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

Alex Doney,David M Flavell,Douglas Boyle,Michael World,David Frew,Bettina Fischer,Andrew Morris,Hugh E Montgomery,Colin Na Palmer,Alastair Cumming

doi:10.1186/1471-2156-3-21

Abstract

BackgroundVariation at the PPARG locus may influence susceptibility to type 2 diabetes and related traits. The Pro12Ala polymorphism may modulate receptor activity and is associated with protection from type 2 diabetes. However, there have been inconsistent reports of its association with obesity. The silent C1431T polymorphism has not been as extensively studied, but the rare T allele has also been inconsistently linked to increases in weight. Both rare alleles are in linkage disequilibrium and the independent associations of these two polymorphisms have not been addressed.ResultsWe 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.ConclusionThis 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.

Highlights

Variation at the PPARG locus may influence susceptibility to type 2 diabetes and related traits
The two polymorphisms were in tight linkage disequilibrium, as shown in table 2, suggesting that phenotypes observed with one polymorphism may be due to linkage with the other
PPARG polymorphisms are associated with altered weight ranges As the effect of genotype was dependant on the weight range of the population, we examined the distribution of BMI in the total population in more detail

Summary

Introduction

Variation at the PPARG locus may influence susceptibility to type 2 diabetes and related traits. The silent C1431T polymorphism has not been as extensively studied, but the rare T allele has been inconsistently linked to increases in weight. 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 [3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25]. Shown an association of the T1431 allele with higher BMI [25,33]

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Conclusion