Association between the P12A and c1431t polymorphisms in the peroxisome proliferator activated receptor γ (PPARγ) gene and type 2 diabetes

Summary:

Variation in the peroxisome proliferator-activated receptor γ (PPARγ) gene may play a role in the development of type 2 diabetes mellitus. Therefore we investigated the association between the P12A and c1431t polymorphisms in the PPARγ gene and type 2 diabetes. The incidence of the P12A polymorphism was determined by PCR-RFLP and the c1431t by single-strand conformation polymorphism analysis in 219 patients with, and 429 without type 2 diabetes. The frequency of the A allele of P12A polymorphism was 0.16 and the t allele of c1431t polymorphism, 0.13 in patients with type 2 diabetes, and 0.13 and 0.12 respectively in subjects without diabetes. 3.2% of patients with and 1.4% without type 2 diabetes were A12A. Since the polymorphisms are not linked the association of the 9 possible genotypes with type 2 diabetes was determined. All patients with genotype A12A/c1431c had type 2 diabetes (n = 3, p = 0.038). There was no association between A12A/t1431t and diabetes. DNA sequencing revealed no additional mutations in the coding region of the PPARγ gene in genotypes A12A/c1431c or A12A/t1431t. The associations found between polymorphisms in the PPARγ gene and type 2 diabetes suggest that either the A12 isoform is functional leading to a predisposition to type 2 diabetes in homozygotes or that there is a third, unknown mutation linked to the A12/c1431 haplotype which is responsible.

PPARγ - mutations - polymorphisms - type 2 diabetes

References

• 1 Alberti K G, Zimmet P Z. 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. 15(7) 539-553 1998; 
• 2 Auwerx J. PPARγ, the ultimate thrifty gene.  Diabetologia. 42 1033-1049 1999; 
• 3 Barroso I, Gurnell M, Crowley V EF, Agostini M, Schwabe J W, Soos M A, Maslen G L, Williams T DM, Lewis H, Schafer A J, Chatterjee V KK, O'Rahilly S. Dominant negative mutations in human PPARγ associated with severe insulin resistance, diabetes mellitus and hypertension.  Nature. 402 880-883 1999; 
• 4 Beamer B A, Yen C-J, Andersen R E, Muller D, Elahi D, Cheskin L J, Andres R, Roth J. Association of the pro12ala variant in the peroxisome proliferator-activated receptor-γ2 gene with obesity in two Caucasian populations.  Diabetes. 47 1806-1808 1998; 
• 5 Deeb S S, Fajas L, Nemoto M, Pihlajamäki J, Mykkänen L, Kuusisto J, Laakso M, Fujimoto W, Auwerx J. A pro12ala substitution in PPARγ associated with decreased receptor activity, lower body mass index and improved insulin sensitivity.  Nature Genetics. 20 284-287 1998; 
• 6 Evans D, Mann W A, de Heer J, Michel U, Wendt D, Kortner B, Wolf A, Beisiegel U. Variation in the gene for human peroxisome proliferator activated receptor γ (PPARγ) does not play a major role in the development of morbid obesity.  Int J of Obesity. 24 647-651 2000; 
• 7 Kliewer S A, Sundseth S S, Jones S A, Brown P J, Wisely G B, Koble C S, Devchand P. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator activated receptors α and γ.  Proc Natl Acad Sci USA. 94 4318-4323 1997; 
• 8 Koch M, Rett K, Maerker E, Volk A, Haist K, Deninget M, Renn W, Häring H U. The PPAR-γ2 amino acid polymorphism pro12ala is prevalent in offspring of Type II diabetic patients and is associated to increased insulin sensitivity in a subgroup of obese subjects.  Diabetologia. 42 758-762 1999; 
• 9 Lehmann J, Moore L B, Smith-Oliver T A, Wilkison W O, Wilson T M, Kliewer S A. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ).  J Biol Chem. 270 12953-12956 1995; 
• 10 Mancini F P, Vaccaro O, Sabatino L, Tufano A, Rivellese A A, Riccardi G, Colantuoni V. Pro12ala substitution in the peroxisome proliferator-activated receptor-γ2 is not associated with type II diabetes.  Diabetes. 48 1466-1468 1999; 
• 11 Okazawa H, Mori H, Tamori Y, Araki S, Niki T, Masugi J, Kawanishi M, Kubota T, Shinoda H, Kasuga M. No coding mutations are detected in the peroxisome-activated receptor-γ gene in Japanese patients with lipoatrophic diabetes.  Diabetes. 46 1904-1906 1997; 
• 12 Ringel J, Engeli S, Distler A, Sharma A M. Pro12ala missense mutation of the peroxisome proliferator activated receptor γ and diabetes mellitus.  Biochem Biophys Res Commu. 254 450-453 1999; 
• 13 Schoonjans K, Staels B, Auwerx J. Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression.  J Lipid Res. 37 907-925 1996; 
• 14 Spiegelman B M. PPAR-gamma: adipogenic regulation and thiazolidinedione receptor.  Diabetes. 47 507-514 1998; 
• 15 Vigouroux C, Fajas L, Khallouf E, Meier M, Gyapay G, Lascols O, Auwerx J, Weissenbach J, Capeau J, Magre J. Human peroxisome proliferator-activated receptor-γ2. Genetic mapping, identification of a variant in the coding sequence, and exclusion as the gene responsible for lipotrophic diabetes.  Diabetes. 47 490-492 1998; 
• 16 Yen C-J, Beamer B A, Negri C, Silver K, Brown K A, Yarnall D P, Burns D K, Roth J, Shuldiner A R. Molecular Scanning of the human peroxisome proliferator activated receptor γ (hPPARγ) gene in diabetic Caucasians: Identification of a pro12ala PPARγ2 missense mutation.  Biochem Biophys Res Comm. 241 270-274 1997;