PPARG and ADIPOQ gene polymorphisms increase type 2 diabetes risk in Asian Indian Sikhs: Pro12Ala still remains the strongest predictor

摘要

We have examined the association of 14 tagging single nucleotide polymorphisms (tagSNPs) in peroxisome proliferator activated-receptor gamma transcripts 1 and 2 (PPARG1&2) and 5 tagSNPs in adiponectin (ADIPOQ) genes for their effect on type 2 diabetes (T2D) risk in Asian Indian Sikhs. A total of 554 T2D cases and 527 normoglycemic (NG) controls were examined for association with T2D and other sub-phenotypes of T2D. With the exception of a strong association of PPARG2/Pro12Ala with T2D [OR 0.13, 95%CI (0.03–0.56), p=0.0007], no other tagSNP in the PPARG locus revealed any significant association with T2D in this population. Similarly, none of the tagSNPs in the ADIPOQ gene was associated with T2D susceptibility in single-site analysis. However, haplotype analysis provided strong evidence of association of these loci with T2D. Three-site haplotype analysis in the PPARG locus using the two marginally associated SNPs (P/rs11715073 and P/rs3892175) in combination with Pro12 Ala (P/rs1801282) revealed a strong association of one ‘risk’ (CGC) (p=0.003; permutation p=0.015) and one ‘protective’ (CAC) (p =0.001; permutation p=0.005) haplotype associated with T2D. However, the major effect still appears to be driven by Pro12Ala as the association of these haplotypes did not remain significant when analyzed conditional upon Pro12Ala (p = 0.262). Additionally, two-site haplotype analysis in the ADIPOQ locus using only two marginally associated SNPs (AD/rs182052 and AD/rs7649121) revealed a significant protective association of the GA haplotype with T2D (p=0.009; permutation p=0.026). Multiple linear regression analysis also revealed significant association of an ADIPOQ variant (AD/rs12495941) with total body weight (p= 0.010), waist (p=0.024) and hip (p=0.021), although these associations were not significant after adjusting for multiple testing. Our new findings strongly suggest that the genetic variation in PPARG and ADIPOQ loci could contribute to risk for the development of T2D in Indian Sikhs. Identification of causal SNPs in these important biological and positional candidate genes would help determine true physiological significance of these loci in T2D and obesity.