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BMC Medical Genetics
Published in: BMC Medical Genetics 1/2005

Open Access 01-12-2005 | Research article

Implication of the Pro12Ala polymorphism of the PPAR-gamma 2gene in type 2 diabetes and obesity in the French population

Authors: Maya Ghoussaini, David Meyre, Stéphane Lobbens, Guillaume Charpentier, Karine Clément, Marie-Aline Charles, Maïté Tauber, Jacques Weill, Philippe Froguel

Published in: BMC Medical Genetics | Issue 1/2005

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Abstract

Background

The Pro12Ala Single Nucleotide Polymorphism (SNP) of the Peroxisome Proliferator-Activated Receptor gamma 2 (PPAR-gamma 2) has been associated with insulin resistance and type 2 diabetes (T2D) and also inconsistently with obesity. The aim of this study was to evaluate the impact of this SNP with regards to T2D and childhood and adult obesity in the French Caucasian population.

Methods

We conducted three independent case/control studies encompassing 2126 cases and 1124 controls.

Results

We found a significant association between PPAR-gamma 2 Pro12Ala SNP and T2D (p = 0.04, OR = 1.37), which was stronger when the T2D cohort was stratified according to the obesity status (p = 0.03, OR = 1.81 in obese T2D subjects). In contrast, there was no association between the Pro12Ala SNP and childhood and adulthood obesity. In normal glucose tolerant obese adults (but not in lean subjects), the Pro12 allele was associated with a significant increase in fasting insulin levels (p = 0.01), and in insulin resistance estimated by the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) (p = 0.003), after adjustment for age, gender and BMI. We didn't detect evidence for an interaction effect between the Pro12Ala SNP and the obesity status with respect to the HOMA-IR index in normal glucose tolerant children, but we found a borderline interaction (p = 0.06) in normal glucose tolerant adults.

