PLA2G7 genotype, lipoprotein-associated phospholipase A2 activity, and coronary heart disease risk in 10 494 cases and 15 624 controls of European Ancestry

Abstract

Background: Higher lipoprotein-associated phospholipase A(2)(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 studies; n=26 118) was undertaken to examine the association of the following: (1) Lp-PLA2 activity versus cardiovascular biomarkers and risk factors and CHD events (2 prospective studies; n=4884); (2) PLA2G7 single-nucleotide polymorphisms and Lp-PLA2 activity (3 prospective, 2 case-control, 2 cross-sectional studies; up to n=6094); and (3) PLA2G7 single-nucleotide polymorphisms 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 ratios for CHD events for the top versus bottom quartile of Lp-PLA2 activity were 1.61 (95% confidence interval, 1.31 to 1.99) and 1.17 (95% confidence interval, 0.91 to 1.51) after adjustment for baseline traits. Of 7 single-nucleotide polymorphisms, rs1051931 (A379V) showed the strongest association with Lp-PLA2 activity, with VV subjects having 7.2% higher activity than AAs. Genotype was not associated with risk markers, angiographic coronary disease (odds ratio, 1.03; 95% confidence interval, 0.80 to 1.32), or CHD events (odds ratio, 0.98; 95% confidence interval, 0.82 to 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 single-nucleotide polymorphisms with larger effects, or randomized trials of specific Lp-PLA2 inhibitors are needed to confirm or refute a contributory role for Lp-PLA2 in CHD.

Figure 1

Mean differences in cardiovascular traits by quartiles of Lp-PLA2 activity in NPHS-II and EPIC-Norfolk. Subjects from the bottom quartile (Q1) were used as the reference group. Footnote: This analysis are based on data from the control group of the EPIC-Norfolk study (n = 1760) and the all participants from the prospective study NPHS-II (n= 2278) with the relevant information.

Figure 2

Hazard ratio (HR) of coronary heart disease risk by quartiles of Lp-PLA2 activity in NPHS-II and EPIC-Norfolk. Left panel describe the shape of the association using the minimally adjusted model (model-1). Right panel describe the effect on the HR (top vs. bottom quartile) of progressive levels of adjustment. Footnote: Hazard ratios for all the quartile with the different level of adjustment are reported in supplementary Table-4.

Figure 3

Mean differences by genotype in the Lp-PLA2 activity levels according the PLA2G7 variants evaluated. Data pooled from up to 7 studies (NPHS-II, EPIC-Norfolk, Cyprus, UDACS, AtheroGene, LURIC and THROMBO) including up to 6094 individuals.

Figure 4

Mean differences in cardiovascular risk factors by rs1051931 genotype according to the PLA2G7 variants evaluated. Data pooled from up to 10 studies (all studies excluding SAS and WTCCC-CHD) and 13,544 individuals. The X-axes from the previous plots are the same as those in Figure 1, in order to increase visual comparability.

Figure 5a

Relative odds of CHD associated with PLA2G7 variants. Data pooled from up to 10 studies (NPHS-II, EPIC-Norfolk, WH-II, HIFMECH, Edinburgh Artery, AtheroGene, LURIC, Cyprus, SAS and WTCCC-CHD) including up to 10,494 CHD events.

Figure 5b

Effect of the rs1051931 variant on the risk of CHD stratified by outcome. CHD: Coronary heart disease includes fatal and non-fatal events. Specific definitions used within each studies are described in methods section. Angiographic-CAD: coronary artery disease defined by coronary angiography, specific study definitions reported in methods section. * P-values for heterogeneity between outcome (CHD vs. angiographic-CAD) were calculated by meta-regression.