Association of Hypertension with β ₂ - and α _2c10 -Adrenergic Receptor Genotype

Abstract

The adrenergic receptors have been implicated in the pathogenesis of essential hypertension. We hypothesized that hypertension is associated with variants at the beta2-adrenergic receptor locus and at one of the alpha2-adrenergic receptor loci. In unrelated individuals, we measured untreated blood pressure and characterized each subject as hypertensive or normotensive. We then used genomic DNA to identify beta2- and alpha2c10-adrenergic receptor restriction fragment length polymorphisms. In 175 subjects (49 percent with hypertension, 55 percent black), both hypertension and race were associated with genotype at the beta2 locus (chi2 for hypertension = 11, P = .004, chi2 for race = 8.8, P = .012). The association with hypertension persisted in each race group separately (blacks only: chi2 = 9.6, P = .008; whites only; chi2 = 14.2, P = .001). This association persisted in a logistic model that controlled for race (P = .01). Genotype was also significantly associated with baseline systolic, diastolic, and mean arterial blood pressures (P = .05, .01, and .02, respectively). These data suggest that the beta2-adrenergic receptor gene is a candidate gene for hypertension in blacks and whites. We also genotyped subjects at the alpha2-adrenergic receptor coded on chromosome 10. There was no association between hypertension and genotype at the alpah2c10 locus in the total group or in blacks, but there was significant association in whites (chi2 = 6.7, P = .03). These data suggest that the beta2- and alph2c10-adrenergic receptor genes may contribute, in a race-specific manner, to the inheritance of essential hypertension. Linkage studies in related individuals are needed to confirm these findings.

Clinical and pharmacological significance of α2-adrenoceptor polymorphisms in cardiovascular diseases

“…Genotyping using the restriction enzyme DraI, which allows the detection of polymorphism in the 3V-flanking region of the a2A-AR gene, generated inconsistent results. Indeed, association between this polymorphism and hypertension was found in a white population in one study [40] but not in another [50]. On the other hand, a third report has demonstrated the presence of association in black American population [38].…”

Complex haplotypes derived from noncoding polymorphisms of the intronless α 2A -adrenergic gene diversify receptor expression

“…The most frequently studied is the DraI RFLP in the context of hypertension and related phenotypes. An initial report showed a marginal (P ϭ 0.03) association between the DraI RFLP and hypertension in Caucasians but not African Americans (11). In contrast, another study revealed a marginal (P ϭ 0.02) association with this RFLP and hypertension in African Americans but not Caucasians (12).…”

“…The critical roles of ␣ 2A ARs in these physiologic processes has prompted association and family studies of receptor genetic variability to identify potential risk factors or disease modifiers and pharmacogenomic studies to identify potential treatment-response loci for multiple central nervous system, cardiovascular, and metabolic diseases (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23). These studies were performed with single restriction fragment-length polymorphisms (RFLPs) of the ␣ 2A AR gene, such as a DraI RFLP, and generally have shown only weak or no associations or a lack of reproducibility.…”

Pharmacology and Physiology of Human Adrenergic Receptor polymorphisms

“…For most of the noncoding polymorphisms, no associations have been found with multiple pathological conditions linked to α 2A AR function, including hypertension, panic and mood disorders, schizophrenia, and obesity (92,99,(101)(102)(103)(104)(105). In contrast, several clinical phenotypes, including hypertension, body fat distribution, and glucose metabolism, have been shown to be associated with a Dra I restriction fragment length polymorphism within the 3 UTR (106)(107)(108)(109). However, because the functional relevance of this polymorphism has not been determined, the significance of these results remains unclear.…”