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

Tandi E Matsha³  Rajiv T Erasmus²  Andre P Kengne¹  Yandiswa Y Yako³  Zelda Vergotine² 

[1] Department of Medicine, University of Cape Town, Cape Town, South Africa;Division of Chemical Pathology, Stellenbosch University, Cape Town, South Africa;Biomedical Sciences, Faculty of Health and Wellness Sciences, Cape Peninsula University of Technology, PO Box 1906, Bellville 7530, Cape Town, South Africa

关键词: Africa;    Type 2 diabetes;    Insulin resistance;    PPARG Pro12Ala;    IRS1 Gly972Arg;   

Others  :  1085972
DOI  :  10.1186/1471-2156-15-10

 received in 2013-10-07, accepted in 2014-01-18,  发布年份 2014

【 摘 要 】

Background

The peroxisome proliferator-activated receptor gamma (PPARG), Pro12Ala and the insulin receptor substrate (IRS1), Gly972Arg confer opposite effects on insulin resistance and type 2 diabetes mellitus (T2DM). We investigated the independent and joint effects of PPARG Pro12Ala and IRS1 Gly972Arg on markers of insulin resistance and T2DM in an African population with elevated risk of T2DM. In all 787 (176 men) mixed-ancestry adults from the Bellville-South community in Cape Town were genotyped for PPARG Pro12Ala and IRS1 Gly972Arg by two independent laboratories. Glucose tolerance status and insulin resistance/sensitivity were assessed.

Results

Genotype frequencies were 10.4% (PPARG Pro12Ala) and 7.7% (IRS1 Gly972Arg). Alone, none of the polymorphisms predicted prevalent T2DM, but in regression models containing both alleles and their interaction term, PPARG Pro12 conferred a 64% higher risk of T2DM. Furthermore PPARG Pro12 was positively associated in adjusted linear regressions with increased 2-hour post-load insulin in non-diabetic but not in diabetic participants.

Conclusion

The PPARG Pro12 is associated with insulin resistance and this polymorphism interacts with IRS1 Gly972Arg, to increase the risk of T2DM in the mixed-ancestry population of South Africa. Our findings require replication in a larger study before any generalisation and possible application for risk stratification.

