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Author: Grafiati

Published: 10 March 2023

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1

Yazdanyar, Shiva, Maren Weischer, and Børge G. Nordestgaard. "Genotyping for NOD2 Genetic Variants and Crohn Disease: a Metaanalysis." Clinical Chemistry 55, no. 11 (November 1, 2009): 1950–57. http://dx.doi.org/10.1373/clinchem.2009.127126.

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Abstract Background: Arg702Trp, Gly908Arg, and Leu1007fsinsC variants of the NOD2 gene (nucleotide-binding oligomerization domain containing 2; alias, CARD15) influence the risk of Crohn disease. Methods: We conducted a systematic review to examine whether Arg702Trp, Gly908Arg, and Leu1007fsinsC are equally important risk factors for Crohn disease. In addition, we used studies for which combined information from all genotypes was available to compare risks in simple heterozygotes, compound heterozygotes, and homozygotes. PubMed, EMBASE, and Web of Science were searched. Seventy-five articles (18 727 cases and 17 102 controls) met the inclusion criteria and contributed data to the metaanalyses. Results: The odds ratios per allele for Crohn disease were 2.2 (95% CI, 2.0–2.5) for Arg702Trp, 2.6 (2.2–2.9) for Gly908Arg, and 3.8 (3.4–4.3) for Leu1007fsinsC (z-test results: Arg702Trp vs Gly908Arg, P = 0.03; Arg702Trp vs Leu1007fsinsC, P < 0.001; Gly908Arg vs Leu1007fsinsC, P < 0.001). When all 3 genotypes were combined, odds ratios for Crohn disease were 2.4 (95% CI, 2.0–2.8) for simple heterozygotes, 9.0 (6.0–13.5) for compound heterozygotes, and 6.7 (4.1–10.9) for homozygotes, compared with noncarriers (z-test results: simple heterozygotes vs compound heterozygotes, P < 0.001; simple heterozygotes vs homozygotes, P < 0.001; compound heterozygotes vs homozygotes, P = 0.18). Conclusions: The per-allele risk of Crohn disease was markedly higher for Leu1007fsinsC than for Arg702Trp and Gly908Arg. Combining all genotypes revealed the risks of Crohn disease for compound heterozygotes and homozygotes to be similar and markedly higher than for simple heterozygotes.

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2

Ehrmann, David A., Xu Tang, Issei Yoshiuchi, Nancy J. Cox, and Graeme I. Bell. "Relationship of Insulin Receptor Substrate-1 and -2 Genotypes to Phenotypic Features of Polycystic Ovary Syndrome." Journal of Clinical Endocrinology & Metabolism 87, no. 9 (September 1, 2002): 4297–300. http://dx.doi.org/10.1210/jc.2002-020216.

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Insulin resistance is a key component in the pathogenesis of polycystic ovary syndrome (PCOS) and type 2 diabetes. Polymorphisms in the genes encoding the insulin receptor substrate (IRS) proteins, IRS-1 (Gly972Arg) and IRS-2 (Gly1057Asp), influence susceptibility to type 2 diabetes. This study was undertaken to assess the influence of these polymorphisms on insulin resistance, glucose tolerance, and androgen levels in nondiabetic PCOS women. We studied 227 PCOS subjects including 126 and 48 nondiabetic white and African-American subjects, respectively. The IRS-1 Gly972Arg allele frequencies were identical in whites and African-Americans [0.95 (Gly) and 0.05 (Arg)]. The IRS-2 Gly1057Asp allele frequencies were 0.85 (Gly) and 0.15 (Asp) in African-Americans and 0.59 (Gly) and 0.41 (Asp) in whites. There was no association of IRS-1 genotype with any clinical or hormonal measure in nondiabetic white or African-American PCOS subjects. However, nondiabetic subjects with the IRS-2 Gly/Gly genotype had significantly higher 2-h oral glucose tolerance test glucose levels compared with those with Gly/Asp and Asp/Asp genotypes in whites or Gly/Asp genotype in African-Americans (there were no Asp/Asp subjects in our modest size African-American sample). These results suggest that the IRS-2 Gly1057Asp polymorphism influences blood glucose levels in nondiabetic white and African-American women with PCOS. Thus, individuals with the common IRS-2 Gly/Gly genotype may be at increased risk of developing type 2 diabetes.

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3

Li, Peng, Lingjun Wang, Lihua Liu, Hong Jiang, Chong Ma, and Tao Hao. "Association between IRS-1 Gly972Arg polymorphism and colorectal cancer risk." Tumor Biology 35, no. 7 (April 3, 2014): 6581–85. http://dx.doi.org/10.1007/s13277-014-1900-6.

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4

Tin, Sim Sai, and Viroj Wiwanitkit. "Insulin receptor substrate-1 Gly972Arg variant and type 2 diabetes mellitus." South African Medical Journal 104, no. 12 (November 15, 2014): 837. http://dx.doi.org/10.7196/samj.8922.

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5

Zhang, Hongtuan, Andi Wang, Hui Ma, and Yong Xu. "Association between insulin receptor substrate 1 Gly972Arg polymorphism and cancer risk." Tumor Biology 34, no. 5 (May 25, 2013): 2929–36. http://dx.doi.org/10.1007/s13277-013-0855-3.

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6

Bhatt, Surya Prakash, and Randeep Guleria. "Association of IRS1 (Gly972Arg) and IRS2 (Gly1057Asp) genes polymorphisms with OSA and NAFLD in Asian Indians." PLOS ONE 16, no. 8 (August 27, 2021): e0245408. http://dx.doi.org/10.1371/journal.pone.0245408.

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Aim and objective The aim of the study was to investigate the relationships between insulin receptor substrate (IRS) 1 (Gly972Arg) and IRS2 (Gly1057Asp) genes with obstructive sleep apnea (OSA) and non-alcoholic fatty liver disease (NAFLD) in Asian Indians. Method A total of 410 overweight/obese subjects (130 with OSA with NAFLD, 100 with OSA without NAFLD, 95 without OSA and with NAFLD and 85 without OSA and without NAFLD) were recruited. Degree of NAFLD was based on liver ultrasound and of OSA on overnight polysomnography. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism and confirmed by gene sequencing. Result Mean values of blood pressure, body fat markers, blood glucose, lipids, liver function, and markers of insulin resistance were significantly increased in OSA and NAFLD subjects (p<0.05). In addition, according to age (years) categories, blood pressure, blood glucose, lipids, obesity markers, and markers of insulin resistance were significantly higher in 45–60 years group as compared to 20–45 years group (p<0.05). In IRS1 gene, the genotype frequency (%) of Arg/Arg was significantly higher in NAFLD and OSA subjects. In addition, Gly/Arg genotype of IRS1 gene was associated with significantly higher body mass index, fat mass, %body fat, triglycerides, cholesterol, alkaline phosphate, aspartate transaminase, fasting insulin and HOMA-IR levels in OSA and NAFLD subjects. No significant difference in genotype frequencies of IRS2 was observed between four groups. Further we found that subjects carrying IRS1 Gly/Arg (OR 4.49, 95% C.I. 1.06–12.52, p = 0.002) genotype possess a much higher risk of OSA and NAFLD compared to IRS2 Gly/Asp (OR 1.01, 95% C.I. 0.8–2.56, p = 0.05). In sub group analysis of IRS1 Gly/Arg have significant differences between the mild, moderate and severe group (P<0.05). In addition, patients with the ‘Gly’ allele were inclined to develop more severe OSA. Conclusion We concluded that Asian Indian subject carrying the allele Gly972Arg polymorphism of IRS1 is predisposed to develop OSA and NAFLD.

