in the study (students, masters, clinical residents). Among the sick men there were 144 (73%), women – 64 (27%). The age of the patients ranged from 18 to 70 years, averaging 44.5 ± 6.8 years. Molecular genetic studies were carried out in the Department of Molecular Medicine and Cell Technologies of the RSNPMC Hematology. This part of the work consisted of several stages: 1. Blood sampling. 2. Isolation of DNA from peripheral blood lymphocytes. 3. Carrying out PCR. 4. Conducting electrophoresis and visualizing the results (if necessary). The analysis of the TGFb1 gene polymorphism associations was carried out using a case-control model (case-control, comparison of two samples). The sample “case” was formed from 104 patients with ronchopathy. Conclusion. Since this work is one of the few works on the study of the relationship between rs 2010963 of the VEGFA gene and the risk of developing ronchopathy, our data may become the subject of further discussions.

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Concas, Maria Pina, Anna Morgan, Fabrizio Serra, Andries Paul Nagtegaal, Berthe C. Oosterloo, Sudha Seshadri, Nancy Heard-Costa, et al. "Hearing Function: Identification of New Candidate Genes Further Explaining the Complexity of This Sensory Ability." Genes 12, no. 8 (August 10, 2021): 1228. http://dx.doi.org/10.3390/genes12081228.

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To date, the knowledge of the genetic determinants behind the modulation of hearing ability is relatively limited. To investigate this trait, we performed Genome-Wide Association Study (GWAS) meta-analysis using genotype and audiometric data (hearing thresholds at 0.25, 0.5, 1, 2, 4, and 8 kHz, and pure-tone averages of thresholds at low, medium, and high frequencies) collected in nine cohorts from Europe, South-Eastern USA, Caucasus, and Central Asia, for an overall number of ~9000 subjects. Three hundred seventy-five genes across all nine analyses were tagged by single nucleotide polymorphisms (SNPs) reaching a suggestive p-value (p < 10−5). Amongst these, 15 were successfully replicated using a gene-based approach in the independent Italian Salus in the Apulia cohort (n = 1774) at the nominal significance threshold (p < 0.05). In addition, the expression level of the replicated genes was assessed in published human and mouse inner ear datasets. Considering expression patterns in humans and mice, eleven genes were considered particularly promising candidates for the hearing function: BNIP3L, ELP5, MAP3K20, MATN2, MTMR7, MYO1E, PCNT, R3HDM1, SLC9A9, TGFB2, and YTHDC2. These findings represent a further contribution to our understanding of the genetic basis of hearing function and its related diseases.

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Ayala de Miguel, Pablo, María Valle Enguix-Riego, Jon Cacicedo, Blas David Delgado, Marco Pérez, Juan Manuel Praena-Fernández, Laura Quintana Cortés, Pablo Borrega, Eleonor Rivin del Campo, and Jose Lopez Guerra. "Prognostic value of the TGFß1 rs4803455 single nucleotide polymorphism and its association with prophylactic cranial irradiation in small cell lung cancer." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e21038-e21038. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e21038.

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e21038 Background: Small cell lung cancer (SCLC) is one of the greatest therapeutic challenges of oncology. Potential associations between single-nucleotide polymorphisms (SNP) in Heat shock protein beta- 1 (HSPB1) and Transforming growth factor (TGFß1) and survival have been investigated. Methods: A prospective multicenter study of 94 SCLC patients treated between 2013 and 2016 was conducted. Several variables clinical, tumour-related, therapeutic, and genetic (9 SNPs of TGFß1 gene and 5 of HSPB1 gene) variables were analyzed. Results: The cohort included 77 men and 17 women with a median age of 61 years. Eighty percent presented with limited stage at diagnosis and received thoracic radiation with a median dose of 45 Gy (BID in 42%). Forty-seven percent received concomitant platinum-based chemotherapy and 57% received prophylactic cranial irradiation (PCI). Overall survival (OS) was 34% at 2 years and 16% at 3 years. In multivariate analysis PCI and the TGFß1 SNP rs4803455 showed a statistically significant association with OS and local control. Patients with the CA genotype of the TGFß1 SNP rs4803455 showed worse OS (HR 2.53; IC 1.22-5.21; p = 0.012) and higher local recurrence (HR 2.26; IC 1.01-5.08;p = 0.048). A combined analysis showed that those patients receiving PCI and carrying the rs4803455:CA genotype had a statistically significant lower OS (p < 0.001) and disease-free survival (p < 0.001) than patients receiving PCI and carrying the rs4803455:AA genotype. Conclusions: Genetic analysis showed that the CA genotype of TGFß1 SNP rs4803455 was associated with worse prognosis in SCLC patients and could be considered as a potential biomarker for OS.

