A study on the genetics of obesity: Influence of polymorphisms of the beta-3-adrenergic receptor and insulin receptor substrate 1 in relation to weight loss, waist to hip ratio and frequencies of common cardiovascular risk factors

Beta-3-adrenergic receptor (beta-3-AR) and insulin receptor substrate 1 (IR S-1) have been implicated in the pathogenesis of obesity and in obesity rel ated increase in insulin resistance which is associated with, among other d iseases. dyslipidemia and type 2 diabetes mellitus. We studied 210 white fe male Caucasian obese subjects, who underwent a formal weight loss program ( Optifast (R)). We examined the association between mutations of the IRS-1 g ene at codon 972, mutations of the beta-3-AR gene at codon 64, and the comb ination of both mutations with the degree of weight loss, waist to hip rati o and the prevalence of hypertension, dyslipidemia and type 2 diabetes mell itus. Twenty-four women (11.4%) were polymorph only for the beta-3-AR mutation. 2 3 women (10.9%) only for the IRS-1 mutation, and 6 subjects (2.9%) were pol ymorph for both alleles. No patient displayed a homozygous polymorphism. Si milar frequencies of these polymorphisms were observed when the 100 non-obe se control women were tested (14.0, 15.0, 3.0, respectively). After 13 week s of weight loss the group with multiple polymorph alleles had lost less of their weight than the obese controls: without mutation (Delta BMI 5.32+/-0 .18 versus 6.12+/-0.2 kg/m(2), p<0.05). In this group. the frequency of typ e 2 diabetes (66.7%) was significantly higher than in the obese control gro up without mutations(16.7%, p=0.008). Our findings suggest there is a synergy between the polymorphisms of Trp64A rg beta-3-AR and Gly972Arg IRS-1 in Caucasian German obese women leading to a decreased weight loss. This seems to be accompanied with an increased fr equency of type 2 diabetes.