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7

Nadyrshina, Dina, Aliya Zaripova, Anton Tyurin, Ildar Minniakhmetov, Ekaterina Zakharova, and Rita Khusainova. "Osteogenesis Imperfecta: Search for Mutations in Patients from the Republic of Bashkortostan (Russia)." Genes 13, no. 1 (January 10, 2022): 124. http://dx.doi.org/10.3390/genes13010124.

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Osteogenesis imperfecta (OI) is an inherited disease of bone characterized by increased bone fragility. Here, we report the results of the molecular architecture of osteogenesis imperfecta research in patients from Bashkortostan Republic, Russia. In total, 16 mutations in COL1A1, 11 mutations in COL1A2, and 1 mutation in P3H1 and IFIMT5 genes were found in isolated states; 11 of them were not previously reported in literature. We found mutations in CLCN7, ALOX12B, PLEKHM1, ERCC4, ARSB, PTH1R, and TGFB1 that were not associated with OI pathogenesis in patients with increased bone fragility. Additionally, we found combined mutations (c.2869C>T, p. Gln957* in COL1A1 and c.1197+5G>A in COL1A2; c.579delT, p. Gly194fs in COL1A1 and c.1197+5G>A in COL1A2; c.2971G>C, p. Gly991Arg in COL1A2 and c.212G>C, p.Ser71Thr in FGF23; c.-14C>T in IFITM5 and c.1903C>T, p. Arg635* in LAMB3) in 4 patients with typical OI clinic phenotypes.

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8

Gorgisen, Gokhan, Ugur Karatas, Can Ates, Murat Oksuz, and Ismail Gulacar. "Association of IRS1 Gly972Arg and IRS2 Gly1057Asp polymorphisms with gastric cancer in Turkish subjects." Oncology Letters 20, no. 2 (June 9, 2020): 2016–20. http://dx.doi.org/10.3892/ol.2020.11717.

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9

Shakeri, H. "Association of Irs1 GLY971ARG Gene Polymorphism With Insulin Resistance in Iranian Newly Diagnosed Diabetic Adults." Acta Endocrinologica (Bucharest) 15, no. 3 (2019): 317–22. http://dx.doi.org/10.4183/aeb.2019.317.

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10

Alharbi, Khalid Khalaf, Imran Ali Khan, Zeinab Abotalib, and Malak Mohammed Al-Hakeem. "Insulin Receptor Substrate-1 (IRS-1) Gly927Arg: Correlation with Gestational Diabetes Mellitus in Saudi Women." BioMed Research International 2014 (2014): 1–5. http://dx.doi.org/10.1155/2014/146495.

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Pregnant women with gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (T2DM) share a common pathophysiology associated with similar risk factors. Genetic variants used to determine the risk of developing T2DM might also be associated with the prevalence of GDM. The aim of the present study was to scrutinize the relationship between the G972R polymorphism of the insulin receptor substrate-1 (IRS-1) gene with GDM in the Saudi female population. This is a case-control study that monitored 500 Saudi women. Subjects with GDM (n=200) were compared with non-GDM (n=300) controls. We opted to evaluate rs1801278 polymorphism in the IRS1 gene, which plays a critical role in the insulin-signaling pathway. Genotyping was performed with the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) method. The frequency of the rs1801278 polymorphism was significantly higher in women with GDM than in women with non-GDM (for TT + CT versus CC:P=0.02). Additionally, there was a significant increase in the frequency of the Arg-encoding mutant allele from GDM to non-GDM (for T versus C:P=0.01). Our results suggest that the rs1801278 polymorphism in theIRS-1gene is involved in the occurrence of GDM in the Saudi population.

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Mahmoudi, Touraj, Keivan Majidzadeh-A, Khatoon Karimi, Hamid Farahani, Reza Dabiri, Hossein Nobakht, Asadollah Asadi, Negar Karimi, Maral Arkani, and Mohammad Reza Zali. "Gly972Arg Variant of Insulin Receptor Substrate 1 Gene and Colorectal Cancer Risk in Overweight/Obese Subjects." International Journal of Biological Markers 31, no. 1 (January 2016): 68–72. http://dx.doi.org/10.5301/jbm.5000159.

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Background Given the major role of obesity and insulin resistance (IR) in colorectal cancer (CRC), we investigated whether genetic variants in ghrelin ( GHRL), resistin ( RETN) and insulin receptor substrate 1 ( IRS1) were associated with CRC risk. Methods This study was conducted as a case-control study, and 750 subjects, including 438 controls and 312 patients with CRC, were enrolled and genotyped using the PCR-RFLP method. Results No significant differences were observed for GHRL (rs696217), RETN (rs3745367) and IRS1 (rs1801278, Gly972Arg or G972R) gene variants between the cases and controls. However, the IRS1 G972R R allele compared with the G allele and the G972R RR+GR genotype compared with the GG genotype appeared to be markers of decreased CRC susceptibility in the overweight/obese subjects (p = 0.024; odds ratio [OR] = 0.42, 95% confidence interval [95% CI], 0.20-0.91; and p = 0.048; OR = 0.42, 95% CI, 0.17-0.99, respectively). Furthermore, the R allele and RR+GR genotype were also associated with decreased risks for obesity in the patients with CRC (p = 0.007; OR = 0.35, 95% CI, 0.15-0.77; and p = 0.015; OR = 0.35, 95% CI, 0.15-0.72, respectively). Conclusions In accordance with previous studies, our findings suggest that the IRS1 G972R R allele and RR+GR genotype have protective effects for CRC in overweight/obese patients and for obesity in patients with CRC. Nevertheless, further studies are required to confirm these findings.

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12

Górska, Aleksandra, Marlena Wolek, Bogusław Czerny, Izabela Uzar, Agnieszka Seremak-Mrozikiewicz, Piotr Olbromski, Justyna Baraniak, Małgorzata Kania-Dobrowolska, Magdalena Sienko, and Anna Bogacz. "Polymorphism analysis of the Gly972Arg IRS-1 and Gly1057Asp IRS-2 genes in obese pregnant women." Reproductive Biology 20, no. 3 (September 2020): 365–70. http://dx.doi.org/10.1016/j.repbio.2020.05.002.

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13

Pechlivanis, Sonali, Barbara Pardini, Justo Lorenzo Bermejo, Kerstin Wagner, Alessio Naccarati, Ludmila Vodickova, Jan Novotny, Kari Hemminki, Pavel Vodicka, and Asta Försti. "Insulin pathway related genes and risk of colorectal cancer: INSR promoter polymorphism shows a protective effect." Endocrine-Related Cancer 14, no. 3 (September 2007): 733–40. http://dx.doi.org/10.1677/erc-07-0107.

