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PO085 MARKERS OF GENETIC SUSCEPTIBILITY TO TYPE 2 DIABETES MELLITUS IN YAKUTIAN POPULATION
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Posters / Diabetes Research and Clinical Practice 106S1 (2014) S47–S267
software, the DNA sequences were aligned and converted into amino acid sequences by using BioEdit & BLAST program from NCBI, and superimpose analysis by Strap JAVA program, 2D- & 3D-structure analysis Swiss Model program by Pymol, SSpro, Phyre dan Metaserverm, 3DJigSaw software from web service Swiss Model. To examine the cytoplasm tyrosine kinase pathway using docking INSR-TyrKinase domain & IRS-1 (PTB domain) analyzed by by using HEX 6.12 software and the ligand details interaction was detected by virtual screening of LigandScout and were performed with the UCSF Chimera package. Result: The result of this study found some deletions and substitutions mutation of DNA sequence on exon 22 of hINSR gene of DM patients from Saeful Anwar hospital, Malang. These mutations of exon 22 hINSR gene is on TyrKinase domain of hINSR protein that located in cytoplasm was reducing stimulating IRS-1 activation and intracellular signaling. Physics-chemistry analysis shown that TyrKinase hINSR was weakly interacted with IRS-1 PTB domain, however, there is reducing activation of IRS-2 PTB domain. These were inhibitions disrupting in GLUT-4 protein releasing from GLUT-4 vesicle on glucose uptake . This mechanism could state that mutation of exon 22 coded TyrKinase hINSR C-terminal region disrupt metabolic signaling pathway. We suggested that the INSR protein mutation of DM patient precede abnormally INSR function against TyrKinase and perhaps correlated with genetic syndrome of insulin resistance. The change function is presumed to inhibit the interaction between INSR and IRS, makes transduction signals disturbance in the process of absorption of glucose leads to insulin resistance of diabetes mellitus. Conclusion: This study finding indicated that the genetic background of DM patients is individually as potential factor leading to provide or inhibit TyrKinase signaling pathway susceptability with diabetes disease. Keywords: Diabetes, insulin, insulin receptor, in silico, tyrosine kinase signaling pathway Reference(s) Longo N, Wang Y, Smith SA, Langley SD, DiMeglio LA, GiannellaNeto D (2002). Genotype-phenotype correlation in inherited severe insulin resistance. Hum. Mol. Genet. 11 (12): 1465–75. Taniguchi, C. M., Emanuelli, B., and Kahn, C. R. 2006. Critical nodes in signaling pathways: insights into insulin action. Nature reviews. Molecular cell biology , 7 (2): 85–96. doi: 10.1038/nrm1837.
PO085 MARKERS OF GENETIC SUSCEPTIBILITY TO TYPE 2 DIABETES MELLITUS IN YAKUTIAN POPULATION I.V. Osokina1 , P. Ignatev2 , F.A. Platonov1,3 , L. Goldfarb4 , V. Osakovskiy5 . 1 Endocrinology, State Research Institute for Medical Studies of the North, Krasnoyarsk, 2 Endocrinology, 3 Director, National Medical Research Center “Institute of Health”, Sakha Republic, Yakutsk, Russian Federation ; 4 Genetics, NINDS/NIH, Clinical Neurogenetics Unit, National Institute of Neurological Disorders and Stroke, NIH„ Bethesda, United States ; 5 Genetics, National Medical Research Center “Institute of Health”, Sakha Republic, Yakutsk, Russian Federation Background: Type 2 diabetes mellitus (DM2) is considered as disease with the essential genetic component, which is confirmed by a family aggregation and studies on the hybrid populations with the high frequency of disease. The achievements of world molecular genetics in recent years it led to the discovery of the numerous genes of receptivity to DM 2 types, which feeds large hopes for the improvement of early diagnostics, and also effective therapy on the basis of the determination of individual genetic profile. Aim: To analyze the genetic factors, which influence on the risk of the development of type 2 diabetes mellitus (DM2) in the Yakut population.