【 授权许可】

   
2014 Vergotine et al.; licensee BioMed Central Ltd.

【 参考文献 】

• [1]Reaven GM: Banting lecture 1988 role of insulin resistance in human disease. Nutrition 1997, 13:64-66.
• [2]Polonsky KS, Given BD, Hirsch L, Shapiro ET, Tillil H, Beebe C, Galloway JA, Frank BH, Karrison T, Van-Cauter E: Quantitative study of insulin secretion and clearance in normal and obese subjects. J Clin Invest 1988, 81:435-441.
• [3]DeFronzo RA, Tobin JD, Andres R: Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979, 237:E214-223.
• [4]Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC: Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985, 28:412-419.
• [5]Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, Quon MJ: Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 2000, 85:2402-2410.
• [6]Buzzetti R, Petrone A, Ribaudo MC, Alemanno I, Zavarella S, Mein CA, Maiani F, Tiberti C, Baroni MG, Vecci E, Arca M, Leonetti F, Di Mario U: The common PPAR-gamma2 Pro12Ala variant is associated with greater insulin sensitivity. Eur J Hum Genet 2004, 12:1050-1054.
• [7]Ludovico O, Pellegrini F, Di Paola R, Minenna A, Mastroianno S, Cardellini M, Marini MA, Andreozzi F, Vaccaro O, Sesti G, Trischitta V: Heterogeneous effect of peroxisome proliferator-activated receptor gamma2 Ala12 variant on type 2 diabetes risk. Obesity (Silver Spring) 2007, 15:1076-1081.
• [8]Gouda HN, Sagoo GS, Harding AH, Yates J, Sandhu MS, Higgins JP: The association between the peroxisome proliferator-activated receptor-gamma2 (PPARG2) Pro12Ala gene variant and type 2 diabetes mellitus: a HuGE review and meta-analysis. Am J Epidemiol 2010, 171:645-655.
• [9]Trombetta M, Bonetti S, Boselli ML, Miccoli R, Trabetti E, Malerba G, Pignatti PF, Bonora E, Del Prato S, Bonadonna RC: PPARG2 Pro12Ala and ADAMTS9 rs4607103 as "insulin resistance loci" and "insulin secretion loci" in Italian individuals. The GENFIEV study and the verona newly diagnosed type 2 diabetes study (VNDS) 4. Acta Diabetol 2013, 50:401-408.
• [10]Jellema A, Zeegers MP, Feskens EJ, Dagnelie PC, Mensink RP: Gly972Arg variant in the insulin receptor substrate-1 gene and association with Type 2 diabetes: a meta-analysis of 27 studies. Diabetologia 2003, 46:990-995.
• [11]Sesti G, Federici M, Hribal ML, Lauro D, Sbraccia P, Lauro R: Defects of the insulin receptor substrate (IRS) system in human metabolic disorders. FASEB J 2001, 15:2099-2111.
• [12]Evans RM, Barish GD, Wang YX: PPARs and the complex journey to obesity. Nat Med 2004, 10:355-361.
• [13]Auwerx J: PPARgamma, the ultimate thrifty gene. Diabetologia 1999, 42:1033-1049.
• [14]Vigouroux C, Fajas L, Khallouf E, Meier M, Gyapay G, Lascols O, Auwerx J, Weissenbach J, Capeau J, Magré J: Human peroxisome proliferator-activated receptor-gamma2: genetic mapping, identification of a variant in the coding sequence, and exclusion as the gene responsible for lipoatrophic diabetes. Diabetes 1998, 47:490-492.
• [15]Yen CJ, Beamer BA, Negri C, Silver K, Brown KA, Yarnall DP, Burns DK, Roth J, Shuldiner AR: Molecular scanning of the human peroxisome proliferator activated receptor gamma (hPPAR gamma) gene in diabetic Caucasians: identification of a Pro12Ala PPAR gamma 2 missense mutation. Biochem Biophys Res Commun 1997, 241:270-274.
• [16]Stumvoll M, Häring H: The peroxisome proliferator-activated receptor-gamma2 Pro12Ala polymorphism. Diabetes 2002, 51:2341-2347.
• [17]Mori H, Ikegami H, Kawaguchi Y, Seino S, Yokoi N, Takeda J, Inoue I, Seino Y, Yasuda K, Hanafusa T: The Pro12 Ala substitution in PPAR-gamma is associated with resistance to development of diabetes in the general population: possible involvement in impairment of insulin secretion in individuals with type 2 diabetes. Diabetes 2001, 50:891-894.
• [18]Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, Lane CR, Schaffner SF, Bolk S, Brewer C, Tuomi T, Gaudet D, Hudson TJ, Daly M, Groop L, Lander ES: The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 2000, 26:76-80.
• [19]Sanghera DK, Ortega L, Han S, Singh J, Ralhan SK, Wander GS, Mehra NK, Mulvihill JJ, Ferrell RE, Nath SK, Kamboh MI: Impact of nine common type 2 diabetes risk polymorphisms in Asian Indian Sikhs: PPARG2 (Pro12Ala), IGF2BP2, TCF7L2 and FTO variants confer a significant risk. BMC Med Genet 2008, 9:59.
• [20]Wang X, Liu J, Ouyang Y, Fang M, Gao H, Liu L: The association between the Pro12Ala variant in the PPARc2 gene and type 2 diabetes mellitus and obesity in a Chinese population. PLoS ONE 2013, 8(8):e71985. doi:10.1371/journal.pone.0071985
• [21]Burguete-Garcia AI, Cruz-Lopez M, Madrid-Marina V, Lopez-Ridaura R, Hernández-Avila M, Cortina B, Gómez RE, Velasco-Mondragón E: 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 2010, 59:38-45.
• [22]Erasmus RT, Soita DJ, Hassan MS, Blanco Blanco E, Vergotine Z, Kengne AP, Matsha TE: High prevalence of diabetes mellitus and metabolic syndrome in a south african mixed ancestry population: The Bellville-South Africa study - baseline data. S Afr Med J 2012, 102:841-844.
