Abstract
Genetic contributions towards Type 2 diabetes (T2D) have been assessed through association studies across different world populations with inconsistencies. The majority of the T2D susceptibility loci are common across different races or populations but show ethnicity-specific differences. The pathogenesis of T2D involves genetic variants in the candidate genes. The interactions between the genes involved in insulin signaling and secretory pathways are believed to play an important role in determining an individual’s susceptibility towards T2D. Therefore, the present study was initiated to examine the differences, if any, in the contribution of polymorphisms towards T2D susceptibility in the background of different ethnic specifications. The present case–control study included a total of 1216 T2D cases and healthy controls from three ethnic groups (Jat Sikhs, Banias and Brahmins) of North-West India. Polymorphisms were selected on the basis of information available in the literature for INS (rs689), INSR (rs1799816) and PP1G.G (rs1799999) in context to T2D. The genotyping was done using PCR–RFLP method. Statistical analysis was done using SPSS 16.0. The analyses revealed that INS (rs689) polymorphism conferred risk towards T2D susceptibility in all the three ethnic groups whereas INSR (rs1799816) polymorphism conferred risk towards T2D in Brahmins only and PP1G.G (rs1799999) polymorphism indicated T2D risk in Jat Sikhs only. Furthermore, interaction analyses indicated the cumulative role of three genetic variants in modulating T2D susceptibility in the three ethnic groups. In conclusion, our results substantiated the evidences for the role of ethnicity in differential susceptibility to T2D in the background of same genetic variants.
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Ali O (2013) Genetics of type 2 diabetes. World J Diabetes 4:114–123
American Diabetes Association (2010) Diagnosis and classification of diabetes mellitus. Diabetes Care 33:S62–S69
Anjana RM, Pradeepa R, Deepa M, Datta M, Sudha V, Unnikrishnan R, Bhansali A, Joshi SR, Joshi PP, Yajnik CS, Dhandhania VK, Nath LM, Das AK, Rao PV, Madhu SV, Shukla DK, Kaur T, Priya M, Nirmal E, Parvathi SJ, Subhashini S, Subashini R, Ali MK, Mohan V (2011) Prevalence of diabetes and prediabetes (impaired fasting glucose and/or impaired glucose tolerance) in urban and rural India: phase I results of the Indian council of Medical Research-INdia DIABetes (ICMR-INDIAB) study. Diabetologia 54:3022–3027
Arnold F, Parasuraman S, Arokiasamy P, Kothari M (2009) Nutrition in India. National Family Health Survey (NFHS-3) Mumbai: International Institute for Population Sciences. ICF Macro, Calverton
Aschenbach WG, Suzuki Y, Breeden K, Prats C, Hirshman MF, Dufresne SD, Sakamoto K, Vilardo PG, Steele M, Kim JH (2001) The muscle-specific protein phosphatase PP1G/R(GL)(G(M)) is essential for activation of glycogen synthase by exercise. J Biol Chem 276:39959–39967
Bell GI, Karam JH, Rutter WJ (1981) Polymorphic DNA region adjacent to the 5′ end of the human insulin gene. Proc Natl Acad Sci 78:5759–5763
Bell GI, Selby MJ, Rutter WJ (1982) The highly polymorphic region near the human insulin gene is composed of simple tandemly repeating sequences. Nature 295:31–35
Bennett ST, Lucassen AM, Gough SC, Powell EE, Undlien DE, Pritchard LE, Merriman ME, Kawaguchi Y, Dronsfield MJ, Pociot F, Nerup J, Bouzekri N, Cambon TA, Ronningen KS, Barnett AH, Todd JA (1995) Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nat Genet 9:284–292
Boden G, Shulman GI (2002) Free fatty acids in obesity and Type 2 Diabetes: defining their role in the development of insulin resistance and β-cell dysfunction. Eur J Clin Invest 32:14–23
