Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies

Abstract

Background: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), an inflammatory enzyme expressed in atherosclerotic plaques, is a therapeutic target being assessed in trials of vascular disease prevention. We investigated associations of circulating Lp-PLA(2) mass and activity with risk of coronary heart disease, stroke, and mortality under different circumstances.

Methods: With use of individual records from 79 036 participants in 32 prospective studies (yielding 17 722 incident fatal or non-fatal outcomes during 474 976 person-years at risk), we did a meta-analysis of within-study regressions to calculate risk ratios (RRs) per 1 SD higher value of Lp-PLA(2) or other risk factor. The primary outcome was coronary heart disease.

Findings: Lp-PLA(2) activity and mass were associated with each other (r=0.51, 95% CI 0.47-0.56) and proatherogenic lipids. We noted roughly log-linear associations of Lp-PLA(2) activity and mass with risk of coronary heart disease and vascular death. RRs, adjusted for conventional risk factors, were: 1.10 (95% CI 1.05-1.16) with Lp-PLA(2) activity and 1.11 (1.07-1.16) with Lp-PLA(2) mass for coronary heart disease; 1.08 (0.97-1.20) and 1.14 (1.02-1.27) for ischaemic stroke; 1.16 (1.09-1.24) and 1.13 (1.05-1.22) for vascular mortality; and 1.10 (1.04-1.17) and 1.10 (1.03-1.18) for non-vascular mortality, respectively. RRs with Lp-PLA(2) did not differ significantly in people with and without initial stable vascular disease, apart from for vascular death with Lp-PLA(2) mass. Adjusted RRs for coronary heart disease were 1.10 (1.02-1.18) with non-HDL cholesterol and 1.10 (1.00-1.21) with systolic blood pressure.

Interpretation: Lp-PLA(2) activity and mass each show continuous associations with risk of coronary heart disease, similar in magnitude to that with non-HDL cholesterol or systolic blood pressure in this population. Associations of Lp-PLA(2) mass and activity are not exclusive to vascular outcomes, and the vascular associations depend at least partly on lipids.

Funding: UK Medical Research Council, GlaxoSmithKline, and British Heart Foundation.

Figure 1

Cross-sectional associations of Lp-PLA₂ activity Table 1 shows number of participants included in each analysis. Webappendix p 9 shows cross-sectional associations of Lp-PLA₂ mass. Error bars represent 95% CIs. r=Pearson's partial correlation coefficient (95% CI) adjusted for age, sex, history of diabetes, and baseline history of vascular disease. Lp-PLA₂=lipoprotein-associated phospholipase A₂. *Lp-PLA₂ activity and mass were standardised to a mean of 0·00 (SD 1·00) in each study.

Figure 2

Minimally adjusted risk ratios for coronary heart disease, ischaemic stroke, and death due to vascular and non-vascular causes by fifths of Lp-PLA₂ activity or mass at baseline Risk ratios were adjusted for age, sex, baseline history of vascular disease, history of diabetes, and trial group (as appropriate). The webappendix p 11 shows more fully adjusted risk ratios. Data are shown for the 71 439 participants who were initially healthy or had a history of stable vascular disease at baseline only. One unit on the standardised scale is equal to 1 SD on the untransformed scale. Error bars represent 95% CIs. The sizes of the boxes are proportional to the inverse of the variance of the risk ratios. Lp-PLA₂=lipoprotein-associated phospholipase A₂. *Fatal and non-fatal events.

Figure 3

Risk ratios for coronary heart disease, ischaemic stroke, and vascular and non-vascular mortality per 1 SD higher Lp-PLA₂ activity or mass at baseline, adjusted for several risk factors Risk ratios were adjusted for the non-lipid and lipid risk factors described in table 2. We noted no significant differences in risk ratios between people with and without a history of stable vascular disease at baseline, apart from for vascular death with Lp-PLA₂ mass (p=0·007). Data for patients with recent acute ischaemic events are shown in webappendix p 16. Error bars represent 95% CIs. The sizes of the boxes are proportional to the inverse of the variance of the RRs. Lp-PLA₂=lipoprotein-associated phospholipase A₂. RR=risk ratio. *Diagnosis more than 30 days before baseline of myocardial infarction, angina, other coronary heart disease, stroke (including transient ischaemic attack), peripheral vascular disease, or coronary surgery (including revascularisations). †Fatal and non-fatal events.

Figure 4

Adjusted risk ratios for coronary heart disease per 1 SD higher baseline Lp-PLA₂ activity, mass, and several conventional risk factors in a common set of participants Analyses were restricted to participants with complete information (3278 events in 34 762 participants who were initially healthy or had a history of stable vascular disease at baseline from seven studies). RRs were adjusted for the non-lipid and lipid risk factors described in table 2. Error bars represent 95% CIs. The sizes of the boxes are proportional to the inverse of the variance of the risk ratios. Lp-PLA₂=lipoprotein-associated phospholipase A₂. RR=risk ratio. *Current smoker versus other (never or ex-smoker). †To aid comparison with the other risk factors, the RR with HDL cholesterol is shown per 1 SD lower baseline levels.