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Adewoye, Adeboye H., Vikki G. Nolan, Clinton T. Baldwin, Diego F. Wyszynski, Qian-Li Ma, John J. Farrell, Alice Bisbee та ін. "Association of Polymorphisms of the Transforming Growth Factor-β/Bone Morphogenetic Protein (TGF-β/BMP) Pathway with Sickle Cell Bacteremia." Blood 106, № 11 (16 листопада 2005): 3170. http://dx.doi.org/10.1182/blood.v106.11.3170.3170.

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Abstract Patients with sickle cell disease have an increased risk of bacteremia. To study the genetic basis for this increased susceptibility we studied the association of single nucleotide polymorphisms (SNPs) in candidate genes that might affect the risk of infection and therefore bacteremia. The Cooperative Study of Sickle Cell Disease enrolled 4,082 patients who were observed for about 5 years. Blood from these patients was used for globin gene analysis and SNP genotyping. We limited the present studies to patients with sickle cell anemia, with or without coincident α thalassemia, yielding a pool of 1473 patients with genotype, demographic and clinical data for which DNA samples were available. A case was defined as a patient seen in a clinic, emergency department, or hospital for which a positive blood culture not associated with a known source of infection such as osteomyelitis, septic arthritis, pneumonia, or meningitis, was found. Control patients had no history of bacteremia and no incident bacteremic events. For genetic studies, the samples were genotyped for informative SNPs in candidate genes selected from public and proprietary databases using the Sequenom mass spectrometry SNP genotyping system. For quality control purposes about 3% of the DNA samples were regenotyped and Hardy-Weinberg equilibrium was assessed for each SNP among controls. Genotypic counts were compared between sickle cell patients with bacteremia and patients using multiple logistic regression adjusting for leukocyte count, penicillin prophylaxis, fetal hemoglobin and total hemoglobin levels. In our initial screen, we considered a SNP to have an association with a phenotype when the p-value was equal to or less than 0.01, or if this and other SNPs in the same gene were significant at the 0.05 level. If a SNP met these criteria, a second phase of genotyping was done to study additional haplotype tagging (ht) SNPs in the gene. Because of the importance of the TGF-β beta pathway in the immune response, additional genes in this pathway were also studied. The ABI SNPlex system was utilized for the second phase of genotyping. Among the 201 subjects with bacteremia and 1238 controls, there was no significant difference in age, sex, HbF concentration, distribution of β-globin gene cluster haplotypes or the presence of coincident α thalassemia. Patients with bacteremia had a slightly lower hemoglobin concentration and higher leukocyte count. Subjects who received antibiotic prophylaxis (p < 0.0001) or H. influenza vaccination (p <0.004) were more likely to develop bacteremia, but with a ‘non-covered’ organism. Four SNPs in BMP6 (rs270387, rs267188, rs267196 and rs366386; p values < 0.039), 2 SNPs in TGFBR3 (rs2148322 and rs2765888; p values < 0.033) and 2 SNPs in SMAD3 (rs10518707 and rs11631380; p values < 0.012) were associated with bacteremia. The TGF-β/BMP pathway modulates immunosuppression, cell migration, wound healing and angiogenesis, among other functions. In some studies, reduced levels of these proteins were associated with increased severity of bacterial pneumonia. SNPs that show an association with susceptibility to bacteremia may help target sickle cell anemia patients who require more prolonged antibiotic prophylaxsis.

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Ashley-Koch, Allison E., Laura M. De Castro, Felicia Lennon-Graham, Jude Jonassaint, Terry L. Jackson, Jennifer Price, Jason Galloway, et al. "Priapism in SCD: Clinical and Genetic Correlations." Blood 106, no. 11 (November 16, 2005): 3174. http://dx.doi.org/10.1182/blood.v106.11.3174.3174.

