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.

Protective role of Lipoprotein-Associated Phospholipase A2 Gene (A379V) Polymorphism against Myocardial Infarction among Egyptians

“…Also, sutton et al, 26 reported that 379V polymorphism was more prevalent among MI patients than controls with a significant difference (p=0.002) which was against our results. this dissimilarity in results may be due to differences in ethnic groups, sample size and selection criteria of patients and controls.…”

Associations of platelet-activating factor acetylhydrolase gene polymorphisms with risk of ischemic stroke

“…The association of R92H with cardiovascular disease is also contradictory. Sutton et al (8) reported that the R92H polymorphism was significantly associated with the risk of CHD, with the R92H variant allele observed more frequently in the experiment group compared to the control group. Zheng et al (14) identified the significant association of the R92H variant with premature myocardial infarction in the Chinese population.…”

“…V279F in exon 9 of the PAF-AH gene is associated with coronary artery disease and carotid atherosclerosis in the Japanese population. R92H in exon 4 is associated with coronary artery disease in the USA (8). According to this information, we hypothesized that the genetic variants in PAF-AH may have a critical role in the susceptibility to ischemic stroke.…”

Nonsynonymous polymorphisms in PLA2G7 gene are associated with the risk of coronary heart disease in a southern Chinese population

“…But in other studies, such as Wang et al (2010), did not find association between V279F and CHD. Views toward roles that R92H and I198T mutations play in the development of CHD have also been controversial (Hou et al 2009;Sutton et al 2008;Wang et al 2010). Study type, ethnic differences, inclusion criteria, and other factors may be the reasons for these diversities of conclusions.…”

“…Studies on the biological function related to the same variant in PLA2G7 SNPs remain quite contrary. For example, Sutton et al found that R92H was the most significantly associated SNP, while no difference was found between case group and control group with I198T mutations (Sutton et al 2008). Xu et al pointed out that R92H was protective factor against CHD in females (Xu et al 2013).…”