Common polymorphisms of the PPAR-?2 (Pro12Ala) and PGC-1? (Gly482Ser) genes are associated with the conversion from impaired glucose tolerance to type 2 diabetes in the STOP-NIDDM trial

Abstract

Aim/hypothesis. We investigated the effects of the common polymorphisms in the peroxisome proliferator-activated receptor γ2 (PPAR-γ2; Pro12Ala) and in PPAR-γ coactivator 1α (PGC-1α; Gly482Ser) genes on the conversion from impaired glucose tolerance to type 2 diabetes in participants in the STOP-NIDDM trial. This trial aimed to study the effect of acarbose in the prevention of type 2 diabetes. Methods. Genotyping was performed in 770 study subjects whose DNA was available. The Gly482Ser variant in the PGC-1α gene was determined with the polymerase chain reaction amplification, Hpa II enzyme digestion, and gel electrophoresis. The Pro12Ala polymorphism of the PPAR-γ2 gene was determined by the polymerase chain reaction-singlestrand conformation polymorphism analysis. Results. The Pro12Pro genotype of the PPAR-γ2 gene predicted the conversion to diabetes in women in the acarbose group (odds ratio 2.89, 95% CI 1.20 to 6.96; p=0.018). The 482Ser allele of the PGC-1α gene had a significant interaction with the mode of treatment (p=0.012), and in the placebo group the 482Ser allele was associated with a 1.6-fold higher risk for type 2 diabetes compared to the Gly482Gly genotype (95% CI 1.06 to 2.33; p=0.023). Acarbose prevented the development of diabetes independently of the genotype of the PPAR-γ2 gene, but only the carriers of the 482Ser allele of the PGC-1α gene were responsive to acarbose treatment. Conclusion/interpretation. We conclude that the Pro12Pro genotype of the PPAR-γ2 gene and the 482Ser allele of the PGC-1α gene are associated with the conversion from impaired glucose tolerance to type 2 diabetes in the STOP-NIDDM trial.

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

“…ORs varied from 2.30 to 2.92 after the adjustment for confounding factors. The presence of one risk allele (that of either PGC-1A or PPARD; Table 2) in subjects of the placebo group resulted in a 1.5 increase in the risk of diabetes, a finding similar to that observed earlier for the 482Ser allele of PGC-1A alone (15). The simultaneous presence of the PPARD risk allele and the 482Ser allele of PGC-1A increased the risk up to 2.2-fold, suggesting an additive effect.…”

“…The C allele of rs6902123 was more frequent among women who converted to diabetes compared with women who did not. In logistic regression analysis, the presence of the C allele in women increased the risk for the conversion to diabetes by 2.47-fold (95% CI 1.32-4.63; Next, we investigated whether the SNPs of PPARD further increased the risk for the conversion to diabetes in carriers of the Gly482Ser (rs8192687) substitution of PGC-1A, which was previously shown to increase the risk of diabetes in participants of the STOP-NIDDM trial (15). To this aim, study participants were classified into three groups: subjects having both the nonrisk genotype of PPARD and the nonrisk genotype of PGC-1A (Gly482Gly) (the reference group), subjects with one risk allele of either PPARD or PGC-1A, and subjects possessing both the risk allele of PPARD and the 482Ser risk allele of PGC-1A.…”

“…Moreover, PPAR-␦ itself can increase expression of PGC-1␣ and lead to mitochondrial biogenesis and enhanced oxidative phosphorylation (3). The Gly482Ser substitution of PGC-1A has been linked to increased risk of diabetes (15,20), but no association of SNPs of PPARD with diabetes has been reported. The novel finding of our study was that SNPs of PPARD together with the Gly482Ser polymorphism of PGC-1A increased the risk of diabetes by 2.2-fold.…”

Meta-analysis of the Gly482Ser variant in PPARGC1A in type 2 diabetes and related phenotypes

“…Other possible explanations for the heterogeneity observed are gene-gene and geneenvironment interactions such that the effect of the Gly482Ser polymorphism is different in different populations. Indeed, evidence for gene-environment interaction at this gene has been demonstrated [23][24][25]. Geneenvironment interactions may lower the power to detect true associations when performing cross-sectional studies, including meta-analysis of cross-sectional studies, such as in this study.…”

The Ala allele in the PPAR-γ2 gene is associated with reduced risk of type 2 diabetes mellitus in Caucasians and improved insulin sensitivity in overweight subjects

“…The I 2 test was 30 %, indicating moderate inconsistency between studies. Grouping by ethnicity, Caucasians (n 36) and non-Caucasians (n 13), and excluding the multicentre Andrulionytè et al (20) , produced the following results Total (95 % CI) Heterogeneity: χ 2 = 57·20, df = 48 (P =0·17); I 2 = 16 % Test for overall effect: Z = 2·30 (P =0·02) Test for subgroup differences: χ 2 = 0·00, df = 1 (P =0·97), I 2 = 0 % Weight (%) 0·5 0·5 0·5 2·5 1·5 9·2 4·6 0·3 1·0 0·1 0·9 0·8 22·4 0·1 0·5 1·1 0·6 0·4 1·2 0·2 2·0 1·6 1·7 6·1 2·6 1·1 1·1 0·6 1·0 1·3 0·5 2·8 1·0 15·3 3·8 4·2 4·9 0·5 0·8 0·6 7·1 4·5 2·2 0·3 2·0 0·9 0·5 0·7 0·3 1·5 0·0 77·6 100·0 -0·50 (-1·02, for Caucasians: OR 2 0·04 (95 % CI 2 0·11, 0·02, P¼0·22); and non-Caucasians: OR 2 0·05 (95 % CI 2 0·12, 0·03, P¼0·23). The subgroup of Caucasians showed heterogeneity (P¼0·01), with 39 % of the studies contributing to this, according to results of I 2 ; however, the subgroup of nonCaucasians was homogeneous (P¼0·49).…”