Genetic invalidation of Lp-PLA(2) as a therapeutic target: Large-scale study of five functional Lp-PLA(2)-lowering alleles

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. 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. RESULTS: Lp-PLA(2) activity was decreased by 64% (p = 2.4 × 10(–25)) with carriage of any of the four loss-of-function variants, by 45% (p < 10(–300)) for every allele inherited at Val279Phe, and by 2.7% (p = 1.9 × 10(–12)) for every allele inherited at Val379Ala. Darapladib 160 mg once-daily reduced Lp-PLA(2) activity by 65% (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. 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.