Haplotype analysis of the PPARγ Pro12Ala and C1431T variants reveals opposing associations with body weight

We have genotyped a large population with type 2 diabetes (n = 1107), two populations of non-diabetics from Glasgow (n = 186) and Dundee (n = 254) and also a healthy group undergoing physical training (n = 148) and investigated the association of genotype with body mass index. This analysis has demonstrated that the Ala12 and T1431 alleles are present together in approximately 70% of the carriers. By considering the other 30% of individuals with haplotypes that only carry one of these polymorphisms, we have demonstrated that the Ala12 allele is consistently associated with a lower BMI, whilst the T1431 allele is consistently associated with higher BMI.This study has therefore revealed an opposing interaction of these polymorphisms, which may help to explain previous inconsistencies in the association of PPARG polymorphisms and body weight.PPARγ plays a fundamental role in adipogenesis and insulin sensitisation [1] and is a candidate gene for susceptibility to obesity and type II diabetes mellitus. A common structural polymorphism has been detected in the PPARγ gene consisting of a proline (Pro) to alanine (Ala) substitution [2]). and is located at codon 12 (Pro12Ala) of PPARγ2. The Ala containing variant may have reduced activity compared to the Pro isoform [3]). This polymorphism has been extensively investigated for association with obesity and type 2 diabetes mellitus [3-25]. The Ala allele is associated with a modest protective effect against type 2 diabetes with an odds ratio of 0.8 [4]. Increased weight and body mass index, which themselves predispose to type 2 diabetes, have however been inconsistently associated with the Pro12Ala polymorphism with some studies indicating that the Ala allele is associated with a higher BMI [5,18,24,25], a lower BMI [3,8,26,27], while other studies have found no association [11,24,28-30]. A second polymorphism has been detected in exon 6 at nucleotide 1431 of PPARG[2] resulting in a silent substitution from C to T (C1431T), th