Genetic invalidation of Lp-PLA$_{2}$ as a therapeutic target: Large-scale study of five functional Lp-PLA$_{2}$-lowering alleles

Abstract

$\textbf{Aims}$ Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A${2}$ (Lp-PLA${2}$), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA$_{2}$ enzyme activity is causally relevant to coronary heart disease. $\textbf{Methods }$ In 72,657 patients with coronary heart disease and 110,218 controls in 23 epidemiological studies, we genotyped five functional variants: four rare loss-of-function mutations (c.109+2T > C (rs142974898), Arg82His (rs144983904), Val279Phe (rs76863441), Gln287Ter (rs140020965)) and one common modest-impact variant (Val379Ala (rs1051931)) in PLA2G7, the gene encoding Lp-PLA${2}$. We supplemented de-novo genotyping with information on a further 45,823 coronary heart disease patients and 88,680 controls in publicly available databases and other previous studies. We conducted a systematic review of randomized trials to compare effects of darapladib treatment on soluble Lp-PLA${2}$ activity, conventional cardiovascular risk factors, and coronary heart disease risk with corresponding effects of Lp-PLA$_{2}$-lowering alleles. $\textbf{Results }$ Lp-PLA${2}$ activity was decreased by 64% ( $\textit{p}$ = 2.4 × 10$^{-25}$) with carriage of any of the four loss-of-function variants, by 45% ( $\textit{p}$ < 10$^{-300}$) for every allele inherited at Val279Phe, and by 2.7% ( $\textit{p}$ = 1.9 × 10$^{-12}$) for every allele inherited at Val379Ala. Darapladib 160 mg once-daily reduced Lp-PLA${2}$ activity by 65% ( $\textit{p}$ < 10$^{-300}$). Causal risk ratios for coronary heart disease per 65% lower Lp-PLA$_{2}$ activity were: 0.95 (0.88-1.03) with Val279Phe; 0.92 (0.74-1.16) with carriage of any loss-of-function variant; 1.01 (0.68-1.51) with Val379Ala; and 0.95 (0.89-1.02) with darapladib treatment. $\textbf{Conclusions }$ In a large-scale human genetic study, none of a series of Lp-PLA${2}$-lowering alleles was related to coronary heart disease risk, suggesting that Lp-PLA${2}$ is unlikely to be a causal risk factor.