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Abstract Priapism is a complication of sickle cell disease (SCD) that occurs due to obstruction of the corpora cavernosa of the penis. We have studied priapism in relation to several clinical and genetic factors in 249 adult male patients with SCD, 92 (37%) of whom reported a positive history of priapism. The mean age of male patients without a history of priapism was 35.2 years (± 10.8 years) compared with a mean age of 36.4 years (± 11.3 years) in male patients with a positive history of priapism. Because of the possible relationship with nitric oxide biology, we examined the co-occurrence of priapism with proteinuria, leg ulcers and stroke. Of the males with a positive history of priapism, 20% also had a history of 2+ or greater proteinuria, compared to a presence of 2+ or greater proteinuria in only 10% of males without a history of priapism (p=0.03). Similarly, 34% of males with a positive history of priapism also had a history of leg ulcers, compared to the presence of leg ulcers in 22% of males without priapism (p=0.03). No statistically significant association between the occurrence of priapism and stroke was observed. In an effort to identify genetic risk factors for priapism, we examined 262 single nucleotide polymorphisms (SNPs) in a total of 56 genes, primarily involved in red blood cell adhesion and inflammation pathways. Chi Square tests of association were constructed for the genotypes of each SNP with two clinical categories: patients with a positive history of priapism and patients without a history of priapism. When the frequency of rare homozygotes was less than five individuals, we combined these rare homozygote individuals with heterozygote individuals for analysis. All p-values were uncorrected for multiple testing. We found associations with 12 SNPs in 8 genes: SLC4A2 (p=0.003); ITGAV (p=0.004 and p=0.02 for two different SNPs); F13A1 (p=0.004 and p=0.02 for two different SNPs); AQP1 (p=0.01 and p=0.04 for two different SNPs); TGFBR2 (p=0.01 and p=0.02 for two different SNPs); ADRB2 (p=0.03); MGC (p=0.04); and ARG2 (p<0.05). These genes are involved in a variety of functions, including adhesion, coagulation, signal transduction, NO biology and immune response. We examined 21 non-coding SNPs in the Klotho gene, but we did not find an association between priapism and Klotho, as was recently reported by Nolan and colleagues (2005). The only possible trend for association we observed in Klotho was at marker rs1888057 (p=0.07); we did not observe association with the SNP (rs2249358) (p=0.82) Nolan and colleagues found associated with priapism. These data support our over-arching hypothesis that genetic factors mediate the variability and risk of developing organ-specific complications of SCD. A better understanding of the genetic factors that contribute to the occurrence of complications such as priapism should ultimately lead to a better understanding of SCD pathophysiology as well as to improved treatment for patients with SCD.

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Martin-Antonio, Beatriz, Rocio Cardesa, Isabel Álvarez, Francisco Márquez-Malaver, Alicia Báez, Magdalena Carmona, Jose Falantes, et al. "Genetic Variability In the Transcriptional Factor EP300 Strongly Influences the Clinical Outcome of Allogeneic Stem Cell Transplantation (Allo-SCT)." Blood 116, no. 21 (November 19, 2010): 527. http://dx.doi.org/10.1182/blood.v116.21.527.527.

