Evidence for Interaction between PPARG Pro12Ala and PPARGC1A Gly482Ser Polymorphisms in Determining Type 2 Diabetes Intermediate Phenotypes in Overweight Subjects

S.-M. Ruchat; S. J. Weisnagel; M-C. Vohl; T. Rankinen; C. Bouchard; L. Pérusse

doi:10.1055/s-0029-1216352

Experimental and Clinical Endocrinology & Diabetes, Table of Contents

Exp Clin Endocrinol Diabetes 2009; 117(9): 455-459
DOI: 10.1055/s-0029-1216352

Article

Evidence for Interaction between PPARG Pro12Ala and PPARGC1A Gly482Ser Polymorphisms in Determining Type 2 Diabetes Intermediate Phenotypes in Overweight Subjects

S.-M. Ruchat¹ ^, ² , S. J. Weisnagel¹ ^, ² , M-C. Vohl² , T. Rankinen³ , C. Bouchard³ , L. Pérusse¹ ^, ²

¹Department of Preventive Medicine, Laval University, Quebec, Canada
²Lipid Research Center, CHUL Research Center, Quebec, Canada
³Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA

Abstract

Background: The peroxisome proliferator-activated receptor-γ (PPARG) Pro12Ala and the PPARG co-activator-1α (PPARGC1A) Gly482Ser polymorphisms (SNPs) have been associated with type 2 diabetes mellitus (T2DM) risk. We hypothesized that independent and interactive effects of the PPARG Pro12Ala and PPARGC1A Gly482Ser polymorphisms influence T2DM intermediate phenotypes.

Material and Methods: PPARG Pro12Ala and PPARGC1A Gly482Ser SNPs were studied in 680 non diabetic subjects who underwent a 75 g oral glucose tolerant test (OGTT). Glucose and insulin plasma levels in the fasting state and derived from the OGTT were included in the present study.

Results: We found significant independent effects of the PPARG and PPARGC1A variants on fasting insulin levels (p=0.02 for both), HOMA-IR (p=0.03 and p=0.02, respectively), insulin area under the curve (AUC) (p=0.007 and p=0.006, respectively) and 2-h glucose levels (p=0.02 for PPARGC1A). Furthermore, significant gene-gene interactions were found for fasting insulin, HOMA-IR and insulin AUC (p=0.03 for all). Carriers of the PPARGC1A Gly allele who were also PPARG Ala-carriers had higher fasting insulin levels (p=0.02), HOMA-IR (p=0.01) and insulin AUC (p=0.01) compared to the Ser/Ser-Ala+genotype combination, whereas no differences between the PPARGC1A genotypes among the PPARG Pro/Pro carriers were observed.

Conclusion: Together, these results showed that PPARG Pro12Ala and PPARGC1A Gly482Ser variants are associated, alone and in interaction, with insulin and glucose homeostasis and suggest that gene-gene interactions should be taken into account in candidate gene studies of T2DM to identify subjects with markedly different risks of developing the disease.

