Haplotype structure of the beta adrenergic receptor genes in US Caucasians and African Americans

Abstract

The beta-adrenergic receptors (beta-AR) are G protein-coupled receptors activated by epinephrine and norepinephrine and are involved in a variety of their physiological functions. Previously, three beta-AR genes (ADRB1, ADRB2 and ADRB3) were resequenced, identifying polymorphisms that were used in genetic association studies of cardiovascular and metabolic disorders. These studies have produced intriguing but inconsistent results, potentially because the known functional variants: ADRB1 Arg389Gly and Gly49Ser, ADRB2 Arg16Gly and Gln27Glu, and ADRB3 Arg64Trp provided an incomplete picture of the total functional diversity at these genes. Therefore, we created marker panels for each beta-AR gene that included the known functional markers and also other markers evenly spaced and with sufficient density to identify haplotype block structure and to maximize haplotype diversity. A total of 27 markers were genotyped in 96 US Caucasians and 96 African Americans. In both populations and for each gene, a single block with little evidence of historical recombination was observed. For each gene, haplotype captured most of the information content of each functional locus, even if that locus was not genotyped, and presumably haplotype would capture the signal from unknown functional loci whose alleles are of moderate abundance. This study demonstrates the utility of using beta-AR gene haplotype maps and marker panels as tools for linkage studies on beta-AR function.

Common ß-adrenergic receptor polymorphisms are not associated with risk of sudden cardiac death in patients with coronary artery disease

“…The observed allele and haplotype frequencies differed by ethnicity and were comparable to those for the general US population. 13 We observed no association between the 4 SNPs and odds of SCD for cases compared to both control groups for all 4 genetic models. Odds ratios for SCD for Case vs. CAD Control and Case vs. Non-CAD Control comparisons for the dominant and recessive models are presented in Figure 1.…”

“…The observed allele and haplotype frequencies differed by ethnicity, and were similar to those obtained in the SCD Case Control study and previous reports. 13,18 Risk for the outcomes of SCD, SCD + NFVA, and all-cause mortality, were examined for each SNP under the 4 genetic models. The risks for SCD, SCD + NFVA, and all-cause mortality as assessed by the dominant and recessive models for all SNPs tested are shown in Figure 2.…”

“…2,[8][9][10][11][12] Two common nonsynonymous single nucleotide polymorphisms (SNPs) in each of the single-exon β1AR and β2AR genes are observed: β1AR Ser49Gly and Arg389Gly, and β2AR Gly16Arg and Gln27Glu, the latter two of which are in linkage disequilibrium (LD). 13 Carriers of the β1AR Gly49 allele are associated with a better survival in congestive heart failure (CHF) 14 , while the β1AR Gly389 allele is associated with a lower risk for VT. 15 β2AR Gly16Arg and Gln27Glu result in altered receptor downregulation and trafficking in transfected cells. 16 Recent evidence also suggests a role of these β2AR SNPs in survival and pharmacogenetic response to β blockers following acute coronary syndrome (ACS) 17 , and in the risk for out-of-hospital sudden death.…”

A46G and C79G polymorphisms in the β2-adrenergic receptor gene (ADRB2) and essential hypertension risk: a meta-analysis

“…This is very likely due to the linkage disequilibrium between A46G and C79G. [38][39][40] Owing to linkage disequilibrium, subjects homozygous for G79 are nearly always homozygous for G46, whereas naturally occurring A46/G79 is rare. [41][42][43] Pojoga et al 6 observed that AA46/ CC79 was significantly associated with higher blood pressure, which might be attributed to the enhancement of the AA46/CC79 diplotype.…”

β2-Adrenergic receptor gene variants and risk for autism in the AGRE cohort

“…[38][39][40] Both polymorphisms showed Hardy-Weinberg proportions among the founders. Haplotype frequencies among founders are given in Table 2, and indicate high LD between these polymorphisms (D 0 = 0.99; P-value < 0.0001; r 2 = 0.42).…”