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Abstract Abstract 527 Despite considerable progress in the management of infections, in more stringent criteria for HLA compatibility, in the use of new immunosuppressive drugs and in tailored conditioning regimens, allo-SCT is still associated with a considerable morbidity and mortality, especially due to infection and leukemic relapse. Little is known about the relative importance of genetic characteristics that influence individual responses to infection and to malignant cells. We hypothesized that individual non-HLA genetic characteristics of the donor and/or recipient may influence the degree of inflammatory and antileukemic responses after allo-SCT. The objective of this study was to examine – in both the donor and the recipient – single nucleotide polymorphisms (SNPs) in genes involved in innate immunity (HAMP, IRF-3, PTX3, HBD1, TGFB1) and in transcriptional factors (TF) (ATBF1 and EP300) and to evaluate their influence on clinical outcomes after allo-SCT, specifically on the incidence of disease free survival (DFS), overall survival (OS), transplant-related mortality (TRM), and relapse. The study was performed in a first cohort of 106 donor-patient pairs (Hospital Virgen del Rocío, Seville) and was later validated in a second cohort of 99 donor-patient pairs (Hospital Clinic, Barcelona). In the first cohort, patient median age was 38 years (range, 5–66); 52% were in advanced phase of disease; and 29% received a reduced intensity conditioning regimen. Although several SNPs were associated with clinical outcome in this cohort, the strongest association was found with the transcriptional factor EP300. The dominant variant AA in rs7193297 in EP300 codes for a missense change. Patients with this variant attained a higher DFS (44% vs 37%, p=0.01; OR=2, p=0.03) and OS (54% vs 25%, p=0.009; OR=2, p=0.03) and showed a trend towards a lower TRM (16% vs 31%, p=0.1; OR=2, p=0.1). In the second cohort, median age was 45 years (range, 17–64); 55% were in advanced phase of disease; and 23% received a reduced intensity conditioning regimen. Results in this group of patients were very similar to those found in the first cohort. Patients with the dominant variant in EP300 attained a higher DFS (53% vs 24%, p=0.018; OR=2, p=0.03) and OS (65% vs 34%, p=0.016; OR=2, p=0.03) and showed a trend towards a lower TRM (21 vs 32%, p=0.3). When both cohorts were analyzed together, differences between patients with the dominant variant and those with the recessive variant were more significant. Those with the dominant variant had a higher DFS (53% vs 24%, p<0.0001; OR=2, p=0.004) and OS (54% vs 34%, p=0.001; OR=2, p=0.005) and showed a trend towards a lower TRM (18% vs 31%, p=0.07; OR=1.7, p=0.09) and a lower relapse rate (31% vs 45%, p=0.04; OR=1.6, p=0.05). When the analysis was performed according to the presence of the SNP in donor and/or in patient, the association of EP300 with clinical outcome was stronger when the variant was present in both donor and recipient (figureA). EP300 is a histone acetiltranspherase that regulates transcription via chromatin remodelling; it is involved in viral infection by interacting with IRF3 to activate interferon transcription and plays an important role in hemopoietic stem cell proliferation and differentiation. Due to the importance of EP300 in the regulation of mRNA expression of innate immunity and cell proliferation genes, we analyzed rs7193297 in EP300 by real-time RT-PCR in healthy individuals. The dominant variant was associated with higher expression of innate immune genes (IRF-3, p=0.02; MIF, p=0.006), cell cycle genes (AURKB, p=0.01; CCNA2, p=0.005; CCNB1, p=0.02) and osmotic stress genes (NFAT5, p=0.03; SLC38A2, p=0.03) (figureB). Our findings indicate a beneficial effect for the dominant variant in EP300 on clinical outcome after allo-SCT, which might be explained by its influence in the mRNA expression of innate immunity and cell proliferation genes. Actuarial probability of disease-free survival according to the presence (+) or absence (-) of the dominant variant in rs7193297 in EP300 in donor (D) or in patient (P). B. Real-time RT-PCR in healthy individuals carrying the dominant genotype (AA) in rs7193297 in EP300 compared to individuals carrying the recessive genotype (GG). Disclosures: No relevant conflicts of interest to declare.

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Giraud, Sophie, Claire Bardel, Sophie Dupuis-Girod, Marie-France Carette, Brigitte Gilbert-Dussardier, Sophie Riviere, Jean-Christophe Saurin, et al. "Sequence variations of ACVRL1 play a critical role in hepatic vascular malformations in hereditary hemorrhagic telangiectasia." Orphanet Journal of Rare Diseases 15, no. 1 (September 22, 2020). http://dx.doi.org/10.1186/s13023-020-01533-2.

