Abstract
BackgroundThe Asia-specific PLA2G7 994G-T transversion leads to V279F substitution within the lipoprotein-associated phospholipase-A2 (Lp-PLA2) and to absence of enzyme activity in plasma. This variant offers a unique natural experiment to assess the role of Lp-PLA2 in the pathogenesis of coronary artery disease (CAD) in humans. Given conflicting results from mostly small studies, a large two-stage case-control study was warranted.Methodology/Principal Findings PLA2G7 V279F genotypes were initially compared in 2890 male cases diagnosed with CAD before age 60 with 3128 male controls without CAD at age 50 and above and subsequently in a second independent male dataset of 877 CAD cases and 1230 controls. In the first dataset, the prevalence of the 279F null allele was 11.5% in cases and 12.8% in controls. After adjustment for age, body mass index, diabetes, smoking, glucose and lipid levels, the OR (95% CI) for CAD for this allele was 0.80 (0.66–0.97, p = 0.02). The results were very similar in the second dataset, despite lower power, with an allele frequency of 11.2% in cases and 12.5% in controls, leading to a combined OR of 0.80 (0.69–0.92), p = 0.002. The magnitude and direction of this genetic effect were fully consistent with large epidemiological studies on plasma Lp-PLA2 activity and CAD risk.ConclusionsNatural deficiency in Lp-PLA2 activity due to carriage of PLA2G7 279F allele protects from CAD in Korean men. These results provide evidence for a causal relationship between Lp-PLA2 and CAD, and support pharmacological inhibition of this enzyme as an innovative way to prevent CAD.
Highlights
Elevated levels of lipoprotein-associated phospholipase A2 (LpPLA2), an enzyme involved in the generation of pro-inflammatory products in atherosclerotic plaques, have been consistently associated with an increased risk for coronary artery disease (CAD) and other vascular diseases in Caucasian and other ethnic groups, including Koreans
Natural deficiency in lipoprotein-associated phospholipase-A2 (Lp-PLA2) activity due to carriage of PLA2G7 279F allele protects from CAD in Korean men
These results provide evidence for a causal relationship between Lp-PLA2 and CAD, and support pharmacological inhibition of this enzyme as an innovative way to prevent CAD
Summary
Elevated levels of lipoprotein-associated phospholipase A2 (LpPLA2), an enzyme involved in the generation of pro-inflammatory products in atherosclerotic plaques, have been consistently associated with an increased risk for coronary artery disease (CAD) and other vascular diseases in Caucasian and other ethnic groups, including Koreans. The amplitude of the association with CAD was comparable to that of non-HDL cholesterol or systolic blood pressure in these populations These epidemiological studies have prompted the discovery of pharmacological agents which would inhibit this enzyme and so may prevent the development of cardiovascular diseases. The 279F null allele is relatively frequent in Japan, with approximately 25% and 2% of the population carrying one or two copies[6], respectively, and its prevalence shows a declining gradient towards the West, with intermediate frequencies in China and Korea[8], rare carriers in the Middle East [15] and almost complete absence in Europeans This discovery provides a natural experiment to gain insight into the causal contribution of Lp-PLA2 to the pathogenesis of CAD, and as such shall complement epidemiological studies and contribute to our understanding of the causality of Lp-PLA2 in atherogenesis in humans. Given conflicting results from mostly small studies, a large two-stage case-control study was warranted
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