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Western lifestyle leading to obesity and type 2 diabetes has been associated with increased risk of colorectal cancer (CRC). Diet and related factors may affect the risk by modifying plasma insulin levels. Thus, the inter-individual variation in insulin signaling may play a plausible role in the development of CRC. We hypothesized that functional polymorphisms in the insulin pathway genes INS, INSR, IGFBPI, insulin receptor substrate 1 (IRS1), and IRS2 may be associated with CRC. We studied the association of five single nucleotide polymorphisms (SNPs) with the risk of CRC using a hospital-based case–control design with 712 cases and 748 controls from the Czech Republic. The INSR A-603G promoter SNP, which is located within a known Sp1-binding site, was associated with the risk of CRC, with carriers of the G allele having a decreased risk (odds ratios (OR) 0.71, 95% confidence interval (CI) 0.54–0.93). Carrying the variant allele of the IRS1 Gly972Arg SNP further decreased the risk among the INSR-603G allele carriers (OR 0.28, 95% CI 0.11–0.70). SNPs in the INS, IGFBPI, and IRS2 genes did not affect the risk of CRC. In conclusion, genetic variation in the insulin signaling pathway genes may affect the risk of CRC.

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14

Stumvoll, Michael, Norbert Stefan, Andreas Fritsche, Alexander Madaus, Otto Tschritter, Matthias Koch, Fausto Machicao, and Hans Häring. "Interaction effect between common polymorphisms in PPARγ2 (Pro12Ala) and insulin receptor substrate 1 (Gly972Arg) on insulin sensitivity." Journal of Molecular Medicine 80, no. 1 (January 2002): 33–38. http://dx.doi.org/10.1007/s001090100282.

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15

Dorofeyev, Andriy E., Anna A. Dorofeyeva, Elena A. Kiriyan, Olga A. Rassokhina, and Yulia Z. Dynia. "GENETIC POLYMORPHISM IN PATIENTS WITH EARLY AND LATE ONSET OF ULCERATIVE COLITIS." Wiadomości Lekarskie 73, no. 1 (January 2020): 87–90. http://dx.doi.org/10.36740/wlek202001116.

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The aim was to investigate SNPs of TLR-2,3,4, NOD2/CARD15, JAK-2, and IL-10 in patients with the early and late UC onset. Matherials and methods: 126 patients with UC were investigated. To assess the predisposition of the early and late UC onset the incidence of the following SNPs: Arg753Gln TLR2 gene, Phe412Leu TLR3 gene, Asp299Gly and Thr399Ile TLR4 gene, C-819T, G-1082A and C-592A gene IL-10, Val617Phe gene JAK2, Gly908Arg gene NOD2/CARD15 were analyzed. Results: 76 patients had early disease onset and 50 had a late one. SNPs of TLR3 were observed in 50.8% cases. TLR4 polymorphism was more common than TLR3, and was observed in 81 (64.3%) UC patients. Polymorphism of NOD2/CARD15 and IL-10 genes were revealed with almost the same frequency 49 (38.9%) and 50 (39.9%) patients, respectively. Conclusions: Polymorphisms of TLR-2,3 genes and TLR4 Asp299Gly, NOD2/CARD15 prevailed in patients with the late UC onset that allows to suppose that bacterial flora plays one of the key roles in modification of immune response and UC development. In patients with early UC onset polymorphisms of the JAK2 and IL-10 genes prevailed responsible for the cytokine cascade activation and cause the immune mechanism that might lead to a more aggressive course of the disease.

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Dilek, Saffet, Devrim Ertunc, Ekrem C. Tok, Emin M. Erdal, and Atil Aktas. "Association of Gly972Arg variant of insulin receptor substrate-1 with metabolic features in women with polycystic ovary syndrome." Fertility and Sterility 84, no. 2 (August 2005): 407–12. http://dx.doi.org/10.1016/j.fertnstert.2005.01.133.

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17

Not Available, Not Available. "The Gly972Arg variant in insulin receptor substrate-1 is not associated with birth weight in contemporary English children." Diabetologia 43, no. 9 (September 1, 2000): 1201–2. http://dx.doi.org/10.1007/s001250051513.

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18

Ertunc, D., E. C. Tok, A. Aktas, E. M. Erdal, and S. Dilek. "The importance of IRS-1 Gly972Arg polymorphism in evaluating the response to metformin treatment in polycystic ovary syndrome." Human Reproduction 20, no. 5 (May 1, 2005): 1207–12. http://dx.doi.org/10.1093/humrep/deh747.

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19

Tsai, Chia-Ti, Juey-Jen Hwang, Ling-Ping Lai, Fu-Tien Chiang, and Yung-Zu Tseng. "IRS-1 Gly971Arg Variant Is Not a New Risk Factor for Coronary Artery Disease in the Taiwanese Population." Arteriosclerosis, Thrombosis, and Vascular Biology 22, no. 1 (January 2002): 194. http://dx.doi.org/10.1161/atvb.22.1.194.

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20

Pappalardo, M. A., R. Vita, F. Di Bari, M. Le Donne, F. Trimarchi, and S. Benvenga. "Gly972Arg of IRS-1 and Lys121Gln of PC-1 polymorphisms act in opposite way in polycystic ovary syndrome." Journal of Endocrinological Investigation 40, no. 4 (October 26, 2016): 367–76. http://dx.doi.org/10.1007/s40618-016-0569-7.

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21

Juhasz, A., A. Fehér, A. Rimanóczy, M. Gálfi, J. Kálmán, and Z. Janka. "P.1.a.007 The role of insulin receptor substrate-1 Gly972Arg polymorphism in the pathogenesis of Alzheimer's disease." European Neuropsychopharmacology 19 (September 2009): S228—S229. http://dx.doi.org/10.1016/s0924-977x(09)70323-2.

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22

Van Dam, R. M., B. Hoebee, J. C. Seidell, M. M. Schaap, E. E. Blaak, and E. J. M. Feskens. "The insulin receptor substrate-1 Gly972Arg polymorphism is not associated with Type 2 diabetes mellitus in two population-based studies." Diabetic Medicine 21, no. 7 (April 13, 2004): 752–58. http://dx.doi.org/10.1111/j.1464-5491.2004.01229.x.

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23

Valdés, Patricio, Alvaro Cerda, Cristobal Barrenechea, Marlene Kehr, Carolina Soto, and Luis A. Salazar. "No association between common Gly972Arg variant of the insulin receptor substrate-1 and polycystic ovary syndrome in Southern Chilean women." Clinica Chimica Acta 390, no. 1-2 (April 2008): 63–66. http://dx.doi.org/10.1016/j.cca.2007.12.018.