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Abstract Background Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by multiple telangiectases and caused by germline disease-causing variants in the ENG (HHT1), ACVRL1 (HHT2) and, to a lesser extent MADH4 and GDF2, which encode proteins involved in the TGF-β/BMP9 signaling pathway. Common visceral complications of HHT are caused by pulmonary, cerebral, or hepatic arteriovenous malformations (HAVMs). There is large intrafamilial variability in the severity of visceral involvement, suggesting a role for modifier genes. The objective of the present study was to investigate the potential role of ENG, ACVRL1, and of other candidate genes belonging to the same biological pathway in the development of HAVMs. Methods We selected 354 patients from the French HHT patient database who had one disease causing variant in either ENG or ACVRL1 and who underwent hepatic exploration. We first compared the distribution of the different types of variants with the occurrence of HAVMs. Then, we genotyped 51 Tag-SNPs from the Hap Map database located in 8 genes that encode proteins belonging to the TGF-β/BMP9 pathway (ACVRL1, ENG, GDF2, MADH4, SMAD1, SMAD5, TGFB1, TGFBR1), as well as in two additional candidate genes (PTPN14 and ADAM17). We addressed the question of a possible genetic association with the occurrence of HAVMs. Results The proportion of patients with germline ACVRL1 variants and the proportion of women were significantly higher in HHT patients with HAVMs. In the HHT2 group, HAVMs were more frequent in patients with truncating variants. Six SNPs (3 in ACVRL1, 1 in ENG, 1 in SMAD5, and 1 in ADAM17) were significantly associated with HAVMs. After correction for multiple testing, only one remained significantly associated (rs2277383). Conclusions In this large association study, we confirmed the strong relationship between ACVRL1 and the development of HAVMs. Common polymorphisms of ACVRL1 may also play a role in the development of HAVMs, as a modifying factor, independently of the disease-causing variants.

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Zhang, Xiaoying, Shasha Yu, Wencai Chen, Jianfei Ren та Xiaofeng Chen. "Abstract 246: TGF-β1 and TGFBR2 Polymorphisms With ISH". Arteriosclerosis, Thrombosis, and Vascular Biology 37, suppl_1 (травень 2017). http://dx.doi.org/10.1161/atvb.37.suppl_1.246.

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Background and Objective: Isolated systolic hypertension (ISH) is characterized by increased aortic stiffness and associated with a significantly increased risk of cardiovascular morbidity and mortality. It has been reported that elevated plasma transforming growth factor-beta 1(TGF-β1)levels predicted development of hypertension. However, little is known about the association of TGF- β 1 pathway gene polymorphisms and ISH. The aim of the present study was to study the association of transforming growth factor-beta 1(TGF-β1)and its receptor 2(TGFBR2)functional gene polymorphisms with isolated systolic hypertension (ISH). Methods and Results: One hundred and three consecutive ISH patients and 169 healthy controls were recruited in this study. All subjects were genotyped for TGFβ1-869T/C, TGFBR2-3779A/G and TGFBR2-1444C/G by the technology of polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and then confirmed by direct sequencing. No significant difference in genotype (and allele) frequency of TGFβ1-869T/C, TGFBR2-3779A/G and TGFBR2-1444C/G polymorphisms were observed between ISH group and healthy group (p>0.05). Conclusion: Our findings suggest that TGFβ1-869T/C, TGFBR2-3779A/G and TGFBR2-1444C/G polymorphisms may not be associated with susceptibility of isolated systolic hypertension in Chinese population.

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Varghese, Sindhu, та Subbaraj Gowtham Kumar. "Role of eNOS and TGFβ1 gene polymorphisms in the development of diabetic nephropathy in type 2 diabetic patients in South Indian population". Egyptian Journal of Medical Human Genetics 23, № 1 (12 січня 2022). http://dx.doi.org/10.1186/s43042-022-00216-w.

