ASSOCIATION OF TRP64ARG MUTATION OF THE BETA-3-ADRENERGIC-RECEPTOR WITH NIDDM AND BODY-WEIGHT GAIN

A possible pathogenic mutation in the beta 3-adrenergic-receptor gene (Trp64Arg) has been reported to be associated with an earlier age of o nset of non-insulin-dependent diabetes mellitus (NIDDM) and clinical f eatures of the insulin resistance syndrome in Pima Indian, Finnish and French subjects. Since marked heterogeneity has been reported in the association of mutations of candidate genes with NIDDM between Japanes e and other ethnic groups, we investigated the association of Trp64Arg with NIDDM in Japanese subjects. The allele frequency of the mutation (Arg) was slightly but not significantly, higher in NIDDM than in con trol subjects (70 out of 342 alleles [20.5%] vs 40 out of 248 [16.1%], respectively, p > 0.2). When our data were combined with those of Pim a Indian and Finnish subjects, however, the Arg/Arg genotype was signi ficantly associated with NIDDM as compared with the other two genotype s (p < 0.005, relative risk [RR] 2.13, 95% confidence interval [CI] 1. 28-3.55). The Arg allele was also associated with NIDDM (p < 0.05, RR 1.27, 95% CI 1.06-1.52). Japanese subjects homozygous for the mutation had a significantly higher body mass index (mean +/- SD: 25.5 +/- 3.9 kg/ m(2)) than heterozygotes (22.6 +/- 4.1, p < 0.05) and normal homo zygotes (22.8 +/- 3.8, p < 0.05). NIDDM patients homozygous for the mu tation tended to have an earlier age of onset of NIDDM than those with other genotypes. These data suggest that the Trp64Arg mutation not on ly contributes to weight gain and age-at-onset of NIDDM but is also as sociated with susceptibility to NIDDM.