Comprehensive genetic analysis of the platelet activating factor acetylhydrolase (PLA2G7) gene and cardiovascular disease in case-control and family datasets

Abstract

Platelet-activating factor acetylhydrolase (PLA2G7) 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 PLA2G7 on coronary artery disease (CAD) risk in two large, independent datasets with CAD. Using a haplotype tagging (ht) approach, 19 ht single nucleotide polymorphisms (SNPs) were genotyped in CATHGEN case-control samples (cases = 806 and controls = 267) and in the GENECARD Family Study (n = 1101 families, 2954 individuals). Single SNP analysis using logistic regression revealed nine SNPs with significant association in all CATHGEN subjects (P = 0.0004-0.02). CATHGEN cases were further stratified into subgroups based on age of CAD onset (AOO) and severity of disease; 599 young affecteds (YA, AOO <56) and 207 old affected (OA, AOO >56). Significant genetic effects were observed in both OA and YA (P = 0.0001-0.02). The GENECARD probands demonstrated results similar to those seen in the YA CATHGEN cases (P = 0.002-0.05). Of the 19 SNPs genotyped, 3 SNPs result in nonsynonymous coding changes (I198T, A379V and R92H). Two of the coding SNPs, R92H and A379V, constitute two of the most significantly associated SNPs, even after Bonferroni correction and appear to represent independent associations (r(2) = 0.09). Multiple additional polymorphisms in low linkage disequilibrium with these coding SNPs were also strongly associated. In summary, PLA2G7 represents an important, potentially functional candidate in the pathophysiology of CAD based on replicated associations using two independent datasets and multiple statistical approaches. Further functional studies involving a combination of risk alleles are warranted.

Figure 1

PLA2G7 gene schematic and linkage disequilibrium (LD). Nineteen SNPs genotyped in PLA2G7 are depicted in the schematic and are placed according to their genetic location. Coding SNPs are denoted by a double solid arrow. Open arrow indicate intergenic regions, and solid arrows indicate SNPs located in intronic regions. LD plot was visualized using the program Haploview. R² values for Caucasian control samples from CATHGEN are depicted.

Figure 2

PLA2G7 genotype odds ratio plot for old affected (OA) and young affected (YA) individuals. Solid circles represent SNPs with P-values of <0.05 in the OA, open circles represent P-values of >.0.05 in OA. Circles with a SNP name on graph indicate SNPs with P < 0.001 in OA. Odds ratios are adjusted for race and sex.