Abstract 293: Comprehensive Genetic Analysis of the Platelet Activating Factor Acetylhydrolase Gene and Cardiovascular Disease in Case/Control and Family Datasets
Platelet Activating Factor Acetylhydrolase (PAFAH) is a potent pro- and anti-inflammatory molecule that has been implicated in multiple inflammatory disease processes, including cardiovascular disease. The goal of this study was to investigate the genetic effects of PAFAH in two large, independent coronary artery disease (CAD) datasets (CATHGEN and GENECARD) to better elucidate its genetic role in CAD. Using a haplotype tagging (ht) approach, 19 htSNPs were genotyped in CATHGEN case/control samples (cases = 807 and controls = 267) and in the GENECARD Family Study (n= 1,101 families, 2,954 individuals). Single SNP analysis using logistic regression was performed on all CATHGEN subjects, resulting in nine SNPs showing significant association in all CATHGEN subjects (P-values ranged 0.0004 – 0.02). CATHGEN cases were further stratified into subgroups based on age of CAD onset (AOO) and severity of disease; 600 young affecteds (YA, AOO<56) and 207 old affected (OA, AOO >56) to provide a consistent validation set for the early onset CAD GENECARD Family study. After stratification of subjects based on AOO, the OA subgroup remained the most associated, with 14 SNPs significantly associated (P-value ranged 0.0001– 0.02). Logistic regression analysis of the GENECARD probands resulted in similar association to that seen in the YA CATHGEN cases (P-values ranged 0.002– 0.05). Of the 19 SNPs genotyped, three SNPs (I198T, A379V, and R92H) were nonsynonymous coding changes. Interestingly, rs1051931 (A379V) and rs1805017 (R92H) constituted the most significantly associated SNPs, even after Bonferroni correction and appear to represent independent associations (r2 = 0.09). Haplotype analysis was also performed on all 19 SNPs using a two-SNP sliding window approach, resulting in significant association in 161 of 171 haplotypic combinations. In summary, PAFAH represents an important, potentially functional candidate in the pathophysiology of CAD based on numerous associations using two independent data sets and multiple statistical approaches. Functional studies are warranted to evaluate the functional consequences of R92H and A379V polymorphisms.