Molecular scanning for mutations in the β₃-adrenergic receptor gene in nauruans with obesity and noninsulin-dependent diabetes mellitus

We recently identified a mutation in the human β₃-adrenergic receptor (β₃AR) gene (codon 64 TGG(Trp)→CGG(Arg); TRP64ARG) that associates with features of the insulin resistance syndrome and an earlier onset of noninsulin-dependent diabetes mellitus (NIDDM). We scanned the β₃AR gene for mutations by single stranded conformational polymorphism analysis in 20 Nauruans with obesity and NIDDM. No mutations were identified. Sixty-five Nauruan subjects were genotyped for the TRP64ARG β₃AR. All subjects were homozygous for the normal allele. We genotyped Samoans and Asians for the TRP64ARG β₃AR. Seven of 52 Samoans were heterozygous for the mutant arginine allele (allele frequency, 0.07). Of these, 5 were diabetic and 2 were nondiabetic (by Fisher's exact test, P = 0.4). There were trends toward increased body mass indices, waist to hip ratios, and 2-h insulin levels during oral glucose tolerance tests in Samoans with the mutation; however, the limited number of subjects available for study precluded rigorous statistical analysis. The TRP64ARG β₃AR was also detected in Chinese, Chinese Americans, and subjects from the Indian subcontinent. In conclusion, the TRP64ARG β₃AR mutation or any other mutation in the β₃AR gene is not a major contributor to genetic susceptibility to NIDDM and obesity likely in Nauruans.