Complex haplotypes derived from noncoding polymorphisms of the intronless α2A-adrenergic gene diversify receptor expression

α2A-adrenergic receptors (α2AAR) regulate multiple central nervous system, cardiovascular, and metabolic processes including neurotransmitter release, platelet aggregation, blood pressure, insulin secretion, and lipolysis. Complex diseases associated with α2AAR dysfunction display familial clustering, phenotypic heterogeneity, and interindividual variability in response to therapy targeted to α2AARs, suggesting common, functional polymorphisms. In a multiethnic discovery cohort we identified 16 single-nucleotide polymorphisms (SNPs) in the α2AAR gene organized into 17 haplotypes of two major phylogenetic clades. In contrast to other adrenergic genes, variability of the α2AAR was primarily due to SNPs in the promoter, 5′ UTR and 3′ UTR, as opposed to the coding block. Marked ethnic variability in the frequency of SNPs and haplotypes was observed: one haplotype represented 70% of Caucasians, whereas Africans and Asians had a wide distribution of less common haplotypes, with the highest haplotype frequencies being 16% and 35%, respectively. Despite the compact nature of this intronless gene, local linkage disequilibrium between a number of SNPs was low and ethnic-dependent. Whole-gene transfections into BE(2)-C human neuronal cells using vectors containing the entire ≈5.3-kb gene without exogenous promoters were used to ascertain the effects of haplotypes on α2AAR expression. Substantial differences (P < 0.001) in transcript and cell-surface protein expression, by as much as ≈5-fold, was observed between haplotypes, including those with common frequencies. Thus, signaling by this virtually ubiquitous receptor is under major genetic influence, which may be the basis for highly divergent phenotypes in complex diseases such as systemic and pulmonary hypertension, heart failure, diabetes, and obesity.