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24

Dravecká, Ingrid, Ivica Lazúrová, and Viera Habalová. "The prevalence of Gly972Arg and C825T polymorphisms in Slovak women with polycystic ovary syndrome and their relation to the metabolic syndrome." Gynecological Endocrinology 26, no. 5 (February 19, 2010): 356–60. http://dx.doi.org/10.3109/09513590903511497.

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25

Rasool, Shayaq Ul Abeer, Mudasar Nabi, Sairish Ashraf, and Shajrul Amin. "Insulin Receptor Substrate 1 Gly972Arg (rs1801278) Polymorphism Is Associated with Obesity and Insulin Resistance in Kashmiri Women with Polycystic Ovary Syndrome." Genes 13, no. 8 (August 17, 2022): 1463. http://dx.doi.org/10.3390/genes13081463.

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Background: Polycystic ovary syndrome (PCOS) is commonly associated with metabolic abnormalities such as hyperinsulinemia, insulin resistance and obesity. The genetic variants of genes regulating insulin action, expression and regulation are suggested as possible factors involved in development and severity of clinical manifestations in PCOS. Aim: We investigated whether IRS-1Gly972Arg (rs1801278) polymorphism is associated with increased risk of PCOS in Kashmiri women. The correlation of various clinical, metabolic and hormonal markers with rs1801278 single nucleotide polymorphism was analyzed. The genotypic–phenotypic association of clinical manifestations of PCOS with the tested genetic variant was also assessed. Results: There were no significant differences in allele frequency (OR = 0.87, CI = 0.59–1.29, χ2 = 0.456, p = 0.499) or genotypic distribution (χ2 = 3.73, p = 0.15) between PCOS women and controls. No significant association was also found in the dominant (OR = 1.63, χ2 = 0.377, p = 0.53), recessive (OR = 0.79, χ2 = 1.01, p = 0.31) or heterozygote vs. homozygote (OR = 1.34, χ2 = 1.53, p = 0.22) genotype model analysis. The genotype–phenotype correlation analysis showed that the Arg allele was significantly associated with increased central adiposity markers hip circumference (p = 0.012), and body adiposity index BAI (p = 0.002) in the recessive model in PCOS women. The two-hour glucose (p = 0.04) and insulin resistance marker HOMA (p = 0.44) were significantly higher in Arg allele carriers. The androgen excess markers dehydroepiandrosterone sulfate DHEAS (p = 0.02), Ferriman–Gallwey score (p = 0.012), prevalence of acne, alopecia and hirsutism (all p < 0.01) were significantly elevated in the wild-type GG genotype. Conclusions:IRS-1Gly972Arg genetic variant does not increase the risk of PCOS in Kashmiri women. However, this polymorphism is associated with clinical manifestations of insulin resistance, obesity and hyperandrogenism, suggesting its possible role in variable phenotypic manifestations of PCOS.

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Permana, Hikmat, Gaga Irawan Nugraha, and Sri Hartini K. S. Kariadi. "Polimorfisme Gly972Arg Gen IRS-1 dan Cys981Tyr Gen PTPN1 sebagai Faktor Risiko pada Sindrom Metabolik dengan Riwayat Berat Bayi Lahir Rendah." Majalah Kedokteran Bandung 44, no. 3 (2012): 170–78. http://dx.doi.org/10.15395/mkb.v44n3.137.

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27

Jellema, A., M. P. A. Zeegers, E. J. M. Feskens, P. C. Dagnelie, and R. P. Mensink. "Gly972Arg variant in the insulin receptor substrate-1 gene and association with Type 2 diabetes: a meta-analysis of 27 studies." Diabetologia 46, no. 7 (July 1, 2003): 990–95. http://dx.doi.org/10.1007/s00125-003-1126-4.

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Alsalman, Hawra, and Yahia Kaabi. "Lack of association between the insulin receptor substrates-1 Gly972Arg polymorphism and type-2 diabetes mellitus among Saudis from Eastern Saudi Arabia." Saudi Medical Journal 36, no. 12 (December 1, 2015): 1420–24. http://dx.doi.org/10.15537/smj.2015.12.12904.

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29

Bezerra, R. M. N., V. de Castro, T. Sales, R. Passini, S. T. M. Marba, S. T. O. Saad, and M. J. A. Saad. "The Gly972Arg Polymorphism in Insulin Receptor Substrate-1 Is Associated With Decreased Birth Weight in a Population-Based Sample of Brazilian Newborns." Diabetes Care 25, no. 3 (March 1, 2002): 550–53. http://dx.doi.org/10.2337/diacare.25.3.550.

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30

Hölzl, B., B. Iglseder, A. Stadlmayr, M. Hedegger, E. Moré, R. Reiter, F. Sandhofer, and B. Paulweber. "Intima media thickness of carotid arteries is reduced in heterozygous carriers of the Gly972Arg variant in the insulin receptor substrate-1 gene." European Journal of Clinical Investigation 33, no. 2 (February 2003): 110–16. http://dx.doi.org/10.1046/j.1365-2362.2003.01113.x.

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31

Strohmer, B., R. Reiter, B. Holzl, and B. Paulweber. "Lack of association of the Gly972Arg mutation of the insulin receptor substrate-1 gene with coronary artery disease in the Austrian population." Journal of Internal Medicine 255, no. 1 (January 2004): 146–47. http://dx.doi.org/10.1046/j.0954-6820.2003.01251.x.

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32

Arikoglu, Hilal, Melda Aksoy Hepdogru, Dudu Erkoc Kaya, Aycan Asik, Suleyman Hilmi Ipekci, and Funda Iscioglu. "IRS1 gene polymorphisms Gly972Arg and Ala513Pro are not associated with insulin resistance and type 2 diabetes risk in non-obese Turkish population." Meta Gene 2 (December 2014): 579–85. http://dx.doi.org/10.1016/j.mgene.2014.07.008.

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33

Stumvoll, M., A. Fritsche, A. Volk, N. Stefan, A. Madaus, E. Maerker, A. Teigeler, M. Koch, F. Machicao, and H. Haring. "The Gly972Arg Polymorphism in the Insulin Receptor Substrate-1 Gene Contributes to the Variation in insulin Secretion in Normal Glucose-Tolerant Humans." Diabetes 50, no. 4 (April 1, 2001): 882–85. http://dx.doi.org/10.2337/diabetes.50.4.882.

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34

Dongiovanni, P., L. Valenti, R. Rametta, A. K. Daly, V. Nobili, E. Mozzi, J. B. S. Leathart, et al. "Genetic variants regulating insulin receptor signalling are associated with the severity of liver damage in patients with non-alcoholic fatty liver disease." Gut 59, no. 2 (February 2010): 267–73. http://dx.doi.org/10.1136/gut.2009.190801.

