Academic literature on the topic 'TGFBR1/2 polymorphisms'

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.

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.

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.

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.

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.

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.

<b><i>Background:</i></b> 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. <b><i>Objectives:</i></b> 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. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> The genotype and allele frequencies of 3 SNPs (rs1590 in <i>TGFBR1</i>; rs1434536 and rs17023107 in <i>BMPR1B</i>) 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. <b><i>Conclusions:</i></b> 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.

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.

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.