Conclusion

Our results showed that the Pro12Ala polymorphism is not associated with childhood or adult obesity in the French Caucasian population. In contrast, we confirm a contribution of the PPAR-gamma 2 Pro12 allele in the genetic risk forT2D, especially in obese subjects, where this allele worsens insulin resistanceand increases fasting insulin levels.
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Literature
1.
2.
Smith SA: Central role of the adipocyte in the insulin-sensitising and cardiovascular risk modifying actions of the thiazolidinediones. Biochimie. 2003, 85: 1219-1230. 10.1016/j.biochi.2003.10.010.CrossRefPubMed
3.
Kroder G, Bossenmaier B, Kellerer M, Capp E, Stoyanov B, Muhlhofer A, Berti L, Horikoshi H, Ullrich A, Haring H: Tumor necrosis factor-alpha- and hyperglycemia-induced insulin resistance. Evidence for different mechanisms and different effects on insulin signaling. J Clin Invest. 1996, 97: 1471-1477.CrossRefPubMedPubMedCentral
4.
Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA: The hormone resistin links obesity to diabetes. Nature. 2001, 409: 307-312. 10.1038/35053000.CrossRefPubMed
5.
Hu E, Liang P, Spiegelman BM: AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem. 1996, 271: 10697-10703. 10.1074/jbc.271.18.10697.CrossRefPubMed
6.
Hotamisligil GS, Shargill NS, Spiegelman BM: Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. 1993, 259: 87-91.CrossRefPubMed
7.
Nolan JJ, Ludvik B, Beerdsen P, Joyce M, Olefsky J: Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med. 1994, 331: 1188-1193. 10.1056/NEJM199411033311803.CrossRefPubMed
8.
Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA: An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995, 270: 12953-12956. 10.1074/jbc.270.50.30221.CrossRefPubMed
9.
Berg AH, Combs TP, Du X, Brownlee M, Scherer PE: The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med. 2001, 7: 947-953. 10.1038/90992.CrossRefPubMed
10.
Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T: The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001, 7: 941-946. 10.1038/90984.CrossRefPubMed
11.
Guan HP, Li Y, Jensen MV, Newgard CB, Steppan CM, Lazar MA: A futile metabolic cycle activated in adipocytes by antidiabetic agents. Nat Med. 2002, 8: 1122-1128. 10.1038/nm780.CrossRefPubMed
12.
Peraldi P, Xu M, Spiegelman BM: Thiazolidinediones block tumor necrosis factor-alpha-induced inhibition of insulin signaling. J Clin Invest. 1997, 100: 1863-1869.CrossRefPubMedPubMedCentral
13.
Rajala MW, Obici S, Scherer PE, Rossetti L: Adipose-derived resistin and gut-derived resistin-like molecule-beta selectively impair insulin action on glucose production. J Clin Invest. 2003, 111: 225-230. 10.1172/JCI200316521.CrossRefPubMedPubMedCentral
14.
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. 10.1006/bbrc.1997.7798.CrossRefPubMed
15.
Deeb SS, Fajas L, Nemoto M, Pihlajamaki J, Mykkanen L, Kuusisto J, Laakso M, Fujimoto W, Auwerx J: A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet. 1998, 20: 284-287. 10.1038/3099.CrossRefPubMed
16.
Masugi J, Tamori Y, Mori H, Koike T, Kasuga M: 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. 10.1006/bbrc.2000.2096.CrossRefPubMed
17.
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. 10.1038/79839.CrossRefPubMed
18.
Douglas JA, Erdos MR, Watanabe RM, Braun A, Johnston CL, Oeth P, Mohlke KL, Valle TT, Ehnholm C, Buchanan TA, Bergman RN, Collins FS, Boehnke M, Tuomilehto J: The peroxisome proliferator-activated receptor-gamma2 Pro12A1a variant: association with type 2 diabetes and trait differences. Diabetes. 2001, 50: 886-890.CrossRefPubMed
19.
Ek J, Andersen G, Urhammer SA, Hansen L, Carstensen B, Borch-Johnsen K, Drivsholm T, Berglund L, Hansen T, Lithell H, Pedersen O: Studies of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) gene in relation to insulin sensitivity among glucose tolerant caucasians. Diabetologia. 2001, 44: 1170-1176. 10.1007/s001250100629.CrossRefPubMed
20.
Hara K, Okada T, Tobe K, Yasuda K, Mori Y, Kadowaki H, Hagura R, Akanuma Y, Kimura S, Ito C, Kadowaki T: The Pro12Ala polymorphism in PPAR gamma2 may confer resistance to type 2 diabetes. Biochem Biophys Res Commun. 2000, 271: 212-216. 10.1006/bbrc.2000.2605.CrossRefPubMed
21.
Vaccaro O, Mancini FP, Ruffa G, Sabatino L, Colantuoni V, Riccardi G: Pro12Ala mutation in the peroxisome proliferator-activated receptor gamma2 (PPARgamma2) and severe obesity: a case-control study. Int J Obes Relat Metab Disord. 2000, 24: 1195-1199. 10.1038/sj.ijo.0801366.CrossRefPubMed
22.
