Program Nr: 1715 for the 2006 ASHG Annual Meeting

Influence of 2-adrenergic receptor (ADRB2) haplotypes on obesity-related traits and interaction with physical activity in adolescent Caucasians. C.N. Moran1, M.E.S. Bailey1, A. Tsiokanos2, A.Z. Jamurtas2, Y.P. Pitsiladis1, R.H. Wilson1. 1) Div. of Molec. Genet. and IDEAL, IBLS, Univ. of Glasgow, Glasgow, UK; 2) Dept of Phys. Education and Sport Sci., University of Thessaly, Trikala, Greece.
   Genetic variation in human ?adrenergic receptor genes has been reported to be associated with obesity and degree of adiposity. We have carried out an association study of obesity-related phenotypes and the ADRB2 gene in 1084 teenage Greeks. Three polymorphisms were investigated, p.G16R (c.46G>A), p.E27Q (c.79G>C) and the rarer p.T164I (c.491C>T). Ancestral and derived alleles are known from primate sequences and from existing haplotype data. The receptor encoded by the A-allele at codon 16 (p.16R) is known to desensitise less quickly in the presence of agonist, thus extending signalling half-life and probably affecting downstream lipolytic pathways in adipocytes. Associations (tested by ANOVA) were found only in males, there being a strong association between p.G16R genotype and both BMI (P=0.002), and skinfold thicknesses. These associations were best explained by an A-allele dominant model with homozygotes and heterozygotes for the derived A-allele exhibiting lower values of BMI. Investigating the influence of lifestyle on these associations, we found that the association was strongest in very active males, accounting for up to 9.4% of the phenotypic variance in BMI by ANOVA. Cumulative probability plots showed that the association acts across the full phenotype distribution. The three common haplotypes defined by the p.G16R and p.E27Q polymorphisms showed the same degree of association with BMI as p.G16R alone. p.T164I arose on a haplotype that contained the ancestral p.16G and derived p.27Q variants. When p.16G-27Q haplotypes were split into those with and without the derived p.164I variant (MAF=2%), the proportion of phenotypic variance in BMI explained rose from 3.2% to 5.2%, suggesting that the p.T164I polymorphism influences adiposity phenotypes through interaction effects with other coding or noncoding variants. These findings are commensurate both with a history of selection at this locus and an impact on body composition and response of adipose tissue to exercise in modern populations.