Bodhini D, Sandhiya M, Ghosh S, Majumder PP, Satyanarayana Rao MR, Mohan V, Radha V (2012) Association of His1085His INSR gene polymorphism with type 2 diabetes in South Indians. Diabetes Technol Ther 14:696–700
Cai CQ, Zhang T, Breslin MB, Giraud M, Lan MS (2011) Both polymorphic variable number of tandem repeats and autoimmune regulator modulate differential expression of insulin in human thymic epithelial cells. Diabetes 60:336–344
Cox NJ, Epstein PA, Spielman RS (1989) Linkage studies on NIDDM and the insulin and insulin receptor genes. Diabetes 38:653–658
Elbein SC, Sorensen LK, Schumacher MC (1993) Methionine for valine substitution in exon 17 of the insulin receptor gene in a pedigree with familial NIDDM. Diabetes 42:429–434
Franquesa AG, Nigris VD, Lerin C, Garcia-Roves PM (2012) Skeletal muscle mitochondrial function/dysfunction and Type 2 Diabetes. Intech. doi:10.5772/50130
Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499–502
Frojdo S, Vidal H, Pirola L (2009) Alterations of insulin signaling in type 2 diabetes: a review of the current evidence from humans. Biochim Biophys Acta 1792(2):83–92
Gauderman WJ (2002) Sample size requirements for association studies of gene–gene interaction. Am J Epidemiol 155:478–484
Gaulton KJ, Wiler CJ, Li Y, Scott LJ, Conneely KN, Jackson AU, Duren WL, Chines PS, Narisu N, Bonnycastle LL, Luo J, Tong M, Sprau AG, Pugh EW, Doheny KF, Valle TT, Abecasis GR, Tuomilehto J, Bergman RN, Collins FS, Boehnke M, Mohlke KL (2008) Comprehensive association study of type 2 diabetes and related quantitative traits with 222 candidate genes. Diabetes 57:3136–3144
Grarup N, Sandholt CH, Hansen T, Pedersen O (2014) Genetic susceptibility to type 2 diabetes and obesity: from genome-wide association studies to rare variants and beyond. Diabetologia 57:1528–1541
Gupta V, Khadgawat R, Ng HKT, Kumar S, Rao VR, Sachdeva MP (2010) Population structure of Aggarwals of North India as revealed by molecular markers. Genet Test Mol Biomark 14:781–785
Hansen L, Hansen T, Vestergaard H, Bjorbaek C, Echwald SM, Clausen JO, Chen YH, Chen MX, Cohen PTW, Pederson O (1995) A widespread amino acid polymorphism at codon 905 of the glycogen associated regulatory subunit of protein phosphatase-1 is associated with insulin resistance and hypersecretion of insulin. Hum Mol Genet 4:1313–1320
Hansen L, Hansen T, Clausen JO, Echwald SM, Urhammer SA, Rasmussen SK, Pederson O (1997) The val985met insulin-receptor variant in the Danish caucasian population: lack of associations with non-insulin dependent diabetes mellitus or insulin resistance. Am J Hum Genet 60:1532–1535
Hansen SK, Gjesing AP, Rasmussen SK, Glumer C, Urhammer SA, Anderson G, Rose SC, Drivsholm T, Torekov SK, Jensen DP, Ekstrom Johnsen KB, Jorgensen T, McCarthy MI, Hansen T, Pedersen O (2004) Large-scale studies of the Hph I insulin gene variable number of tandem repeats polymorphism in relation to type 2 diabetes mellitus and insulin release. Diabetologia 47:1079–1087
Hart LM, Stolk RP, Heine RJ, Grobbee DE, Vander Does FEE, Maassen JA (1996) Association of the insulin-receptor variant Met-985 with hyperglycemia and non-insulin-dependent diabetes mellitus in the Netherlands: a population-based study. Am J Hum Genet 59:1119–1125
Hers I, Vincent EE, Tavare JM (2011) Akt signaling in health and disease. Cell Signal 23(10):1515–1527
Hubbard MJ, Cohen P (1993) On target with a new mechanism for the regulation of protein phosphatase. Trends Biochem Sci 18:172–177
Huxtable SJ, Saker PJ, Haddad L, Walker M, Frayling TM, Levy JC (2000) Analysis of parent-offspring trios provides evidence for linkage and association between the insulin gene and type 2 diabetes mediated exclusively through paternally transmitted class III variable number tandem repeat alleles. Diabetes 49:126–130
Ibanez L, Ong KK, Poteau N, Marcos MV, Zegher F, Dunger D (2001) Insulin gene variable number of tandem repeat genotype and the low birth weight, precocious pubarche, and hyperinsulinism sequence. J Clin Endocrinol Metab 86:5788–5793