Beamer BA, Yen CJ, Andersen RE, Muller D, Elahi D, Cheskin LJ, Andres R, Roth J, Shuldiner AR: Association of the Pro12Ala variant in the peroxisome proliferator-activated receptor-gamma2 gene with obesity in two Caucasian populations. Diabetes. 1998, 47: 1806-1808.CrossRefPubMed
23.
Clement K, Hercberg S, Passinge B, Galan P, Varroud-Vial M, Shuldiner AR, Beamer BA, Charpentier G, Guy-Grand B, Froguel P, Vaisse C: The Pro115Gln and Pro12Ala PPAR gamma gene mutations in obesity and type 2 diabetes. Int J Obes Relat Metab Disord. 2000, 24: 391-393. 10.1038/sj.ijo.0801191.CrossRefPubMed
24.
Li S, Chen W, Srinivasan SR, Boerwinkle E, Berenson GS: The peroxisome proliferator-activated receptor-gamma2 gene polymorphism (Pro12Ala) beneficially influences insulin resistance and its tracking from childhood to adulthood: the Bogalusa Heart Study. Diabetes. 2003, 52: 1265-1269.CrossRefPubMed
25.
Meyre D, Lecoeur C, Delplanque J, Francke S, Vatin V, Durand E, Weill J, Dina C, Froguel P: A genome-wide scan for childhood obesity-associated traits in French families shows significant linkage on chromosome 6q22.31-q23.2. Diabetes. 2004, 53: 803-811.CrossRefPubMed
26.
Rolland-Cachera MF, Cole TJ, Sempe M, Tichet J, Rossignol C, Charraud A: Body Mass Index variations: centiles from birth to 87 years. Eur J Clin Nutr. 1991, 45: 13-21.PubMed
27.
Poskitt EM: Defining childhood obesity: the relative body mass index (BMI). European Childhood Obesity group. Acta Paediatr. 1995, 84: 961-963.CrossRefPubMed
28.
Lafay L, Basdevant A, Charles MA, Vray M, Balkau B, Borys JM, Eschwege E, Romon M: Determinants and nature of dietary underreporting in a free-living population: the Fleurbaix Laventie Ville Sante (FLVS) Study. Int J Obes Relat Metab Disord. 1997, 21: 567-573. 10.1038/sj.ijo.0800443.CrossRefPubMed
29.
30.
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. 10.1007/BF00280883.CrossRefPubMed
31.
32.
Buzzetti R, Petrone A, Ribaudo MC, Alemanno I, Zavarella S, Mein CA, Maiani F, Tiberti C, Baroni MG, Vecci E, Arca M, Leonetti F, Mario UD: The common PPAR-gamma2 Pro12Ala variant is associated with greater insulin sensitivity. Eur J Hum Genet. 2004, 12: 1050-1054. 10.1038/sj.ejhg.5201283.CrossRefPubMed
33.
Risch NJ: Searching for genetic determinants in the new millennium. Nature. 2000, 405: 847-856. 10.1038/35015718.CrossRefPubMed
34.
Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN: Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet. 2003, 33: 177-182. 10.1038/ng1071.CrossRefPubMed
35.
Doney AS, Fischer B, Cecil JE, Boylan K, McGuigan FE, Ralston SH, Morris AD, Palmer CN: Association of the Pro12Ala and C1431T variants of PPARG and their haplotypes with susceptibility to Type 2 diabetes. Diabetologia. 2004, 47: 555-558. 10.1007/s00125-003-1323-1.CrossRefPubMed
36.
Yamauchi T, Kamon J, Waki H, Murakami K, Motojima K, Komeda K, Ide T, Kubota N, Terauchi Y, Tobe K, Miki H, Tsuchida A, Akanuma Y, Nagai R, Kimura S, Kadowaki T: The mechanisms by which both heterozygous peroxisome proliferator-activated receptor gamma (PPARgamma) deficiency and PPARgamma agonist improve insulin resistance. J Biol Chem. 2001, 276: 41245-41254. 10.1074/jbc.M103241200.CrossRefPubMed
37.
Kubota N, Terauchi Y, Miki H, Tamemoto H, Yamauchi T, Komeda K, Satoh S, Nakano R, Ishii C, Sugiyama T, Eto K, Tsubamoto Y, Okuno A, Murakami K, Sekihara H, Hasegawa G, Naito M, Toyoshima Y, Tanaka S, Shiota K, Kitamura T, Fujita T, Ezaki O, Aizawa S, Kadowaki T, et al: PPAR gamma mediates high-fat diet-induced adipocyte hypertrophy and insulin resistance. Mol Cell. 1999, 4: 597-609. 10.1016/S1097-2765(00)80210-5.CrossRefPubMed
38.
Miles PD, Barak Y, He W, Evans RM, Olefsky JM: Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency. J Clin Invest. 2000, 105: 287-292.CrossRefPubMedPubMedCentral
39.
Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM: mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes Dev. 1994, 8: 1224-1234.CrossRefPubMed
40.
Stumvoll M, Haring H: The peroxisome proliferator-activated receptor-gamma2 Pro12Ala polymorphism. Diabetes. 2002, 51: 2341-2347.CrossRefPubMed
41.
Boden G: Free fatty acids, insulin resistance, and type 2 diabetes mellitus. Proc Assoc Am Physicians. 1999, 111: 241-248. 10.1046/j.1525-1381.1999.99220.x.CrossRefPubMed
Metadata
Title
Implication of the Pro12Ala polymorphism of the PPAR-gamma 2gene in type 2 diabetes and obesity in the French population
Authors
Maya Ghoussaini
David Meyre
Stéphane Lobbens
Guillaume Charpentier
Karine Clément
Marie-Aline Charles
Maïté Tauber
Jacques Weill
Philippe Froguel
Publication date
01-12-2005
Publisher
BioMed Central
Published in
BMC Medical Genetics / Issue 1/2005
Electronic ISSN: 1471-2350
DOI
https://doi.org/10.1186/1471-2350-6-11

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