ROLE OF THE BETA(3)-ADRENERGIC RECEPTOR LOCUS IN OBESITY AND NONINSULIN-DEPENDENT DIABETES AMONG MEMBERS OF CAUCASIAN FAMILIES WITH A DIABETIC SIBLING PAIR

Obesity and insulin resistance are important risk factors for the deve lopment of noninsulin-dependent diabetes (NIDDM) and are prevalent amo ng predisposed first degree relatives of diabetic individuals. Recent molecular screening and analysis of a common missense mutation of the beta(3)-adrenergic receptor gene suggested this locus as a strong cand idate for increased obesity, earlier age of diabetes onset, and insuli n resistance. To test the hypothesis that the beta(3)-adrenergic recep tor locus affects diabetes susceptibility, obesity as measured by body mass index, and components of the insulin resistance syndrome, we exa mined the role of this region in families ascertained for two or more NIDDM siblings. Linkage analysis was conducted using both parametric a nd nonparametric analyses, including multipoint sibling pair analysis. We found no evidence for linkage to NIDDM as a dichotomsus trait and no evidence for Linkage to body mass index, waist/hip ratio, insulin l evels, or glucose levels as quantitative traits or to reported age of onset among NIDDM individuals. The Trp(64) Arg missense mutation was p resent in 11% of the population. The mutation was not associated with NIDDM, and Arg(64) carriers did not have earlier NIDDM onset, higher b ody mass index, or higher waist/hip ratio than Trp(64) homozygotes. Am ong relatives, Arg(64) carriers had significantly lower fasting glucos e levels and lower waist/hip ratios than Trp(64) homozygotes, but no c haracteristics of the insulin resistance syndrome. We conclude that th e beta(3)-adrenergic receptor locus does not play an important role in NIDDM susceptibility or in the insulin resistance syndrome among memb ers of families with a strong predisposition to NIDDM.