Comprehensive Biochemical Analysis of Rare Prostacyclin Receptor Variants: STUDY OF ASSOCIATION OF SIGNALING WITH CORONARY ARTERY OBSTRUCTION*

摘要: Currently, pharmacogenetic studies are at an impasse as the low prevalence (<2%) of most variants hinder their analysis with population sizes often inadequate for sufficiently powered studies. Grouping rare mutations by functional phenotype rather than mutation site can potentially increase sample size. Using human population-based (n = 1,761) to search dysfunctional prostacyclin receptor (hIP) variants, we recently discovered 18 non-synonymous mutations, all frequencies less 2% in our study cohort. Eight had defects binding, activation, and/or protein stability/folding. Mutations (M113T, L104R, and R279C) three highly conserved positions demonstrated severe misfolding manifested impaired binding activation cell surface receptors. To assess association coronary artery disease, performed a case-control comparing angiographic results from patients reduced cAMP production arising 23) that no reduction 17). Major obstruction was significantly increased group comparison silent mutations. We then compared 23 69 age- risk factor-matched controls (1:3). This verified disease variant demonstrates potential utility vitro characterization predicting clinical phenotypes represents comprehensive genetic date.