Kahn CR (1994) Banting Lecture: insulin action, diabetogenes, and the cause of type II diabetes. Diabetes 43:1066–1084
Kennedy GC, German MS, Rutter WJ (1995) The minisatellite in the diabetes susceptibility locus IDDM2 regulates insulin transcription. Nat Genet 9:293–298
Kohei K (2010) Pathophysiology of type 2 diabetes and its treatment policy. Japan Med Assoc J 53:41–46
Kozarova M, Javorsky M, Stancakova A, Dobrikova M, Habalova V, Klimcakova L, Zidzik J, Haluskova J, Salagovic J, Tkac I (2010) Relationship of five type 2 diabetes candidate gene polymorphism to the age at diagnosis of diabetes in the Slovakian population. Bratisl lek Listy 111(3):150–152
Le Stunff C, Fallin D, Bougneres P (2001) Paternal transmission of the very common class I INS VNTR alleles predisposes to childhood obesity. Nat Genet 29:96–99
Matharoo K, Arora P, Bhanwer AJS (2013) Association of adiponectine (AdipoQ) and sulphonylurea receptor (ABCC8) gene polymorphism with type 2 diabetes in North Indian population of Punjab. Gene 527:228–234
Meigs JB, Muller DC, Nathan DM, Blake DR, Andres R (2003) The natural history of progression from normal glucose tolerance to type 2 diabetes in the Baltimore Longitudinal Study of Aging. Diabetes 52:1475–1484
Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for 439 extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215
Mitchell SM, Hattersley AT, Knight B (2004) Lack of support for a role of the insulin gene variable number of tandem repeats minisatellite (INS-VNTR) locus in fetal growth or type 2 diabetes-related intermediate traits in United Kingdom populations. J Clin Endocrinol Metab 89:310–317
Montori-Grau M, Guitart M, Lerin C, Andreu A, Newgard C, Garcia Martinez C, Gomez-Foix A (2007) Expression and glycogenic effect of glycogen targeting protein phosphatase 1 regulatory subunit GL in cultured human muscle. J Biochem 405(1):107–113
O’Rahilly S, Choi WH, Pate P, Turner RC, Flier JS, Moller DE (1991) Detection of mutations in the insulin receptor gene in non-insulin dependent diabetic patients by analysis of single-stranded conformation polymorphisms. Diabetes 40:777–782
Ong KK, Phillips DI, Fall C, Poulton J, Bennett ST, Golding J, Todd JA, Dunger DB (1999) The insulin gene VNTR, type 2 diabetes and birth weight. Nat Genet 21:262–263
O’Rahilly S, Krook A, Morgan R, Rees A, Flier JS, Moller DE (1992) Insulin receptor and insulin-responsive glucose transporter (Glut4) mutations and polymorphisms in a welsh type 2 (non-insulin dependent) diabetic population. Diabetologia 35:486–489
Pandya H, Lakhani JD, Dadhania J, Trivedi A (2012) The prevalence and pattern of dyslipidemia among Type 2 Diabetic patients at rural based hospital in Gujarat, India. Indian J Clin Pract 22:36–44
Puddu A, Sanguineti R, Mach F, Dallegri F, Viviani GL, Montecucco F (2013) Update on the protective molecular pathways improving pancreatic β-Cell dysfunction. Mediators Inflamm. doi:10.1155/2013/750540
Pugliese A, Miceli D (2002) The insulin gene in diabetes. Diabetes Metab Res Rev 18:13–25
Reich D, Thangaraj K, Patterson N, Price AL, Singh L (2009) Reconstructing Indian population history. Nature 461:489–494
Rhodes CJ, White MF (2002) Molecular insights into insulin action and secretion. Eur J Clin Invest 32:3–13
Ritchie MD, Hahn LW, Roodi N, Bailey R, Dupont WD, Parl FF, Moore JH (2001) Multifactor-dimensionality reduction reveals high-order interactions among estrogen metabolism genes in sporadic breast cancer. Am J Hum Genet 69:138–147
Seino S, Seino M, Nishi S, Bell GI (1989) Structure of the human insulin receptor gene and characterization of its promoter. Proc Natl Acad Sci 86:114–118
Seino S, Seino M, Bell GI (1990) Human insulin receptor gene: partial sequence and amplification of exons by polymerase chain reaction. Diabetes 39:129–133
