Haplotype structure of the β₂-adrenergic receptor gene in 814 Danish Caucasian subjects and association with body mass index

Several single nucleotide polymorphisms (SNPs) have been identified in the beta(2)-adrenergic receptor gene (ADRB2). By the use of five SNPs (G46A, C79G, C491T, C523A, G1053C) for identification of ADRB2 haplotypes in 814 Danish Caucasians, we investigated whether ADRB2 haplotypes are associated with body mass index (BMI). The SNPs showed organization into 13 distinct haplotypes and 41 haplotype pairs. The study identified four common haplotypes: ACCCC (10.1 +/- 0.3%), ACCCG (27.9 +/- 0.3%), GCCAC (10.8 +/- 0.1%) and GGCCG (41.0 +/- 0.2%) (frequencies +/- SD), seen in 91% of the population. In the total population (mean age +/- SD: 50 +/- 16 years), BMI was not related to haplotype pairs, individual SNPs or allelic haplotypes. However, in subjects<50 years (N = 356, 36 +/- 8 years) BMI levels varied significantly between pairs of major haplotype groups (p=0.014) but were not related to individual SNPs. In subjects <37 years, the haplotype pair homozygote for the Gly16 and Glu27 amino acid variants (GGCCG/GGCCG) had a higher frequency of lean subjects (BMI <= 25 kg/m(2)) compared with the GCCAC/GGCCG pair (73% versus 35%, odds ratio with 95% confidence interval: 4.95 (1.50-16.38)). In conclusion, the haplotype analysis clearly revealed the prevalence of four major ADRB2 haplotypes in Caucasians. The results suggest that unique interactions in specific haplotype pairs rather than individual SNPs may affect BMI and that this effect of ADRB2 haplotypes is blunted by age-related factors.