Single Nucleotide Polymorphisms of PPARD in Combination With the Gly482Ser Substitution of PGC-1A and the Pro12Ala Substitution of PPARG2 Predict the Conversion From Impaired Glucose Tolerance to Type 2 Diabetes
The STOP-NIDDM Trial
- Laura Andrulionytė1,
- Paula Peltola1,
- Jean-Louis Chiasson2,
- Markku Laakso1 and
- for the STOP-NIDDM Study Group*
- 1Department of Medicine, University of Kuopio, Kuopio, Finland
- 2Research Centre, Centre Hospitalier de l’Université de Montréal, Hôtel-Dieu, Department of Medicine, University of Montreal, Quebec, Canada
- Address correspondence and reprint requests to Markku Laakso, MD, Academy Professor, Department of Medicine, University of Kuopio, 70210 Kuopio, Finland. E-mail: markku.laakso{at}kuh.fi
Abstract
Peroxisome proliferator–activated receptor (PPAR)-δ regulates fatty acid oxidation and improves insulin sensitivity. We screened six single nucleotide polymorphisms (SNPs) of the PPAR-δ gene (PPARD) for an association with the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in 769 subjects participating in the STOP-NIDDM trial. A 2.7-fold increase in the risk of diabetes was observed in female carriers of the C allele of rs6902123 (95% CI 1.44–5.30; adjusted P = 0.002). In the placebo group, subjects possessing both the 482Ser allele of the PPAR-γ coactivator-1α gene (PGC-1A) and the rare allele of two SNPs of PPARD (rs6902123 and rs3734254) had up to 2.5-fold increased risk for diabetes. Furthermore, women carrying the C allele of rs6902123 of PPARD and the Pro12Pro genotype of the PPAR-γ2 gene (PPARG2) had a 3.9-fold (95% CI 1.79–8.63; P = 0.001)-higher risk for diabetes than women with protective genotypes. Expression levels of PPAR-δ in subcutaneous adipose tissue of 87 offspring of Finnish patients with type 2 diabetes did not differ among the genotype groups of SNPs of PPARD. We conclude that SNPs in PPARD modify the conversion from IGT to type 2 diabetes, particularly in combination with the SNPs of PGC-1A and PPARG2.
- FFA, free fatty acid
- IGT, impaired glucose tolerance
- LD, linkage disequilibrium
- PGC-1α, PPAR-γ coactivator 1α
- PPAR, peroxisome proliferator–activated receptor
- SNP, single nucleotide polymorphism
Footnotes
- *
* A complete list of STOP-NIDDM trial members can be found in ref. 12.
J.-L.C. and M.L. have received honoraria/consulting fees and grant/research support from Bayer.
Additional information on this article can be found in an online appendix available at http://diabetes.diabetesjournals.org.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact
-
- Accepted April 4, 2006.
- Received December 16, 2005.
- DIABETES