Method: We examined 552 representatives of the Yakut nationality. Genetic studies were carried out in 204 patients with type 2 diabetes (63 men and 141 women), and 348 controls without the DM heredity (136 men and 212 women). Average age of patients was 60±12.2 years, in the control group – 62±14 years. For the isolation of DNA the venous blood was used. DNA was extracted from the leukocytes with the system of cleaning Wizard® Genomic DNA Purification System (Promega, Madison, WI). Gene-candidates were selected on the basis their assumed functional participation in the pathogenesis type 2 DM: genes, which participate in the metabolism of lipids and carbohydrates, in the oxidizing stress and the inflammatory processes, and also the secretions of insulin. The 41 a polymorphic variant of the 20 candidate genes were studied. Gene research was carried out in NINDS/NIH, USA. Statistical data analysis is carried out with the use of Statistica 8.0 and SAS 7.0. Result: The conducted genetic investigations showed that the most significant genetic factors, which influence on the risk of DM2 in the Yakut population, are the genes ABCC8 (version of rs1799859), (relative risk, RR = 1.34); CDKN2A/B (version of rs10811661), (RR = 1.38); LPL (versions of int6/PvuII G> A Int8/Hind3), (RR = 4.36); and RSTN (versions of rs34861192 and rs32119177; RR = 2.8 and RR = 2.0, respectively). This study point to the role of genes of insulin secretion and lipid metabolism in pathogenesis of DM2. The variability of their combinations determines the variety of clinical course and the spectrum of late complications of DM2 in the Yakut population. Conclusion: Our study showed that the markers of genetic predisposition to type 2 diabetes mellitus in the Yakut population are genes ABCC8 (version of rs1799859); CDKN2A/B (version of rs10811661); LPL (versions of int6/PvuII G> A Int8/Hind3) and RSTN (versions of rs34861192 and rs32119177). These molecular-genetic data can be used for medico-genetic consultation for evaluating the individual risk of DM2, early diagnostics and effective therapy of type 2 diabetes in the Yakut population. Reference(s) [1] Yan Y, North KE, Ballantyne CM, Brancati FL, Chambless LE, Franceschini N, Heiss G, Kottgen A, Pankow JS, Selvin E, West SL, and Boerwinkle E. Transcription factor 7-like 2 (TCF7L2 ) polymorphism and context-specific risk of type 2 diabetes in African American and Caucasian adults. Diabetes. 2009 January; 58(1): 285–289. [2] Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, Styrkarsdottir U, Magnusson KP, Walters GB, Palsdottir E, Jonsdottir T, Gudmundsdottir T, Gylfason A, Saemundsdottir J, Wilensky RL, et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat. Genet. 2006; 38: 320–323. [3] Lyssenko V, Lupi R, Marchetti P, Del Guerra S, Orho-Melander M, Almgren P, Sjøgren M, Ling C, Eriksson KF, Lethagen AL, Mancarella R, Berglund G, Tuomi T, Nilsson P, Del Prato S, Groop L. Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Invest. 2007 Aug; 117(8): 2155–2163. [4] Wei Cui, Cuilin Zhang, Yiqing Song. Genome-Wide Association studies (GWAS) deliver big breakthroughs in identifying type 2 diabetes susceptibility genes in the general population. N A J Med Sci. 2009; 2(1): 6–8.
Posters / Diabetes Research and Clinical Practice 106S1 (2014) S47–S267
software, the DNA sequences were aligned and converted into amino acid sequences by using BioEdit & BLAST program from NCBI, and superimpose analysis by Strap JAVA program, 2D- & 3D-structure analysis Swiss Model program by Pymol, SSpro, Phyre dan Metaserverm, 3DJigSaw software from web service Swiss Model. To examine the cytoplasm tyrosine kinase pathway using docking INSR-TyrKinase domain & IRS-1 (PTB domain) analyzed by by using HEX 6.12 software and the ligand details interaction was detected by virtual screening of LigandScout and were performed with the UCSF Chimera package. Result: The result of this study found some deletions and substitutions mutation of DNA sequence on exon 22 of hINSR gene of DM patients from Saeful Anwar hospital, Malang. These mutations of exon 22 hINSR gene is on TyrKinase domain of hINSR protein that located in cytoplasm was reducing stimulating IRS-1 activation and intracellular signaling. Physics-chemistry analysis shown that TyrKinase hINSR was weakly interacted with IRS-1 PTB domain, however, there is reducing activation of IRS-2 PTB domain. These were inhibitions disrupting in GLUT-4 protein releasing from GLUT-4 vesicle on glucose uptake . This mechanism could state that mutation of exon 22 coded TyrKinase hINSR C-terminal region disrupt metabolic signaling pathway. We suggested that the INSR protein mutation of DM patient precede abnormally INSR function against TyrKinase and perhaps correlated with genetic syndrome of insulin resistance. The change function is presumed to inhibit the interaction between INSR and IRS, makes transduction signals disturbance in the process of absorption of glucose leads to insulin resistance of diabetes mellitus. Conclusion: This study finding indicated that the genetic background of DM patients is individually as potential factor leading to provide or inhibit TyrKinase signaling pathway susceptability with diabetes disease. Keywords: Diabetes, insulin, insulin receptor, in silico, tyrosine kinase signaling pathway Reference(s) Longo N, Wang Y, Smith SA, Langley SD, DiMeglio LA, GiannellaNeto D (2002). Genotype-phenotype correlation in inherited severe insulin resistance. Hum. Mol. Genet. 11 (12): 1465–75. Taniguchi, C. M., Emanuelli, B., and Kahn, C. R. 2006. Critical nodes in signaling pathways: insights into insulin action. Nature reviews. Molecular cell biology , 7 (2): 85–96. doi: 10.1038/nrm1837.
