Editorials

Polymorphisms of β-adrenergic receptors in heart failure

In humans, three genes—ADRB1, ADRB2 and ADRB3—encode β-adrenoreceptors (ADRB); these molecules mediate the action of catecholamines in multiple tissues and play pivotal roles in cardiovascular, respiratory, metabolic, and immunological functions. Genetic variants in ADRB genes have been associated with widespread diseases and conditions, but inconsistent results have often been obtained. Here, we addressed the recent evolutionary history of ADRB genes in human populations. Although ADRB1 is neutrally evolving, most tests rejected neutral evolution for ADRB2 in European, African, and Asian population samples. Analysis of inferred haplotypes for ADRB2 revealed three major clades with a coalescence time of 1–1.5 million years, suggesting that the gene is either subjected to balancing selection or undergoing a selective sweep. Haplotype analysis also revealed ethnicity-specific differences. Additionally, we observed significant deviations from Hardy-Weinberg equilibrium (HWE) for ADRB2 genotypes in distinct European cohorts; HWE deviation depends on sex (only females are in disequilibrium), and genotypes displaying maximum and minimum relative fitness differ across population samples, suggesting a complex situation possibly involving epistasis or maternal selection. Overall, our data indicate that future association studies involving ADRB2 will benefit from taking into account ethnicity-specific haplotype distributions and sex-based effects. With respect to ADRB3, our data indicate that the gene has been subjected to a selective sweep in African populations, the Trp64 variant possibly representing the selection target. Given the previous association of the ancestral ADRB3 Arg64 allele with obesity and type 2 diabetes, dietary adaptations might represent the underlying selective force.

β-Adrenoceptor antagonists have revolutionized the management of heart failure in humans. However, fundamental questions remain concerning their use. Currently, there is considerable debate about the role of β₂-adrenoceptors in heart failure and whether incremental clinical benefit can be obtained by blockade of β₂-adrenoceptors in addition to β₁-adrenoceptors. Polymorphic forms of β₁- and β₂-adrenoceptors exist, which might contribute to the variable clinical outcomes that are observed with β-adrenoceptor antagonists. There is evidence for a low-affinity state of β₁-adrenoceptors and ventricular β₃-adrenoceptors, and these are discussed in the context of heart failure. Finally, there is seemingly paradoxical evidence that restoration and normalization of the β-adrenoceptor system is beneficial in animal models of heart failure. We reconcile this view with the current clinical use and proven benefit of β-adrenoceptor antagonists.