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Background/aimsThe aim of this study was to assess the effect of functional ENPP1(ectoenzyme nucleotide pyrophosphate phosphodiesterase 1)/PC-1 (plasma cell antigen-1) and IRS-1 (insulin receptor substrate-1) polymorphisms influencing insulin receptor activity on liver damage in non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome, whose progression is associated with the severity of insulin resistance.Patients and methods702 patients with biopsy-proven NAFLD from Italy and the UK, and 310 healthy controls. The Lys121Gln ENPP1/PC-1 and the Gly972Arg IRS-1 polymorphisms were evaluated by restriction analysis. Fibrosis was evaluated according to Kleiner. Insulin signalling activity was evaluated by measuring phosphoAKT levels by western blotting in a subset of obese non-diabetic patients.ResultsThe ENPP1 121Gln and IRS-1 972Arg polymorphisms were detected in 28.7% and 18.1% of patients and associated with increased body weight/dyslipidaemia and diabetes risk, respectively. The ENPP1 121Gln allele was significantly associated with increased prevalence of fibrosis stage >1 and >2, which was higher in subjects also positive for the 972Arg IRS-1 polymorphism. At multivariate analysis, the presence of the ENPP1 121Gln and IRS-1 972Arg polymorphisms was independently associated with fibrosis >1 (OR 1.55, 95% CI 1.24 to 1.97; and OR 1.57, 95% CI 1.12 to 2.23, respectively). Both polymorphisms were associated with a marked reduction of ∼70% of AKT activation status, reflecting insulin resistance and disease severity, in obese patients with NAFLD.ConclusionsThe ENPP1 121Gln and IRS-1 972Arg polymorphisms affecting insulin receptor activity predispose to liver damage and decrease hepatic insulin signalling in patients with NAFLD. Defective insulin signalling may play a causal role in the progression of liver damage in NAFLD.

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Grigorescu, Florin, Corinne Lautier, Samira Ait El Mkadem, Francoise Macari, Jean-Frederic Brun, Jean-Christophe Gris, Janice Guttierez, et al. "Gly1057Asp allelic variant of IRS-2 gene has synergistic effect with Gly972Arg variant of IRS-1 on insulin secretion in obesity and NIDDM." Diabetes Research and Clinical Practice 50 (September 2000): 226. http://dx.doi.org/10.1016/s0168-8227(00)82228-7.

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Vergotine, Zelda, Andre Pascal Kengne, Rajiv Timothy Erasmus, and Tandi Edith Matsha. "No evidence for association of insulin receptor substrate-1 Gly972Arg variant with type 2 diabetes mellitus in a mixed-ancestry population of South Africa." South African Medical Journal 104, no. 6 (May 12, 2014): 420. http://dx.doi.org/10.7196/samj.7419.

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Kazumian, M. A., I. G. Kozlov, A. V. Vasilenok, E. D. Teplyakova, and T. P. Shkurat. "NOD2 GENE POLYMORPHISM IN CHILDREN WITH RECURRENT RESPIRATORY INFECTIONS." Pediatria. Journal named after G.N. Speransky 101, no. 2 (April 15, 2022): 38–43. http://dx.doi.org/10.24110/0031-403x-2022-101-2-38-43.

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The highest incidence rate is recorded among children with recurrent respiratory infections (RRI). It has been shown that changes in the NOD2 gene, which encodes the innate immunity receptor, can be factors in susceptibility to viral pathogens. The aim of the study was to analyze the polymorphism of the NOD2 gene in children with RRI. Materials and methods of research: a single-center cohort observational retrospective cohort study was carried out. The study was conducted among children aged 1–18 years. The study included 500 patients with an annual number of proven RRI episodes of at least 6 in the last year in relation to the date of the start of the study (10.01.2017–12.31.2019; mean age 15±2.7 years, male sex 51.2%) and 100 conditionally healthy children included in the control group (mean age 12±2.6, male sex 48.0%). Leu1007fsinsC, Cly908Arg, and Arg702Trp, polymorphic variants of the NOD2 gene were determined by the allele-specific polymerase chain reaction (PCR). Results: it was found that in children with the insertion of the nucleotide «C» (Leu1007fsinsC), the chance of developing RRI is higher compared to other NOD2 gene polymorphism. Age-specific features of the occurrence of the Leu1007fsinsC polymorphism of the NOD2 gene in patients with the N/insC genotype were revealed. Conclusion: there were no statistically significant differences in the frequency of occurrence of polymorphic variants Arg702Trp (2104 С>T) и Gly908Arg (2722G>C) of the NOD2 gene in children with RRI compared with the control group. The predisposition of children to RRI may be associated with a Leu1007fsinsC polymorphisms of the NOD2 gene. These data require further study and may be useful for the development of new approaches to personalized RRI therapy, since the use of pattern recognition receptors (PRRs) agonists and drugs that modulate PRR-mediated signaling pathways is the most rational therapeutically effective approach for children with RRI.

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El Mkadem, S. A., C. Lautier, F. Macari, N. Molinari, P. Lefebvre, E. Renard, J. C. Gris, et al. "Role of Allelic Variants Gly972Arg of IRS-1 and Gly1057Asp of IRS-2 in Moderate-to-Severe Insulin Resistance of Women With Polycystic Ovary Syndrome." Diabetes 50, no. 9 (September 1, 2001): 2164–68. http://dx.doi.org/10.2337/diabetes.50.9.2164.

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Haghani, Karimeh, and Salar Bakhtiyari. "The Study on the Relationship Between IRS-1 Gly972Arg and IRS-2 Gly1057Asp Polymorphisms and Type 2 Diabetes in the Kurdish Ethnic Group in West Iran." Genetic Testing and Molecular Biomarkers 16, no. 11 (November 2012): 1270–76. http://dx.doi.org/10.1089/gtmb.2012.0160.

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Burguete-Garcia, Ana I., Miguel Cruz-Lopez, Vicente Madrid-Marina, Ruy Lopez-Ridaura, Mauricio Hernández-Ávila, Bernardo Cortina, Rosa E. Gómez, and Eduardo Velasco-Mondragón. "Association of Gly972Arg polymorphism of IRS1 gene with type 2 diabetes mellitus in lean participants of a national health survey in Mexico: a candidate gene study." Metabolism 59, no. 1 (January 2010): 38–45. http://dx.doi.org/10.1016/j.metabol.2009.07.007.

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Rashidi, Batool, Leila Azizy, Farhad Najmeddin, and Ebrahim Azizi. "Prevalence of the insulin receptor substrate-1(IRS-1) Gly972Arg and the insulin receptor substrate-2(IRS-2) Gly1057Asp polymorphisms in PCOS patients and non-diabetic healthy women." Journal of Assisted Reproduction and Genetics 29, no. 2 (December 29, 2011): 195–201. http://dx.doi.org/10.1007/s10815-011-9693-7.

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Vergotine, Zelda, Yandiswa Y. Yako, Andre P. Kengne, Rajiv T. Erasmus, and Tandi E. Matsha. "Proliferator-activated receptor gamma Pro12Ala interacts with the insulin receptor substrate 1 Gly972Arg and increase the risk of insulin resistance and diabetes in the mixed ancestry population from South Africa." BMC Genetics 15, no. 1 (2014): 10. http://dx.doi.org/10.1186/1471-2156-15-10.

