PLA2G7 Genotype, Lipoprotein-Associated Phospholipase A ₂ Activity, and Coronary Heart Disease Risk in 10 494 Cases and 15 624 Controls of European Ancestry

Abstract

Background Higher Lp-PLA2 activity is associated with increased risk of coronary heart disease (CHD), making Lp-PLA2 a potential therapeutic target. PLA2G7 variants associated with Lp-PLA2 activity could evaluate whether this relationship is causal. Methods and Results A meta-analysis including a total of 12 studies (5 prospective, 4 case-control, 1 case-only and 2 cross-sectional, n=26,118) was undertaken to examine the association of: (i) LpPLA2 activity vs. cardiovascular biomarkers and risk factors and CHD events (two prospective studies; n=4884); ii) PLA2G7 SNPs and Lp-PLA2 activity (3 prospective, 2 case-control, 2 cross-sectional studies; up to n=6094); and iii) PLA2G7 SNPs and angiographic coronary artery disease (2 case-control, 1 case-only study; n=4971 cases) and CHD events (5 prospective, 2 case-control studies; n=5523). Lp-PLA2 activity correlated with several CHD risk markers. Hazard ratio for CHD events top vs. bottom quartile of Lp-PLA2 activity was 1.61 (95%CI: 1.31, 1.99) and 1.17 (95%CI: 0.91, 1.51) after adjustment for baseline traits. Of seven SNPs, rs1051931 (A379V) showed the strongest association with Lp-PLA2 activity, VV subjects having 7.2% higher activity than AAs. Genotype was not associated with risk markers, angiographic coronary disease (OR 1.03 (95%CI 0.80, 1.32), or CHD events (OR 0.98 (95%CI 0.82, 1.17). Conclusions Unlike Lp-PLA2 activity, PLA2G7 variants associated with modest effects on Lp-PLA2 activity were not associated with cardiovascular risk markers, coronary atheroma or CHD. Larger association studies, identification of SNPs with larger effects, or randomised trials of specific Lp-PLA2 inhibitors are needed to confirm/refute a contributory role for Lp-PLA2 in CHD.

Modulation of oxidative stress, inflammation, and atherosclerosis by lipoprotein-associated phospholipase A2

“…In a Taiwanese cohort, A379V was associated with increased risk of MI and increased severity of CAD ( 138 ). In contrast, a study of European Caucasians revealed reduced risk of MI in homozygotes for A379V ( 158 ), but metaanalyses of European Caucasian populations reported no association with CHD risk ( 56,156 ). In South Koreans, a similar lack of association between A379V and CVD disease was reported ( 137 ).…”

“…In contrast to the V279F allele associated primarily with Asian populations, three relatively well-studied nonsynonymous Lp-PLA 2 polymorphisms (R92H, I198T, and A379V) have been observed in all populations studied so far ( 142,156 ). The variants have been functionally characterized using molecular approaches ( 157 ).…”

Genetics of Coronary Artery Disease

“…Similarly, although data from epidemiological and clinical studies supported a potentially important role of lipoprotein-associated phospholipase A2 in atherosclerosis and its sequelae, 74,75 the genetic variants near PLA2G7 and CETP associated with LP-PLA2 levels and activity did not confer CAD risk. 76,77 In accord with these findings, the results of phase III randomized controlled trials of inhibitors of these enzymes (varespladib 78 and darapladib 79 ) were also negative. A closer inspection of MR data before drug design and initiation of clinical trials could, thus, help to mitigate the high costs of drug development.…”

Genome-Wide Association Study Evaluating Lipoprotein-Associated Phospholipase A 2 Mass and Activity at Baseline and After Rosuvastatin Therapy

“…[9][10][11] Previous investigations of genetic determinants of plasma Lp-PLA 2 focused on the gene that encodes Lp-PLA 2 (PLA2G7) and genes encoding other inflammatory molecules. 8,12,13 A genome-wide association study (GWAS) of circulating Lp-PLA 2 was performed among 6688 participants of the Framingham Heart Study (FHS).…”