Functional Variant in the α _2B Adrenoceptor Gene, a Positional Candidate on Chromosome 2, Associates With Hypertension

Abstract

Abstract-In a genome-wide scan in Scandinavians, we found suggestive linkage between early-onset primary hypertension and a region on chromosome 2. The ␣ 2B -adrenoceptor gene, a candidate gene within this region, harbors a functional insertion/deletion (I/D) polymorphism of three glutamate residues. The aim of this study was to investigate if the DD genotype is associated with hypertension in Swedes. We performed an association study between the I/D polymorphism of the ␣ 2B -adrenoceptor and hypertension in the Skaraborg population. The material consists of all known patients with primary hypertension in Skara (nϭ772 nondiabetic subjects; nϭ171 normoalbuminuric type 2 diabetic subjects) and 817 population control subjects. We first compared genotype frequencies between patients with early-onset hypertension (aged 50 years or younger at onset) and subjects with normotension (blood pressure Ͻ120/80 mm Hg). Thereafter, the polymorphism was tested for association with hypertension at the population level. When comparing patients with early-onset hypertension and normotensive subjects, the DD versus II genotype was associated with early-onset hypertension when diabetic subjects were excluded from the analysis (ORϭ2.0; 95% CIϭ1.2 to 3.5) or when they were not excluded (ORϭ1.8; 95% CIϭ1.0 to 3.1). At the population level, the DD versus II genotype was weakly associated with nondiabetic hypertension (ORϭ1.4; 95% CIϭ1.0 to 1.8). Our data suggest that carriers of the DD versus II genotype of the ␣ 2B -adrenoceptor are at increased risk for hypertension. The genotypic effect is most evident when comparing groups corresponding to the upper and lower tails of the blood pressure distribution in the population; however, in nondiabetic hypertensive subjects it is weakly detectable even at the population level. Key Words: receptors Ⅲ adrenergic Ⅲ genetics Ⅲ hypertension H uman primary hypertension is likely to be of a complex nature, arising from environmental and genetic factors. A positive family history of hypertension strongly predicts early-onset hypertension, but the predictive value gradually decreases with increasing age at onset of the disease. 1 This suggests that hypertension susceptibility gene variants are more common in patients with early-onset primary hypertension (EOHT) than in patients with late-onset hypertension.To clarify the genetics behind blood pressure variation and the development of primary hypertension, a wide variety of techniques have been developed. Of these, the genome-wide scan method is the only one that can identify regions of the genome that are linked to variation in blood pressure and to primary hypertension independently of available physiological knowledge of blood pressure regulation. We recently published a genome-wide scan for EOHT in Scandinavian families and found suggestive evidence of linkage on chromosome 2 with a 1-LOD decrease interval stretching between Ϸ109 to 121 cM. 2 Interestingly, this locus overlaps with linkage results of several other genome-wide scans for hypertension ...

Genetic Variation at the Human α 2B -Adrenergic Receptor Locus

“…With respect to hypertension, our data in the large cohorts are consistent with an earlier study with a smaller sample 20 but contrast with those of Von Wowern et al (2004), 21 who showed an increased risk (ORϭ2.01) for early-onset (younger than 50 years old) hypertension in Swedish ␣ 2B -AR Del/Del homozygotes, an effect that lost significance in an all-age population. Even when we stratified our data and compared younger versus older subjects (using age 40, as reported, or when we used age 50 as a cutoff, data not shown), we failed to find evidence to support the conclusions of Von Wowern et al (2004), perhaps because of differences between our white population and their more ethnically homogenous Swedish population.…”

“…We did not observe statistically significant association with the SNPs at ␣ 2A -AR and ␣ 2C -AR; however, we observed a trend for association with the ␣ 2B -AR SNP. This result, coupled with evidence for association of a variant in that receptor with early-onset hypertension, 21 led us to undertake more thorough sequencing and genotyping studies on ␣ 2B -AR.…”

“…19 Although some studies have found no association between this genotype and hypertension, 15,20 a Swedish population of individuals homozygous for the deletion were reported to have increased risk for early-onset hypertension. 21 Akin to the ␣ 2B -AR, the ␣ 2C -AR has a 12-bp deletion variant in its third intracellular loop, which leads to decreased coupling of the receptor to G␣ i 22 ; blacks homozygous for the deletion allele are at increased risk for developing congestive heart failure. 23 In this study, we identified novel genetic variants of the ␣ 2B -ARs and assessed the contribution of common genetic variants of ␣ 2A , ␣ 2B , and ␣ 2C -ARs to interindividual differences in BP using 3 independent cohorts of subjects phenotyped for BP traits.…”

Genome-Wide Scan for Premature Hypertension Supports Linkage to Chromosome 2 in a Large Kyrgyz Family

“…[17][18][19] With the accumulated evidence for the implication of 2q23 to q36 in harboring loci, which may influence control of bp, the focus is now on taking such studies forward into candidate gene analysis. 28 Haplotype analysis of our Kyrgyz pedigree has suggested a small interval that may be responsible for the premature hypertensive phenotype. The current release of the human genome assembly, available through Ensembl (www.ensembl.org), indicates that the 2q24.3 to q31.1 region between markers D2S2380 and D2S335 (166.5 to 175.9 cM) spans Ͻ9 megabase pairs and encompasses 36 genes of known or predicted function.…”

Recent Trends in Hypertension Genetics Research

“…The human  2B -adrenoceptor is encoded by the ADRA2B gene located on chromosome 2q12 (Regan et al 1988). A common variant form of the this gene which encodes a receptor protein with a insertion/deletion (I/D) of three glutamate residues located in the third intracellular loop of the receptor has been associated with EHT (Lockette et al1995;Wowern et al 2004). …”