Polymorphisms of cardiac presynaptic α _2C adrenergic receptors: Diverse intragenic variability with haplotype-specific functional effects

Abstract

The presynaptic ␣2C adrenergic receptors (AR) act to inhibit norepinephrine release in cardiac and other presynaptic nerves. We have recently shown that a genetic variant in the ␣2CAR coding region (Del322-325), which renders the receptor partially uncoupled from G i, is a risk factor for heart failure. However, variability of heart failure phenotypes and a dominance of Del322-325 in those of African descent led us to hypothesize that other regions of this gene have functional polymorphisms. In a multiethnic population, we found 20 polymorphisms within 4,625 bp of contiguous sequence of this intronless gene encompassing the promoter, 5 UTR, coding, and 3 UTR. These polymorphisms occur in 24 distinct haplotypes with complex organizations, including multiple 5 -upstream polymorphisms in regions known to direct expression, a 3 UTR substitution polymorphism within an insertion͞ deletion sequence, and the radical coding polymorphism that deletes four amino acids. Relatively low linkage disequilibrium between many polymorphisms, few cosmopolitan haplotypes, prevalent ethnic-specific haplotypes, and substantial genetic divergence among haplotypes was noted. The dysfunctional Del322-325 allele was partitioned into multiple haplotypes, with frequencies of 48% to 2%. The functional implications of the haplotypes were ascertained by whole-gene transfections of human neuronal cells, where haplotype was significantly related (P < 0.001) to expression levels of receptor transcript and protein. Expression varied by as much as Ϸ50% by haplotype, and such studies enabled haplotype clustering by phenotypic, rather than genotypic, similarities. Thus, depending on phenotype, expression-specific haplotypes may amplify, attenuate, or dominate the cardiomyopathic effect attributed to the ␣2CDel322-325 marker.T he adrenergic receptors (ARs), whose endogenous ligands are epinephrine and norepinephrine, are members of the superfamily of seven transmembrane spanning G proteincoupled receptors. ARs modulate a host of functions relative to the sympathetic nervous system, including neurotransmitter release, and cardiac, vascular, pulmonary, renal, metabolic, and central nervous system function. For over a decade, it has been known that the expression and͞or function of ARs varies considerably between individuals (1), even when studies are carried out under stringent conditions in normal individuals. Similarly, the physiologic or clinical response to receptor agonists and antagonists shows marked interindividual variability (2, 3). One explanation for such variability is that ARs are dynamically regulated by multiple mechanisms so as to maintain homeostasis, and that individuals may be under different environmental influences such that receptor expression or function is altered. However, considerable evidence has accumulated over the last few years suggesting that interindividual differences in receptor expression or function is based on genetic variability of the genes encoding these receptors (4).Of recent interest has been genetic variabil...

Effects of a α2C-Adrenoreceptor Gene Polymorphism on Neural Responses to Facial Expressions in Depression

“…This study has limitations. First, recent work shows substantial divergence between certain a 2C haplotypes and a partitioning of the a 2C Del322-325 polymorphism into multiple haplotypes (Small et al, 2004). In addition, it was shown that these haplotypes influence cellular expression of the a 2C -AR transcript and protein.…”

Alpha-adrenoceptor gene variants and autonomic nervous system function in a young healthy Japanese population

“…a 2A -AR Asn251Lys polymorphism was not detected. The allele frequencies of these polymorphisms were different for different ethnic backgrounds as shown in previous reports (Shibata et al 1996;Small et al 2004Small et al , 2006Xie et al 1999). Table 2 shows the clinical characteristics for each a-AR polymorphism according to the genotype.…”

“…Finally, the findings in the present study should be considered as preliminary because several other polymorphisms have been identified in each a-AR (Buzas et al 2004;Gu et al 2006;Small et al 2004Small et al , 2006, and therefore, the haplotype or gene-gene interactions may modulate the association of a-AR polymorphisms with cardiac autonomic function. Analyses stratified by the haplotypes or combined genotypes for the a-AR polymorphisms are required in a large number of subjects.…”

“…However, ethnic variations in the frequencies of different haplotypes consisting of 20 a 2C -AR polymorphisms (Small et al 2004) may be important in the impact of the a 2C Del322-325 variant on the pathology of cardiac disease. In addition, Small et al (2002) reported the synergistic effect of the a 2C Del322-325 and b 1 -AR Gly389Arg polymorphisms on the development of heart failure.…”

“…First, because the study subjects included only male Japanese, our conclusions cannot be generalized to other populations. In this context, the distribution patterns of the studied a-AR polymorphisms are different among various races (Shibata et al 1996;Small et al 2004Small et al , 2006Xie et al 1999). Second, the study subjects were young and healthy, therefore, present observations should be considered cautiously in relation to the pathology of hypertension or cardiovascular diseases and can not be applied to the phenotypes of patients with these diseases.…”