PO085 MARKERS OF GENETIC SUSCEPTIBILITY TO TYPE 2 DIABETES MELLITUS IN YAKUTIAN POPULATION I.V. Osokina1 , P. Ignatev2 , F.A. Platonov1,3 , L. Goldfarb4 , V. Osakovskiy5 . 1 Endocrinology, State Research Institute for Medical Studies of the North, Krasnoyarsk, 2 Endocrinology, 3 Director, National Medical Research Center “Institute of Health”, Sakha Republic, Yakutsk, Russian Federation ; 4 Genetics, NINDS/NIH, Clinical Neurogenetics Unit, National Institute of Neurological Disorders and Stroke, NIH„ Bethesda, United States ; 5 Genetics, National Medical Research Center “Institute of Health”, Sakha Republic, Yakutsk, Russian Federation Background: Type 2 diabetes mellitus (DM2) is considered as disease with the essential genetic component, which is confirmed by a family aggregation and studies on the hybrid populations with the high frequency of disease. The achievements of world molecular genetics in recent years it led to the discovery of the numerous genes of receptivity to DM 2 types, which feeds large hopes for the improvement of early diagnostics, and also effective therapy on the basis of the determination of individual genetic profile. Aim: To analyze the genetic factors, which influence on the risk of the development of type 2 diabetes mellitus (DM2) in the Yakut population.
Method: We examined 552 representatives of the Yakut nationality. Genetic studies were carried out in 204 patients with type 2 diabetes (63 men and 141 women), and 348 controls without the DM heredity (136 men and 212 women). Average age of patients was 60±12.2 years, in the control group – 62±14 years. For the isolation of DNA the venous blood was used. DNA was extracted from the leukocytes with the system of cleaning Wizard® Genomic DNA Purification System (Promega, Madison, WI). Gene-candidates were selected on the basis their assumed functional participation in the pathogenesis type 2 DM: genes, which participate in the metabolism of lipids and carbohydrates, in the oxidizing stress and the inflammatory processes, and also the secretions of insulin. The 41 a polymorphic variant of the 20 candidate genes were studied. Gene research was carried out in NINDS/NIH, USA. Statistical data analysis is carried out with the use of Statistica 8.0 and SAS 7.0. Result: The conducted genetic investigations showed that the most significant genetic factors, which influence on the risk of DM2 in the Yakut population, are the genes ABCC8 (version of rs1799859), (relative risk, RR = 1.34); CDKN2A/B (version of rs10811661), (RR = 1.38); LPL (versions of int6/PvuII G> A Int8/Hind3), (RR = 4.36); and RSTN (versions of rs34861192 and rs32119177; RR = 2.8 and RR = 2.0, respectively). This study point to the role of genes of insulin secretion and lipid metabolism in pathogenesis of DM2. The variability of their combinations determines the variety of clinical course and the spectrum of late complications of DM2 in the Yakut population. Conclusion: Our study showed that the markers of genetic predisposition to type 2 diabetes mellitus in the Yakut population are genes ABCC8 (version of rs1799859); CDKN2A/B (version of rs10811661); LPL (versions of int6/PvuII G> A Int8/Hind3) and RSTN (versions of rs34861192 and rs32119177). These molecular-genetic data can be used for medico-genetic consultation for evaluating the individual risk of DM2, early diagnostics and effective therapy of type 2 diabetes in the Yakut population. Reference(s) [1] Yan Y, North KE, Ballantyne CM, Brancati FL, Chambless LE, Franceschini N, Heiss G, Kottgen A, Pankow JS, Selvin E, West SL, and Boerwinkle E. Transcription factor 7-like 2 (TCF7L2 ) polymorphism and context-specific risk of type 2 diabetes in African American and Caucasian adults. Diabetes. 2009 January; 58(1): 285–289. [2] Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, Styrkarsdottir U, Magnusson KP, Walters GB, Palsdottir E, Jonsdottir T, Gudmundsdottir T, Gylfason A, Saemundsdottir J, Wilensky RL, et al. Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat. Genet. 2006; 38: 320–323. [3] Lyssenko V, Lupi R, Marchetti P, Del Guerra S, Orho-Melander M, Almgren P, Sjøgren M, Ling C, Eriksson KF, Lethagen AL, Mancarella R, Berglund G, Tuomi T, Nilsson P, Del Prato S, Groop L. Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Invest. 2007 Aug; 117(8): 2155–2163. [4] Wei Cui, Cuilin Zhang, Yiqing Song. Genome-Wide Association studies (GWAS) deliver big breakthroughs in identifying type 2 diabetes susceptibility genes in the general population. N A J Med Sci. 2009; 2(1): 6–8.