Sesti G, Federici M, Lauro D, Sbraccia P, Lauro R (2001) Molecular mechanism of insulin resistance in type 2 diabetes mellitus: role of the insulin receptor variant forms. Diabetes Metab Res Rev 17:363–373
Shen GQ, Ikegami H, Kawaguchi Y, Fujisawan T, Hamada Y, Ueda H, Shintani M, Nojima K, Kawabata Y, Yamada K, Babaya N, Ogihara T (1998) Asp905Tyr Polymorphism of the Gene for the Skeletal Muscle-Specific Glycogen-Targetting Subunit of Protein Phosphatase 1 in NIDDM. Diabetes Care 21:1086–1089
Siddle K (2011) Signalling by insulin and IGF receptors: supporting acts and new players. J Mol Endocrinol 47:1–10
Sikka R, Raina P, Matharoo K, Bandesh K, Bhatia R, Chakabrati S, Bhanwer AJS (2014) TNF-a (g. 308G4A) and ADIPOQ (g. + 45T4G) Gene Polymorphisms in Type 2 Diabetes and Microvascular Complications in the Region of Punjab (North-West India). Curr Eye Res 39:1042–1051
Singh IP, Bhasin MK (1968) Anthropometry. Kamla Raj Enterprises, Delhi
Singh S (2011) The genetics of type 2 diabetes mellitus: a review. J Sci Res 55:35–48
Sun X, Yu W, Hu C (2014) Genetics of type 2 diabetes: insights into the pathogenesis and Its clinical Application. Bio Med Res Int. doi:10.1155/2014/926713
Tabara Y, Osawa H, Kawamoto R, Onuma H, Shimizu Miki T, Kohara K, Makino H (2009) Replication study of candidate genes associated with Type 2 Diabetes based on genome wide screening. Diabetes 58:493–498
Vafiadis P, Bennett ST, Todd JA, Nadeau J, Grabs R, Goodyer CG, Wickramasinghe S, Colle E, Polychronakos C (1997) Insulin expression in human thymus is modulated by INS-VNTR alleles at the IDDM2 locus. Nat Genet 15:289–292
Vafiadis P, Ounissi-Benkalha H, Palumbo M, Grabs R, Rousseau M, Goodyer CG, Polychronakos C (2001) Class III alleles of the variable number of tandem repeat insulin polymorphism associated with silencing of thymic insulin predispose to type 1 diabetes. J Clin Endocrinol Metab 86(8):3705–3710
Villegas R, Delahanty R, Gao YT, Long J, Williams SM, Xiang YB, Cai H, Li H, Hu F, Cai Q, Zheng W, Shu XO (2012) Joint effects of genetic and lifestyle risk factors on Type 2 Diabetes risk among Chinese men and women. PLoS ONE 7:1–7
Wang C, Wang B, He H, Li X, Wei D, Zhang J, Ma M, Pan L, Yu T, Xue F, Li L, Shan G (2012) Association between insulin receptor gene polymorphism and the metabolic syndrome in Han and Yi Chinese. Asia Pac J Clin Nutr 21(3):457–463
Weiner JS, Laurie JA (1981) Practical Human Biology. Academic Press, London
Xia J, Scherer SW, Cohen PT, Majer M, Xi T, Norman RA, Knowler WC, Bogardus C, Prochazka M (1998) A common variant in PPP1R3 associated with insulin resistance and type 2 diabetes. Diabetes 47:1519–1524
Yajnik CS, Yudkin JS (2004) The Y-Y Paradox. Lancet 363:163
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This study was funded under the scheme of “Centre with Potential for Excellence in Particular Area” Grant no. F.8-2/2008(NS/PE) (UGC, India); and “University with Potential for Excellence” Grant no. F.14-2/2008(NS/PE) (UGC, India) to Prof. AJS Bhanwer at Guru Nanak Dev University, Amritsar. The financial assistance to Jasmine Sokhi through Maulana Azad National fellowship scheme is greatly acknowledged (Letter no. F.40-50(M/S)/2009(SA-III/MANF). We are also extremely grateful to all the individuals who participated in this study.
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Sokhi, J., Sikka, R., Raina, P. et al. Association of genetic variants in INS (rs689), INSR (rs1799816) and PP1G.G (rs1799999) with type 2 diabetes (T2D): a case–control study in three ethnic groups from North-West India. Mol Genet Genomics 291, 205–216 (2016). https://doi.org/10.1007/s00438-015-1099-2
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DOI: https://doi.org/10.1007/s00438-015-1099-2