A quantitative trait locus influencing BMI maps to the region of the beta-3 adrenergic receptor

The beta-3 adrenergic receptor (ADRB3) has been implicated as a regulator o f energy expenditure, and a polymorphism in codon 64 of this gene (Trp64Arg ) has been associated in some studies with obesity and insulin resistance. However, many studies have failed to detect an effect of this variant, and the importance of the Trp64Arg variant in human obesity remains controversi al. We performed a quantitative linkage analysis of the ADRB3 and obesity, using 12 markers (including the intragenic Trp64Arg polymorphism) spanning a 57-cM region of chromosome 8, The study population consisted of 470 indiv iduals from 10 large multigenerational families of Mexican-American ancestr y residing in San Antonio, TX. In two-point analysis, logarithm of odds (LO D) scores >1.0 were observed for six markers surrounding ADRB3 in a 33-cM r egion spanned by markers D8S1477 and D8S1136, The multipoint LOD score was 3,21, occurring between markers D8S1121 and ADRB3, similar to 2-3 cM from A DRB3, Adjusting for the presence of the Arg64 allele or excluding from the analysis the 11 individuals homozygous for the Arg64 allele did not reduce the evidence for linkage. A genome scan was conducted at 10 cM map density to detect other loci influencing variation in BMI, Multipoint LOD scores >1 .0 were observed in four other regions, including two on chromosome 17, one on chromosome 6q, and one on chromosome 2p, These data suggest that the AD RB3 should continue to be regarded as a strong candidate gene for obesity e ven though evidence for an effect of the Trp64Arg polymorphism could not be established. It is also possible that a gene closely linked to ADRB3 may i nfluence susceptibility to obesity.