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Sir-Petermann, Teresa, Barbara Angel, Manuel Maliqueo, José Luis Santos, María Virginia Riesco, Henry Toloza, and Francisco Pérez-Bravo. "Insulin secretion in women who have polycystic ovary syndrome and carry the Gly972Arg variant of insulin receptor substrate-1 in response to a high-glycemic or low-glycemic carbohydrate load." Nutrition 20, no. 10 (October 2004): 905–10. http://dx.doi.org/10.1016/j.nut.2004.08.017.

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Odes, Shmuel, Michael Friger, Hillel Vardi, Greet Claessens, Xavier Bossuyt, Lene Riis, Pia Munkholm, et al. "Role of ASCA and the NOD2/CARD15 mutation Gly908Arg in predicting increased surgical costs in Crohnʼs disease patients: A project of the European Collaborative Study Group on Inflammatory Bowel Disease." Inflammatory Bowel Diseases 13, no. 7 (July 2007): 874–81. http://dx.doi.org/10.1002/ibd.20122.

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Giandalia, Annalisa, Maria Angela Pappalardo, Giuseppina T. Russo, Elisabetta L. Romeo, Angela Alibrandi, Flavia Di Bari, Roberto Vita, Domenico Cucinotta, and Salvatore Benvenga. "Influence of peroxisome proliferator-activated receptor-γ exon 2 and exon 6 and insulin receptor substrate (IRS)-1 Gly972Arg polymorphisms on insulin resistance and beta-cell function in southern mediterranean women with polycystic ovary syndrome." Journal of Clinical & Translational Endocrinology 13 (September 2018): 1–8. http://dx.doi.org/10.1016/j.jcte.2018.05.002.

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Lange, Andrzej, Sylwia Mizia, Jolanta Bochenska, Przemyslaw Czajka, Janusz Lange, Monika Mordak, and Dorota Dlubek. "Th17 Cells Blood Proportions Are Influenced by Factors Associated with CRP Serum Level Increase and with NOD2/CARD15 Gene Mutation." Blood 120, no. 21 (November 16, 2012): 4487. http://dx.doi.org/10.1182/blood.v120.21.4487.4487.

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Abstract Abstract 4487 HLA mismatch constitute the risk of aGvHD. However, environmental factors play a significant role what is exemplified by the protective effect of germ free environment. This association can be discussed on the ground of a significant role of cytokine milieu which determines lymphocytes subsets differentiation. Our previous work showed a decrease of proportions of Th17 cells in blood at the onset of aGvHD (Dlubek et al., Transplantation Proceedings 2010; 42(8):3277-9). These cells, however, were seen at the tissue site likely being marginalized during aGvHD process. In this study we looked at Th17 lymphocytes proportions in blood of patients post alloHSCT in the context of an increase of C-reactive protein in serum and NOD2/CARD15 gene mutations. Eighty four patients (median age: 41 yrs, range: 1–64 yrs) entered the study. All of them were clinically followed for the presence of infections complications and aGvHD. Blood work was done at the very first day of the later complications and in addition routinely in one week intervals beginning from the day of transplantation. The cells were labeled for CD4 (Becton Dickinson, San Jose, CA, USA), intracellular IL-17A (e-biosciences, San Diego, CA, U04)SA) and FoxP3 (Becton Dickinson, San Jose, CA, USA) detection. CRP was measured in serum using a Behring BN Prospect nephelometer (Dade Behring Inc., Marburg, Germany). All studied cases were genotyped for NOD2/CARD15 mutations: 104C-T (SNP8, Arg702W; rs.2066844), 2722G-C (SNP12, Gly908Arg; rs.2066845), and 3020insC (SNP13, Leu1007fsinsC; rs.2066847) with the use of RFLP-PCR technique. It was found: Acute GvHD manifestation was seen in 34 (40%) patients among them 22 (26%) had only skin symptoms and 12 (14%) presented gut manifestation. Gut aGvHD was seen at later time post HSCT than skin aGvHD (median 33 vs. 21 days, M-W U test p=0.035).Twelve patients had NOD2/CARD15 mutations. They had lower proportions of Th17 lymphocytes in blood as compared to those lacking these mutations (median 0.03 vs. 0.07%, M-W U test p=0.052) and 6 (50%) of them presented aGvHD.CRP levels measured from 3 to 5 days before clinically apparent aGvHD were significantly higher in patients with gut symptoms as compared to those presented only skin lesions (median 66.8 vs. 7.61 mg/L, M-W U test p=0.020). Notably, patients having only skin symptoms had rather lower CRP levels in sera than those without aGvHD (median 7.61 vs. 27.6 mg/L, M-W U test p=0.028).In patients with gut manifestation FoxP3+CD4+ cells proportions were negatively correlated with serum CRP levels (Spearman r −0.664, p=0.018) what was not seen in patients presented only skin symptoms aGvHD (0.068, p=0.769). In conclusion: CRP elevation constituted the risk of gut aGvHD and was associated with rather exhausted T regulatory cell function. NOD2/CARD15 mutations associated factors contributed to the lowering of Th17 cells in blood what was previously found to be associated with the overt manifestation of aGvHD (Dlubek et al., Transplantation Proceedings 2010; 42(8):3277-9). These both findings are in line with the hypothetical role of microbial pathogens which via inflammation favor differentiation of lymphocytes to Th17 positive cell subset. Disclosures: No relevant conflicts of interest to declare.

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Lange, Andrzej, Krzysztof Suchniski, Sylwia Mizia, Przemyslaw Czajka, Lach Antonina, and Dlubek Dorota. "Low Blood Levels of Th17 Cells Are Seen in Patients with aGvHD and Associate with Rather Poor Survival Post HSCT,." Blood 118, no. 21 (November 18, 2011): 4079. http://dx.doi.org/10.1182/blood.v118.21.4079.4079.