Key words

PPARG Pro12Ala - PPARGC1A Gly482Ser - interactions - T2DM-related phenotypes

Full Text

References

1 Altshuler D, Hirschhorn JN, Klannemark M. et al . The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet. 2000; 26 76-80
2 Ambye L, Rasmussen S, Fenger M. et al . Studies of the Gly482Ser polymorphism of the peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) gene in Danish subjects with the metabolic syndrome. Diabetes Res Clin Pract. 2005; 67 175-179
3 Andrulionyte L, Zacharova J, Chiasson JL. et al . Common polymorphisms of the PPAR-gamma2 (Pro12Ala) and PGC-1alpha (Gly482Ser) genes are associated with the conversion from impaired glucose tolerance to type 2 diabetes in the STOP-NIDDM trial. Diabetologia. 2004; 47 2176-2184
4 Barroso I, Luan J, Sandhu MS. et al . Meta-analysis of the Gly482Ser variant in PPARGC1A in type 2 diabetes and related phenotypes. Diabetologia. 2006; 49 501-505
5 Bhat A, Koul A, Rai E. et al . PGC-1alpha Thr394Thr and Gly482Ser variants are significantly associated with T2DM in two North Indian populations: a replicate case-control study. Hum Genet. 2007; 121 609-614
6 Bosse Y, Weisnagel SJ, Bouchard C. et al . Combined effects of PPARgamma2 P12A and PPARalpha L162 V polymorphisms on glucose and insulin homeostasis: the Quebec Family Study. J Hum Genet. 2003; 48 614-621
7 Bouchard C. Genetic epidemiology, association and sib-pair linkage:results from the Quebec Family Study. In: Bray G, Ryan D, eds. Molecular and genetic aspects of obesity. Baton Rouge, LA, Louisiana: State University Press 1994
8 Chagnon YC, Borecki IB, Perusse L. et al . Genome-wide search for genes related to the fat-free body mass in the quebec family study. Metabolism. 2000; 49 203-207
9 Choi YS, Hong JM, Lim S. et al . Impaired coactivator activity of the Gly482 variant of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) on mitochondrial transcription factor A (Tfam) promoter. Biochem Biophys Res Commun. 2006; 344 708-712
10 Deeb SS, Fajas L, Nemoto M. et al . A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet. 1998; 20 284-287
11 Ek J, Andersen G, Urhammer SA. et al . Mutation analysis of peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) and relationships of identified amino acid polymorphisms to Type II diabetes mellitus. Diabetologia. 2001; 44 2220-2226
12 Franks PW, Mesa JL, Harding AH. et al . Gene-lifestyle interaction on risk of type 2 diabetes. Nutr Metab Cardiovasc Dis. 2007; 17 104-124
13 Freeman H, Cox RD. Type-2 diabetes: A cocktail of genetic discovery. Hum Mol Genet. 2006; , 15 Spec No 2 R202-R209
14 Hara K, Tobe K, Okada T. et al . A genetic variation in the PGC-1 gene could confer insulin resistance and susceptibility to Type II diabetes. Diabetologia. 2002; 45 740-743
15 Hsueh WC, Cole SA, Shuldiner AR. et al . Interactions between variants in the beta3-adrenergic receptor and peroxisome proliferator-activated receptor-gamma2 genes and obesity. Diabetes Care. 2001; 24 672-677
16 Hu FB, Doria A, Li T. et al . Genetic variation at the adiponectin locus and risk of type 2 diabetes in women. Diabetes. 2004; 53 209-213
17 Ioannidis JP, Ntzani EE, Trikalinos TA. et al . Replication validity of genetic association studies. Nat Genet. 2001; 29 306-309
18 Kunej T, Globocnik PM, Dovc P. et al . A Gly482Ser polymorphism of the peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) gene is associated with type 2 diabetes in Caucasians. Folia Biol (Praha). 2004; 50 157-158
19 Lacquemant C, Chikri M, Boutin P. et al . No association between the G482S polymorphism of the proliferator-activated receptor-gamma coactivator-1 (PGC-1) gene and Type II diabetes in french caucasians. Diabetologia. 2002; 45 602-603 , ; author reply 604
20 Ling C, Del Guerra S, Lupi R. et al . Epigenetic regulation of PPARGC1A in human type 2 diabetic islets and effect on insulin secretion. Diabetologia. 2008; 51 ((4)) 615-622
21 Lohman T, Roche A, Martorell F. et al .eds Anthropometric standardization reference manual. Champaign, IL: Human Kinetics 1988
