Molecular analysis and pharmacogenetic assessment of calcium signaling pathway variation.

摘要

One in three American adults has hypertension. Less than half of those individuals have achieved blood pressure control despite the availability of efficacious pharmacotherapy. The current study aimed to determine whether genetic variation within Ca2+ signaling pathway genes may provide insight into the variability in responses observed to commonly used antihypertensives. Additionally, we sought to investigate the functional mechanisms of a clinically associated polymorphism found within this pathway.;Blood pressure (BP) response to atenolol and hydrochlorothiazide was evaluated relative to genetic variation among Ca2+ signaling pathway candidate genes among uncomplicated hypertensives. We identified several significant and novel associations within CACNA1C (calcium channel, voltage-dependent, L type, alpha 1c subunit) and BP response to atenolol among blacks.;We then evaluated the relationship between genetic variation of the Ca 2+ signaling pathway and clinical susceptibility to adverse cardiovascular outcomes in a high-risk cohort of hypertensives with coronary artery disease. Herein we identified several significant and novel pharmacogenetic treatment interactions among three different racial/ethnic groups. Additionally, several polymorphisms within CACNA1C significant for BP response among uncomplicated hypertensives also demonstrated significant associations with adverse cardiovascular outcomes in our high-risk cohort.;Finally, we used human vascular tissue to evaluate whether differential expression of mRNA, protein, or transcription factor binding could be observed relative to the clinically associated CACNB2 (calcium channel, voltage-dependent, beta 2 subunit) rs2357928 polymorphism. The current data show promising trends for an association with differential expression of mRNA, but definitive conclusions cannot be made due to a limiting sample size. Additional investigation is warranted, as the genetic associations reported here have yet to be replicated in an independent study population and a functional evaluation of molecular mechanisms would benefit greatly from a larger sample cohort.