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Abstract Abstract 4079 Alloreactivity strongly influences the course post HSCT being a primary force in pathomechanism of aGvHD, shapes the immunological reconstitution post-transplant and mounts graft vs leukemia effect. Therefore the understanding of the interplay between the main subsets of CD4 positive cells may help in understanding the mechanism which facilitates the activity of the immune system post HSCT. For that we investigated the presence of cells with a potential to generate IL-17, IFN-gamma and FoxP3 lymphocytes appearing in blood to post HSCT. The cytoplasmic expressions of IL-17A, FoxP3 and IFN-gamma were studied in stimulated PBMC (brefeldin A, Ionomycin and PMA) of alloHSCT patients (63 patients, median age: 43 yrs, range: 5.5 –60 yrs), 12 patients manifested aGvHD at the time of hematological recovery and in 17 patients aGvHD was clinically apparent after hematological reconstitution (from 17 to 93, median 31). The cells were labeled for CD4 (Becton Dickinson, San Jose, CA, USA) and intracellular IL-17A (e-biosciences, San Diego, CA, USA), FoxP3 and IFN-gamma (Becton Dickinson, San Jose, CA, USA) detection. All studied cases were genotyped for NOD2/CARD15 mutations: 104C-T (SNP8, Arg702W; rs.2066844), 2722G-C (SNP12, Gly908Arg; rs.2066845), and 3020insC (SNP13, Leu1007fsinsC; rs.2066847) with the use of RFLP-PCR technique. Patients post HSCT studied at the beginning of hematological recovery (1st observation point) had lower blood levels of IL-17 producing lymphocytes in CD4+ cells (Th17) independently whether they developed aGvHD at the hematological recovery or (later time) post-transplant as compared to those lacking aGvHD (median 0.090% (0.195%) vs 0.425%, p=0.019 (p=0.126)). Primarily low Th17 blood level in aGvHD cases normalized (increased) along the observation time, when a positive response to the therapy was noticed, being in one week intervals in the levels as follow (1st vs 2nd (3rd) time point: median 0.090% vs 0.355% (0.355%), p=0.049 (p=0.061)). Of note, patients lacking aGvHD at any time post HSCT had similar blood levels of Th-17 cells during 30 days post-transplant observation time. The first quartile of Th17 blood values of the whole group was 0.1% and this value was chosen as a cut-off point dividing the whole group into patients with low and higher blood Th17 levels. It became apparent that survival of patients having low Th17 blood levels at the beginning of hematological recovery, irrespective of the presence of absence of aGvHD, had poorer survival (2 yrs survival 30% vs 61%, p=0.045). When fatal cases were analyzed patients with low Th17 blood levels died rather due to aGvHD and those with higher levels due to infectious complications or relapse (7/10 vs 4/16, p=0.043). FoxP3+ cells and IFN-gamma producing lymphocytes were determined in blood of HSCT patients at the same time as it was done for Th17 cells. It was shown that the blood levels of FoxP3+ cells were well correlated with the levels of IFN-gamma producing cells (r=0.405, p=0.003) but not to the similar extent with Th17 cells (r=0.253, p=0.047). Th17 plays an important role in the mucous membrane barrier against microbial infections. Mutations in NOD2/CARD15 gene are described as a risk factor of aGvHD. We found that mutations in the NOD2/CARD15 gene is not more frequent in aGvHD cases but influences the level of Th17 in blood in such a way that patients with mutations had lower blood values of Th17 at the hematological recovery in the aGvHD group (median 0.080% vs 0.210%, p=0.051) as well as in the whole alloHSCT patient group (median 0.080% vs 0.310%, p=0.027). Conclusions: 1.Th17 lymphocytes being lower at the beginning of aGvHD manifestation likely to marginalize at the sites of inflammation. 2.Low levels of Th17 were associated with rather poor survival of HSCT pts with aGvHD as a primary cause of death. 3.NOD2/CARD15 mutations associate with lower values of Th17 in blood. Supported by the grants N N402 430039 and N R13 0082 06 from the Polish Ministry of Science & Higher Education. Disclosures: No relevant conflicts of interest to declare.

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Lange, Andrzej, Antonina Lach, Wojtowicz Agnieszka, Daria Drabczak-Skrzypek, and Dlubek Dorota. "TH17 CD4+ CELLS Disappear FROM BLOOD at the Onset of aGVHD." Blood 116, no. 21 (November 19, 2010): 2307. http://dx.doi.org/10.1182/blood.v116.21.2307.2307.

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Abstract Abstract 2307 IL-17 producing cells expand in the environment rich in IL-6 and TGF-beta. Our previous observation documented an increase in IL-6 and its reading protein CRP during the hematological recovery and later on at the time of frequent infectious complications. Therefore, HSCT patients are in a high risk of the expansion of Th17 lymphocytes which are potent pro-inflammatory lymphocytes. In this study we investigated the proportions of IL-17 producing cells in 7 days intervals beginning from hematological recovery covering the time of a risk of aGvHD and infectious complications post transplant. To illustrate the background to the generation of Th17+ lymphocytes serum CRP levels were measured and the manifestation of aGvHD was noted and followed. This study included also determination of NOD2/CARD15 gene mutation. The cytoplasmic expressions of IL-17A were studied in stimulated PBMC (brefeldin A, Ionomycin and PMA) of alloHSCT pts (58 pts, median age: 42 yrs, range; 1.0–64 yrs), 14 patients manifested aGvHD at the time of hematological recovery and in 13 patients with aGvHD was clinically apparent later time post HSCT (from 18 to 93, median 36). The cells were labeled for CD4 (Becton Dickinson, San Jose, CA, USA) and intracellular IL-17A (e-biosciences, San Diego, CA, USA) detection. Fifty six transplanted cases were genotyped for 2104C-T (SNP8, Arg702W; rs.2066844), 2722G-C (SNP12, Gly908Arg; rs.2066845), and 3020insC (SNP13, Leu1007fsinsC; rs.2066847) mutations with the use of RFLP-PCR technique. We found: (1) 14 pts with aGvHD seen at the time of hematological recovery (median 15.5 days, from 9 to 21 days post HSCT, when WBC > 500/ul and lymphocytes > 200/ul,) had lower percentages of IL-17A producing cells in CD4+ lymphocyte population as compared to those lacking aGvHD at the same stage of recovery (median 15 days, from 10 to 31), (0.29%±0.09 vs 0.78%±0.13, p=0.02, M-W U-Test). (2) 13 pts with aGvHD seen between 18 to 93 day post HSCT (median 36) had also lower percentage of IL-17A producing cells in CD4+ lymphocytes as compared to those lacking aGvHD and examined for the presence of IL-17A+ lymphocytes at the similar time post HSCT (median 35 day, from 27 to 43), (0.29±0.10 vs 0.99%±0.25, p=0.015 M-W U-Test), (2) manifestation of aGvHD at later time post HSCT allowed to examine the presence of IL-17A producing CD4+ lymphocytes prior to and then at the aGvHD manifestation. It was a significant decrease in proportions of IL-17A producing CD4+ lymphocytes at the day of aGvHD manifestation as compared to previous examinations performed 3 to 7 days before aGvHD became clinically apparent (1.02%±0.33 vs 0.29%±0.10, n=13, p=0.0009, Wilcoxon Test for pairs). Among these 13 pts 6 had only skin and 7 also gastrointestinal aGvHD, the latter pts had lower percentage of IL-17A producing CD4+ lymphocytes than those with only skin lesions (0.21%±0.08 vs 1.33%±0.47, for gut and skin aGvHD, respectively). 3) 5 out of 56 (8.9%) transplanted cases were positive for at least one out of three major NOD2/CARD15 mutations (SNP8, SNP12 and SNP13), notably all 3 patients with gut manifestation and investigated for NOD2/CARD15 mutation had this gene mutated what was seen only in 4 out of 17 pts with skin symptoms (p=0.017 Fisher exact test). In the present observation no correlation was found between CRP elevation and the proportion of IL-17 producing cells in CD4+ lymphocytes. Conclusions; 1. Apparent clinical manifestation of aGvHD associates with a low proportion of Th17 lymphocytes in blood, 2. This is rather an active process as Th17+ cells proportions decline in blood during 3 to 7 days prior to overt aGvHD. 3. Gut manifestation associates with significantly lower number of blood Th17+ lymphocytes than seen in pts with only skin lesions. 4. NOD2 mutation may constitute a risk factor of gut aGvHD. Supported by grant N R13 0082 06 from the Polish Ministry of Science & Higher Education. Disclosures: No relevant conflicts of interest to declare.