22 Lohmueller KE, Pearce CL, Pike M. et al . Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet. 2003; 33 177-182
23 Masugi J, Tamori Y, Mori H. et al . Inhibitory effect of a proline-to-alanine substitution at codon 12 of peroxisome proliferator-activated receptor-gamma 2 on thiazolidinedione-induced adipogenesis. Biochem Biophys Res Commun. 2000; 268 178-182
24 Matthews DR, Hosker JP, Rudenski AS. et al . Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985; 28 412-419
25 Mootha VK, Lindgren CM, Eriksson KF. et al . PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 2003; 34 267-273
26 Mousavinasab F, Tahtinen T, Jokelainen J. et al . Common polymorphisms in the PPARgamma2 and IRS-1 genes and their interaction influence serum adiponectin concentration in young Finnish men. Mol Genet Metab. 2005; 84 344-348
27 Muller YL, Bogardus C, Pedersen O. et al . A Gly482Ser missense mutation in the peroxisome proliferator-activated receptor gamma coactivator-1 is associated with altered lipid oxidation and early insulin secretion in Pima Indians. Diabetes. 2003; 52 895-898
28 Nelson TL, Fingerlin TE, Moss L. et al . The peroxisome proliferator-activated receptor gamma coactivator-1 alpha gene (PGC-1alpha) is not associated with type 2 diabetes mellitus or body mass index among Hispanic and non Hispanic Whites from Colorado. Exp Clin Endocrinol Diabetes. 2007; 115 268-275
29 Nitz I, Ewert A, Klapper M. et al . Analysis of PGC-1alpha variants Gly482Ser and Thr612Met concerning their PPARgamma2-coactivation function. Biochem Biophys Res Commun. 2007; 353 481-486
30 Patti ME, Butte AJ, Crunkhorn S. et al . Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proc Natl Acad Sci USA. 2003; 100 8466-8471
31 Puigserver P, Wu Z, Park CW. et al . A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell. 1998; 92 829-839
32 Rice T, Nadeau A, Perusse L. et al . Familial correlations in the Quebec family study: cross-trait familial resemblance for body fat with plasma glucose and insulin. Diabetologia.. 1996; 39 1357-1364
33 Saxena R, Voight BF, Lyssenko V. et al . Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science. 2007; 316 1331-1336
34 Scott LJ, Mohlke KL, Bonnycastle LL. et al . A genome-wide association study of type 2 diabetes in finns detects multiple susceptibility variants. Science. 2007; 316 1341-1345
35 Soyal S, Krempler F, Oberkofler H. et al . PGC-1alpha: a potent transcriptional cofactor involved in the pathogenesis of type 2 diabetes. Diabetologia. 2006; 49 1477-1488
36 Stumvoll M, Stefan N, Fritsche A. et al . Interaction effect between common polymorphisms in PPARgamma2 (Pro12Ala) and insulin receptor substrate 1 (Gly972Arg) on insulin sensitivity. J Mol Med. 2002; 80 33-38
37 Vimaleswaran KS, Radha V, Ghosh S. et al . Peroxisome proliferator-activated receptor-gamma co-activator-1alpha (PGC-1alpha) gene polymorphisms and their relationship to Type 2 diabetes in Asian Indians. Diabet Med. 2005; 22 1516-1521
38 WTCCC. . Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007; 447 661-678
39 Yang WS, Hsiung CA, Ho LT. et al . Genetic epistasis of adiponectin and PPARgamma2 genotypes in modulation of insulin sensitivity: a family-based association study. Diabetologia. 2003; 46 977-983
40 Zeggini E, Weedon MN, Lindgren CM. et al . Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science. 2007; 316 1336-1341
41 Zhang SL, Lu WS, Yan L. et al . Association between peroxisome proliferator-activated receptor-gamma coactivator-1alpha gene polymorphisms and type 2 diabetes in southern Chinese population: role of altered interaction with myocyte enhancer factor 2C. Chin Med J (Engl). 2007; 120 1878-1885
42 Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature. 2001; 414 782-787

Correspondence

L. PérussePhD

Department of Médecine sociale et préventive

Division de Kinésiologie

PEPS – 2300 rue de la Terrasse

Université Laval

Québec, QC, G1 V 0A6

Canada

Email: Louis.Perusse@kin.msp.ulaval.ca