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Abstract Background Diabetic nephropathy is known to be a leading complication of diabetes mellitus, characterized by diverse aspects such as high urinary albumin level, elevated blood pressure, and genetic susceptibility leading to end-stage renal disease. The current study was carried out to investigate the association of eNOS and TGFβ1 gene polymorphisms in the progression of diabetic nephropathy among type 2 diabetic patients in the South Indian population. The eNOS and TGFβ1 genetic variants were genotyped in 280 T2DM patients, 140 with DN, 140 without DN, and 140 controls. Genotyping was performed using ARMS PCR and the genomic variants were confirmed by the Sanger sequencing method. Results A significant (p < 0.05) association was observed in the genotypic frequencies of eNOS (G > T) polymorphism in the T2DM patients with diabetic nephropathy when compared to controls. The frequency of TT (heterozygous) genotype was observed to increase in patients with type 2 diabetes and DN when compared to the diabetic patients without DN and controls. This indicates that diabetic patients with TT genotype are at an increased risk to develop DN. However, TGFβ1 (G > C) polymorphism did not show any association in the allele and genotypic frequencies with DN when compared with T2DM and controls. Conclusion The results of the study propose a strong influence of TT genotype of eNOS gene be significantly linked with diabetic nephropathy in T2DM patients. Whereas no association was examined concerning TGFβ1 gene polymorphism and DN. Nevertheless, large sample size studies are required to confirm the part of these genetic variants in the development of DN.

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Hassab, Hoda, Marwa Hanafi, Ahmed Elbeheiry, Mona Hassan, and Yasmine El Chazli. "Does TGFBR3 Polymorphism Increase the Risk of Silent Cerebral Infarction in Egyptian Children with Sickle Cell Disease?" Indian Journal of Pediatrics, July 4, 2022. http://dx.doi.org/10.1007/s12098-022-04181-5.

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Abstract Objectives To evaluate the relationship between TGFBR3 rs284875 single nucleotide polymorphism (SNP) state and silent cerebral infarction (SCI) in asymptomatic patients with sickle cell disease (SCD). Methods A cross-sectional study was conducted on 50 children with SCD above 2 y of age followed up at the hematology outpatient clinic of Alexandria University Children's Hospital in Egypt. Twenty-four healthy children were included as a control group. All patients included in the study were subjected to complete history and clinical examination. Real-time polymerase chain reaction was performed on patients and controls for identification of SNP rs284875 of the TGFBR3 gene. A magnetic resonance imaging (MRI) of the brain were performed only on patients for detection of SCI. Results Fifty SCD patients were enrolled (26 males and 24 females), with a median age of 10.9 y (2.3–17.8 y), and 24 children as healthy control for the studied SNP. Thirty-five (70%) patients had homozygous SCD, while 30% had sickle β-thalassemia. The brain MRI was normal in all the patients except for 2 patients who had features of SCI. The TGFBR3 rs284875 SNP was detected in 15 (30%) patients in the homozygous state (GG) versus only 1 (4.2%) child from the control group (p = 0.003). The prevalence of SCI was low in the study population and there was no statistically significant relationship between the TGFBR3 rs284875 SNP status and the presence of SCI in the brain MRI (p = 0.621). Conclusions This study confirmed a low prevalence of SCI in the SCD patient included in the study. The TGFBR3 rs284875 SNP did not significantly increase SCI among those patients.

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Corredor, Zuray, Miguel Inácio da Silva Filho, Lara Rodríguez-Ribera, Antonia Velázquez, Alba Hernández, Calogerina Catalano, Kari Hemminki, et al. "Genetic Variants Associated with Chronic Kidney Disease in a Spanish Population." Scientific Reports 10, no. 1 (January 10, 2020). http://dx.doi.org/10.1038/s41598-019-56695-2.

