Comprehensive biochemical analysis of rare prostacyclin receptor variants: study of association of signaling with XXXX .

@entity1 @entity73317 @entity268 @entity73319 @entity301 @entity453 @entity73318
Currently, pharmacogenetic studies are at an impasse as the low prevalence (<2%) of most variants hinder their pharmacogenetic 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 @entity1 population-based studies (n = 1,761) to search for dysfunctional @entity1 prostacyclin receptor (hIP) variants, we recently discovered 18 non-synonymous mutations, all with frequencies less than 2% in our study cohort. Eight of the 18 had defects in binding, activation, and/or protein stability/folding. Mutations ( @entity73317 , @entity73318 , and @entity73319 ) in three highly conserved positions demonstrated severe misfolding manifested by impaired binding and activation of cell surface receptors. To assess for association with @entity453 , we performed a case-control study comparing coronary angiographic results from @entity1 with reduced @entity268 production arising from the non-synonymous mutations (n = 23) with @entity1 with non-synonymous mutations that had no reduction in @entity268 (n = 17). Major @entity453 was significantly increased in the dysfunctional mutation group in comparison with the silent mutations. We then compared the 23 dysfunctional receptor @entity1 with 69 age- and risk factor-matched controls (1:3). This verified the significantly increased @entity301 . This study demonstrates the potential utility of in vitro functional characterization in predicting clinical phenotypes and represents the most comprehensive characterization of @entity1 prostacyclin receptor genetic variants to date.