• [23]Almind K, Inoue G, Pedersen O, Kahn CR: A common amino acid polymorphism in insulin receptor substrate-1 causes impaired insulin signaling. Evidence from transfection studies. J Clin Invest 1996, 97:2569-2575.
• [24]Prudente S, Morini E, Trischitta V: Insulin signaling regulating genes: effect on T2DM and cardiovascular risk. Nat Rev Endocrinol 2009, 5:682-693.
• [25]Federici M, Pandolfi A, De Filippis EA, Pellegrini G, Menghini R, Lauro D, Cardellini M, Romano M, Sesti G, Lauro R, Consoli A: G972R IRS-1 variant impairs insulin regulation of endothelial nitric oxide synthase in cultured human endothelial cells. Circulation 2004, 109:399-405.
• [26]Voight BF, Scott LJ, Steinthorsdottir V, Morris AP, Dina C, Welch RP, Zeggini E, Huth C, Aulchenko YS, Thorleifsson G, McCulloch LJ, Ferreira T, Grallert H, Amin N, Wu G, Willer CJ, Raychaudhuri S, McCarroll SA, Langenberg C, Hofmann OM, Dupuis J, Qi L, Segrè AV, van Hoek M, Navarro P, Ardlie K, Balkau B, Benediktsson R, Bennett AJ, Blagieva R, et al.: Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 2010, 42:579-589.
• [27]Rung J, Cauchi S, Albrechtsen A, Shen L, Rocheleau G, Cavalcanti-Proença C, Bacot F, Balkau B, Belisle A, Borch-Johnsen K, Charpentier G, Dina C, Durand E, Elliott P, Hadjadj S, Järvelin MR, Laitinen J, Lauritzen T, Marre M, Mazur A, Meyre D, Montpetit A, Pisinger C, Posner B, Poulsen P, Pouta A, Prentki M, Ribel-Madsen R, Ruokonen A, Sandbaek A, et al.: Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia. Nat Genet 2009, 41:1110-1115.
• [28]Stumvoll M, Stefan N, Fritsche A, Madaus A, Tschritter O, Koch M, Machicao F, Häring H: Interaction effect between common polymorphisms in PPARgamma2 (Pro12Ala) and insulin receptor substrate 1 (Gly972Arg) on insulin sensitivity. J Mol Med (Berl) 2002, 80:33-38.
• [29]Mousavinasab F, Tähtinen T, Jokelainen J, Koskela P, Vanhala M, Oikarinen J, Keinänen-Kiukaanniemi S, Laakso M: Common polymorphisms in the PPARgamma2 and IRS1 genes and their interaction influence serum adiponectin concentration in young Finnish men. Mol Genet Metab 2005, 84:344-348.
• [30]Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA: Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 2001, 86:1930-1935.
• [31]von Eynatten M, Hamman A, Twardella D, Nawroth PP, Brenner H, Rothenbacher D: Relationships of adiponectin with markers of systemic inflammation, Atherogenic dyslipidaemia, and heart failure in patients with coronary heart disease. Clin Chem 2006, 52:853-59.
• [32]Hasstedt SJ, Ren QF, Teng K, Elbein SC: Effect of the peroxisome proliferator-activated receptor-gamma 2 pro(12)ala variant on obesity, glucose homeostasis, and blood pressure in members of familial type 2 diabetic kindreds. J Clin Endocrinol Metab 2001, 86:536-41.
• [33]Stefan N, Fritsche A, Häring H, Stumvoll M: Effect of experimental elevation of free fatty acids on insulin secretion and insulin sensitivity in healthy carriers of the Pro12Ala polymorphism of the peroxisome proliferator–activated receptor-gamma2 gene. Diabetes 2001, 50:1143-1148.
• [34]de Wit E, Delport W, Rugamika CE, Meintjes A, Möller M, van Helden PD, Seoighe C, Hoal EG: Genome-wide analysis of the structure of the South African coloured population in the Western Cape. Hum Genet 2010, 14:145-153.
• [35]Hancox RJ, Landhuis CE: Correlation between measures of insulin resistance in fasting and non-fasting blood. Diabetol Metab Syndr 2011, 3:23. BioMed Central Full Text
• [36]Deng HW: Population admixture may appear to mask, change or reverse genetic effects of genes underlying complex traits. Genetics 2001, 159:1319-1323.
• [37]Matsha TE, Hassan MS, Kidd M, Erasmus RT: The 30-year cardiovascular risk profile of South Africans with diagnosed diabetes, undiagnosed diabetes, pre-diabetes or normoglycaemia: the Bellville, South Africa pilot study. Cardiovasc J Afr 2012, 23:5-11.
• [38]Chalmers J, MacMahon S, Mancia G, Whitworth J, Beilin L, Hansson L, Neal B, Rodgers A, Ni Mhurchu C,CT, Clark T: World health organization-international society of hypertension guidelines for the management of hypertension. Guidelines sub-committee of the world health organization. Clin Exp Hypertens 1999, 21:1009-1060.
• [39]Alberti KG, Zimmet PZ: Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998, 15:539-553.
• [40]Friedewald WT, Levy RI, Fredrickson DS: Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972, 18:499-502.
• [41]Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D, Modification of Diet in Renal Disease Study Group: A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Ann Intern Med 1999, 130:461-470.
• [42]Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, Kusek JW, Van Lente F, Chronic Kidney Disease Epidemiology Collaboration: Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 2006, 145:247-254.