The PPAR ÃÂ³ (P12A) Locus-Associated Diabetes Risk is Modulated by Central Obesity in Punjabi Sikhs
Background: Several studies have reported a common proline-to-alanine substitution (P12A) in the peroxisome proliferator-activated receptor gamma (PPARγ) gene to be invariably associated with obesity, insulin resistance, type 2 diabetes mellitus (T2DM) and dyslipidemia. The purpose of this study was to determine whether the PPARγ gene (P12A) polymorphism contributes to susceptibility to T2DM and central obesity in Khatri Sikh community from India. Methods: We studied 1711 subjects comprising 1186 individuals from 324 families and 525 unrelated nondiabetic controls. We tested the association between T2D and P12A polymorphism using logistic regression before and after adjusting for age, gender, and other covariates. We also examined the impact of these variants on obesity, glucose homeostasis and lipid traits using multiple linear regression analysis. Results: Our findings could not confirm the association of PPARγ polymorphism with T2DM in this familybased sample. However, the comparison of unrelated controls with affected relatives (n=537) revealed a marginally significant association with this locus with T2DM (odds ratio (OR) 1.48, P=0.016). However, in the data stratified by traits related to abdominal obesity, there was a significant increase in T2DM risk in the individuals with waist circumference (>37 inches, OR 3.51, P=0.005) and waist to hip ratio (>0.95, OR 3.02, P= 0.003) in younger relatives. Conclusions: PPARγ (P12A) locus appears to have profound influence in promoting insulin sensitivity through its interaction with central obesity particularly at younger age.