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Kirschner, Martin, Benjamin Rolles, Martina Crysandt, Christoph Röllig, Friedrich Stolzel, Martin Bornhäuser, Carsten Müller-Tidow, et al. "Prevalence of Inherited Predisposition Syndromes in Young Patients with Acute Myeloid Leukemia and Aberrant Karyotype." Blood 136, Supplement 1 (November 5, 2020): 41–42. http://dx.doi.org/10.1182/blood-2020-142815.

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Introduction Recent studies indicate that particularly in a subgroup of younger patients, acute myeloid leukemia (AML) develops due to an inherited genetic predisposition linked to mutations in genes such as ANKRD26, SAMD9, SAMD9-L, GATA-2, genes causing telomere biology disorders or Shwachman-Diamond syndrome. However, the prevalence of so-called "AML predisposition syndromes" (APS) underlying newly diagnosed cases with AML is unknown. Actual screening strategies for APS are based on the family history and clinical/genetic features. There is growing evidence that APS frequently manifest themselves with an oligosymptomatic phenotype or are lacking specific symptoms altogether. Furthermore, molecular analysis of the clonal population without additional analysis of non-clonal cells do not allow the discrimination between inherited and acquired changes. Thus, new approaches to identify the subset of patients with underlying APS in adult newly diagnosed AML patients are needed. One frequent feature observed in APS is younger age at the time of diagnosis and the initial presence of an aberrant karyotype. Along this line, we retrospectively screened the German SAL-AML registry using age and the presence of an aberrant karyotype as pre-defining parameters to analyze the prevalence of APS in this selected cohort. Patients and methods The database of the German SAL-AML registry includes over 5207 patients with AML. We screened for patients below 35 years of age and with any type of numerical or structural chromosomal aberration at first diagnosis. DNA samples of patients achieving cytological remission (CR) and available samples of peripheral blood or bone marrow were selected. CR samples were chosen to reduce potential contamination by malignant AML blasts. Patients were screened for pathogenic variants using a self-designed NGS panel containing the entire coding sequences of ACD, ANKRD26, CTC1, DDX41, DKC1, ERCC6, ETV6, GATA1, GATA2, LIG4, NHP2, NOP10, PARN, POT1, RPA1, RPL11, RPL15, RPL26, RPL35A, RPL5, RPS10, RPS17, RPS19, RPS24, RPS26, RPS7, RTEL1, SAMD9, SAMD9L, SBDS, SRP72, TERC, TERF1, TERF2, TERT, TINF2, TPP1 and WRAP53. An inherited variant was considered in all patients with a variant allele frequency between 40-60% for heterozygous variants and >90% for homozygous ones. To analyze the functional consequence of SAMD9 variants, proliferation assays with HEK293 cells transfected with the respective identified variant was carried out. Results and discussion On the basis of the inclusion criteria mentioned above, we were able to identify 41 patients. All cases except one were considered de novo AML by the treating physicians and received an anthracycline/cytarabine based induction chemotherapy. Mean age of the 41 patients was 26 ± 5 years (mean ± S.D.). Predominant karyotypic aberration were abnormalities of chromosome 8 (18/41) as well as a complex aberrant karyotype (29/41). NGS analysis revealed five different heterozygous mutations in approx. 10% (4/41) of patients: GATA2 c.1009C>T p.(Arg337Ter), SBDS c.183_184delInsCT and c.258+2T>C (both mutations in the same patient), TINF2 c.848C>A p.(Pro283His), SAMD9 c.2854G>C p.(Gly952Arg). The variants in GATA2, SBDS and TINF2 are known to be pathogenic. For SAMD9, in vitro experiments showed increased inhibition of cell growth compared to wild-type supporting the pathogenicity of the mutation. Focusing on the clinical outcome, 50% (2/4) of the identified APS patients received allogeneic transplantation during follow-up compared to 65% (24/37) in the group without detectable mutations. Median survival in the APS group was significantly shorter with 3.2 months compared to 105.3 months in the remaining 37 AML patients (p<0.001). Conclusions Using age and karyotype as selection criteria, we were able to identify an inherited APS in 10% of newly diagnosed AML patients below 35 years with chromosomal aberrations reaching CR. Obviously, our study is limited by rather stringent inclusion criteria not allowing overall conclusions on the incidence of APS in newly diagnosed AML. However, age and karyotype might provide simple clinical parameters to trigger genetic screening for inherited APS in addition to the actual recommendations. Given the significant difference in survival in patients with and without underlying APS, our study clearly supports inclusion of screening for APS in this cohort pending prospective validation. Figure Disclosures Röllig: Amgen, Astellas, BMS, Daiichi Sankyo, Janssen, Roche: Consultancy; Abbvie, Novartis, Pfizer: Consultancy, Research Funding. Müller-Tidow:Daiichi Sankyo: Research Funding; Pfizer: Research Funding, Speakers Bureau; Janssen-Cilag GmbH: Speakers Bureau; BiolineRx: Research Funding. Panse:Blueprint Medicines: Consultancy, Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Chugai: Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees; Grunenthal: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Apellis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Brümmendorf:Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Novartis: Consultancy, Other: travel, accommodation, expenses, Research Funding; Janssen: Consultancy; Merck: Consultancy; Takeda: Consultancy. Jost:Roche: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Celgene: Other: travel support; JAZZ: Other: travel support.

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Nguyen, Thu. "THE ASSOCIATION BETWEEN THE GLY972ARG POLYMORPHISM IN IRS1 GENE AND THE RISK OF PREDIABETES AMONG VIETNAMESE WOMEN." VNU Journal of Science: Medical and Pharmaceutical Sciences 34, no. 2 (December 24, 2018). http://dx.doi.org/10.25073/2588-1132/vnumps.4129.

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Insulin receptor substrate 1 (IRS1) is a ligand of the insulin receptor tyrosine kinase and participates in the insulin receptor signal transduction pathway. Dysregulations in IRS1 expression and function increase incidence of insulin-resistant states such as prediabetes and type 2 diabetes. The study aimed to investigate the association of the Gly972Arg (rs1801278) polymorphism in IRS1 gene with prediabetes in Northern Vietnamese women. The case-control study consisted of 1617 women (250 prediabetic cases and 1367 normoglycemic controls). The IRS1 Gly972Arg polymorphism was genotyped in these subjects using polymerase chain reaction–restriction fragment length polymorphism. The frequency of the ‘‘A’’ allele of the Gly972Arg (G>A) polymorphism was similar between the normal glucose and prediabetic subjects (2.7% and 2.6%, respectively). There was no significant difference in the genotypic frequency between the control and prediabetic cases (P = 0.673). The IRS1 Gly972Arg polymorphism was not associated with the risk of prediabetes in Vietnamese women before and after adjusted for socio-economic, lifestyles and clinical factors (P > 0.05).

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