Polymorphisms of cardiac presynaptic α2C adrenergic receptors: Diverse intragenic variability with haplotype-specific functional effects

KM Small, J Mialet-Perez, CA Seman… - Proceedings of the …, 2004 - National Acad Sciences
KM Small, J Mialet-Perez, CA Seman, CT Theiss, KM Brown, SB Liggett
Proceedings of the National Academy of Sciences, 2004National Acad Sciences
The presynaptic α2C adrenergic receptors (AR) act to inhibit norepinephrine release in
cardiac and other presynaptic nerves. We have recently shown that a genetic variant in the
α2CAR coding region (Del322-325), which renders the receptor partially uncoupled from Gi,
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 …
The presynaptic α2C adrenergic receptors (AR) act to inhibit norepinephrine release in cardiac and other presynaptic nerves. We have recently shown that a genetic variant in the α2CAR coding region (Del322-325), which renders the receptor partially uncoupled from Gi, 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 insertion/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 ≈50% 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 α2CDel322-325 marker.
National Acad Sciences