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AbstractChronic kidney disease (CKD) patients have many affected physiological pathways. Variations in the genes regulating these pathways might affect the incidence and predisposition to this disease. A total of 722 Spanish adults, including 548 patients and 174 controls, were genotyped to better understand the effects of genetic risk loci on the susceptibility to CKD. We analyzed 38 single nucleotide polymorphisms (SNPs) in candidate genes associated with the inflammatory response (interleukins IL-1A, IL-4, IL-6, IL-10, TNF-α, ICAM-1), fibrogenesis (TGFB1), homocysteine synthesis (MTHFR), DNA repair (OGG1, MUTYH, XRCC1, ERCC2, ERCC4), renin-angiotensin-aldosterone system (CYP11B2, AGT), phase-II metabolism (GSTP1, GSTO1, GSTO2), antioxidant capacity (SOD1, SOD2, CAT, GPX1, GPX3, GPX4), and some other genes previously reported to be associated with CKD (GLO1, SLC7A9, SHROOM3, UMOD, VEGFA, MGP, KL). The results showed associations of GPX1, GSTO1, GSTO2, UMOD, and MGP with CKD. Additionally, associations with CKD related pathologies, such as hypertension (GPX4, CYP11B2, ERCC4), cardiovascular disease, diabetes and cancer predisposition (ERCC2) were also observed. Different genes showed association with biochemical parameters characteristic for CKD, such as creatinine (GPX1, GSTO1, GSTO2, KL, MGP), glomerular filtration rate (GPX1, GSTO1, KL, ICAM-1, MGP), hemoglobin (ERCC2, SHROOM3), resistance index erythropoietin (SOD2, VEGFA, MTHFR, KL), albumin (SOD1, GSTO2, ERCC2, SOD2), phosphorus (IL-4, ERCC4 SOD1, GPX4, GPX1), parathyroid hormone (IL-1A, IL-6, SHROOM3, UMOD, ICAM-1), C-reactive protein (SOD2, TGFB1,GSTP1, XRCC1), and ferritin (SOD2, GSTP1, SLC7A9, GPX4). To our knowledge, this is the second comprehensive study carried out in Spanish patients linking genetic polymorphisms and CKD.

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Lee, Daniel, Clement K. Chan, Prema Abraham, and David Sarraf. "Post-hoc analysis of single nucleotide polymorphism profile for eyes with vascularized pigment epithelial detachment due to ARMD." European Journal of Ophthalmology, June 24, 2020, 112067212093282. http://dx.doi.org/10.1177/1120672120932829.

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Introduction: This post-hoc case-control study compares single nucleotide polymorphism (SNP) profile of eyes with vascularized pigment epithelial detachment (vPED) due to age-related macular degeneration (ARMD) with: (1) Control-1 eyes (no ARMD and AREDS Severity Scale 0); and (2) Control-2 eyes (drusen or AREDS Severity Scale 2). SNP profile of High Responders (HR) was also compared with Low Responders (LR) to ranibizumab. Methods: Blood samples from 40 patients with vPED treated with ranibizumab were sent for SNP-specific genotype analysis for comparison of variant allele frequencies of 23 SNPs associated with ARMD (VAF) to VAF in 184 Control-1 eyes, and VAF in 85 Control-2 eyes. VAF of HR-50 (⩾50% decrease in PED height) and VAF of HR-75 (⩾75% decrease in PED height) were also compared with VAF of LR. Results: These SNPs were more frequent in vPED than Control-1 eyes: APOE rs4420638 (A/G), HTRA1 rs104904924 (G/T), VEGF rs943080 (T/C), CFH rs1061170 (T/C), CFH rs2274700 (C/T), CFH rs10737680 (A/C), CFH rs10801555 (G/A). These SNPs were more frequent in vPED than Control-2 eyes: APOE rs4420638 (A/G), CFI rs4698775 (G/T), COL15A1/TGFBR1 rs334353 (T/G). FRK rs3812111 (T/A) was more frequent in HR-50 and HR-75 eyes compared with LR. Conclusion: Seven SNPs were more frequent in vPED eyes than non-ARMD eyes, and three SNPs were more frequent in vPED eyes than drusen eyes. Adjusting for multiplicity, only CFH rs2274700 (C/T) was significant for first comparison, and only COL15A1/TGFBR1 rs334353 (T/G) was significant for second comparison. APOE rs4420638 (A/G) was the single SNP more frequently linked to vPED eyes for both comparisons. FRK rs3812111 (T/A) was consistently associated with high responders.

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"Preliminary results of the investigations regarding the association of transforming growth factor- beta1 (TGFB1) gene polymorphism to metabolic syndrome in a Romanian patients group." Biointerface Research in Applied Chemistry 9, no. 3 (June 15, 2019): 3974–78. http://dx.doi.org/10.33263/briac93.974978.

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Genetic factors have a variable impact in predisposition for common chronic diseases, such as those grouped as metabolic syndrome (MS). MS, obesity, type 2 diabetes and hypertension have a common factor, represented by the inflammatory processes. There are numerous susceptibility genes associated with inflammation and these diseases; one gene of them is transforming growth factor –beta1 (TGFB1) gene. The promoter SNP TGFb1 -509C>T (rs1800469) has been reported as the risk factor associated with diabetes, kidney and heart diseases in European population. This work describes the distribution of this SNP in the MS and healthy groups from Romanian population. Our preliminary data could not confirm an association between MS and TGFb1 -509C>T.

