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
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