β3-adrenoceptor gene variant in obesity and insulin resistance

Mauriège and Bouchard (Sept 14, p 698)1Mauriège P Bouchard C Trp64Arg mutation in β3-adrenoceptor gene of doubtful significance for obesity and insulin resistance.Lancet. 1996; 348: 698-699Summary Full Text Full Text PDF PubMed Scopus (41) Google Scholar state that the Trp64Arg variant in the β3-adrenoceptor receptor is of doubtful importance for obesity and insulin resistance. On the contrary, we believe that this variant is a modest but important contributor to these polygenic disorders. Several susceptibility genes, each with modest effect–in addition to physiological provocations (ie, caloric excess and sedentary lifestyle) and time–are likely to be required for expression of the obesity and non-insulin dependent diabetes mellitus (NIDDM) phenotypes. The Trp64Arg β3-adrenoceptor variant is probably one of these susceptibility genes. First, association studies in several cohorts (including Pima Indians, French, Finns, Mexican Americans, Danes, Australians, and Japanese) link the Trp64Arg β3-adrenoceptor variant to features of the insulin-resistance syndrome (central obesity, hyperinsulinaemia with insulin resistance, and hypertension), and an earlier onset of NIDDM. In these studies (for review, see 2Shuldiner AR Silver KD Candidate genes for non-insulin dependent diabetes mellitus.in: LeRoith D Taylor SI Olefsky JM Diabetes mellitus. A fundamental and clinical text. Lippincott-Raven, Philadelphia1996: 565-574Google Scholar) the effect of the Trp64Arg variant is modest but consistent. Second, Yoshida3Yoshida T Sakane N Umekawa T Sekal M Takahashi T Kondo M Mutation of β3-adrenergic-receptor gene and response to treatment of obesity.Lancet. 1995; 346: 1433-1434PubMed Scopus (194) Google Scholar has shown that Japanese women with the Trp64Arg variant have lower resting metabolic rates, and are more resistant to weight-loss treatment, a finding suggesting that this variant is clinically relevant. Third, the variant is common in diverse populations, and thus has worldwide health implications. Among the populations studied, there are quantitative (gene dose) and qualitative differences in phenotypic expression of the Trp64Arg variant. These differences suggest that ethnic (genetic) background is an important determinant of expression. The Trp64Arg variant may influence several traits (epistasis) related to the insulin-resistance syndrome, but other genetic factors unique to a given ethnic group may also be influential in trait expression. The presence of other NIDDM and obesity susceptibility genes in a specific population may modify the effects of the Trp64Arg variant, or even mask the signs or symptoms. Differences in the degree or type (s) of environmental provocations among populations with the Trp64Arg allele may account for variation in the expression of particular traits between these populations. The Trp64Arg β3AR variant may also be expressed according to sex. Thus, Trp64Arg β3-adrenoceptor has been associated with obesity and increased visceral fat in women, but not in men.4Kurabayashi T Carey DGP Morrison NA The β3-adrenergic receptor gene Trp64Arg mutation is overrepresented in obese women. Effects on weight, BMI, abdominal fat, blood pressure, and reproductive history in an elderly Australian population.Diabetes. 1996; 45: 1358-1363Crossref PubMed Google Scholar Additionally, differences in the reported effects of Trp64Arg β3-adrenoceptor may be due to subtle variations in study design, the selection of individuals, the characterisation of phenotypes, or in statistical analyses. With respect to NIDDM, several studies have shown that the Trp64Arg variant is no more frequent in persons with diabetes than in those without. However, in a meta-analysis by Fujisawa and colleagues5Fujisawa T Ikegami H Yamato E et al.Association of Trp64Arg mutation of the β3-adrenergic receptor with NIDDM and body weight gain.Diabetologia. 1996; 39: 349-352Crossref PubMed Scopus (159) Google Scholar the variant was significantly associated with NIDDM (OR: 2·13 in Trp64Arg homozygotes, 1·27 in heterozygotes). More important, the Trp64Arg β3-adrenoceptor variant was associated in several populations with a significantly earlier onset of NIDDM.