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Mališić, Emina, Nina Petrović, Muriel Brengues, David Azria, Ivana Z. Matić, Ivana Srbljak Ćuk, Katarina Kopčalić, Tatjana Stanojković, and Marina Nikitović. "Association of polymorphisms in TGFB1, XRCC1, XRCC3 genes and CD8 T-lymphocyte apoptosis with adverse effect of radiotherapy for prostate cancer." Scientific Reports 12, no. 1 (December 9, 2022). http://dx.doi.org/10.1038/s41598-022-25328-6.

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AbstractThe genetic background of each person might affect the severity of radiotherapy (RT)-induced normal tissue toxicity. The aim of study was to evaluate the influence of TGFB1 C-509T and Leu10Pro, XRCC1 Arg280His and XRCC3 Thr241Met polymorphisms as well as the level of radiation-induced CD8 T-lymphocyte apoptosis (RILA) on adverse effects of RT for prostate cancer (PCa). The study included 88 patients with localized or locally advanced PCa who were treated with RT. The polymorphisms were determined by PCR–RFLP analysis on DNA from peripheral blood mononuclear cells. RILA values were measured by flow cytometry. We found that CT genotype of TGFB1 C-509T could be protective biomarker for acute genitourinary (GU) and gastrointestinal (GI) radiotoxicity, while Thr variant of XRCC3 Thr241Met could predict the risk for acute GU radiotoxicity. Correlation between RILA values and toxicity was not detected. Univariate logistic regression analysis showed that Gleason score and risk group were risk factors for late GU, while for late GI radiotoxicity it was diabetes mellitus type 2. However, in multivariate model those were not proven to be significant and independent risk factors. Identification of assays combination predicting individual radiosensitivity is a crucial step towards personalized RT approach.

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Yu, Guopeng, Bo Liang, Keneng Yin, Ming Zhan, Xin Gu, Jiangyi Wang, Shangqing Song, et al. "Identification of Metabolism-Related Gene-Based Subgroup in Prostate Cancer." Frontiers in Oncology 12 (June 16, 2022). http://dx.doi.org/10.3389/fonc.2022.909066.

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Prostate cancer is still the main male health problem in the world. The role of metabolism in the occurrence and development of prostate cancer is becoming more and more obvious, but it is not clear. Here we firstly identified a metabolism-related gene-based subgroup in prostate cancer. We used metabolism-related genes to divide prostate cancer patients from The Cancer Genome Atlas into different clinical benefit populations, which was verified in the International Cancer Genome Consortium. After that, we analyzed the metabolic and immunological mechanisms of clinical beneficiaries from the aspects of functional analysis of differentially expressed genes, gene set variation analysis, tumor purity, tumor microenvironment, copy number variations, single-nucleotide polymorphism, and tumor-specific neoantigens. We identified 56 significant genes for non-negative matrix factorization after survival-related univariate regression analysis and identified three subgroups. Patients in subgroup 2 had better overall survival, disease-free interval, progression-free interval, and disease-specific survival. Functional analysis indicated that differentially expressed genes in subgroup 2 were enriched in the xenobiotic metabolic process and regulation of cell development. Moreover, the metabolism and tumor purity of subgroup 2 were higher than those of subgroup 1 and subgroup 3, whereas the composition of immune cells of subgroup 2 was lower than that of subgroup 1 and subgroup 3. The expression of major immune genes, such as CCL2, CD274, CD276, CD4, CTLA4, CXCR4, IL1A, IL6, LAG3, TGFB1, TNFRSF4, TNFRSF9, and PDCD1LG2, in subgroup 2 was almost significantly lower than that in subgroup 1 and subgroup 3, which is consistent with the results of tumor purity analysis. Finally, we identified that subgroup 2 had lower copy number variations, single-nucleotide polymorphism, and neoantigen mutation. Our systematic study established a metabolism-related gene-based subgroup to predict outcomes of prostate cancer patients, which may contribute to individual prevention and treatment.

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