Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles.
European Journal of Preventive Cardiology
MetadataShow full item record
AIMS: Darapladib, a potent inhibitor of lipoprotein-associated phospholipase A2 (Lp-PLA2), has not reduced risk of cardiovascular disease outcomes in recent randomized trials. We aimed to test whether Lp-PLA2 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-PLA2. 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-PLA2 activity, conventional cardiovascular risk factors, and coronary heart disease risk with corresponding effects of Lp-PLA2-lowering alleles. RESULTS: Lp-PLA2 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-PLA2 activity by 65% (p < 10(-300)). Causal risk ratios for coronary heart disease per 65% lower Lp-PLA2 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-PLA2-lowering alleles was related to coronary heart disease risk, suggesting that Lp-PLA2 is unlikely to be a causal risk factor.
AuthorsGregson, JM; Freitag, DF; Surendran, P; Stitziel, NO; Chowdhury, R; Burgess, S; Kaptoge, S; Gao, P; Staley, JR; Willeit, P; Nielsen, SF; Caslake, M; Trompet, S; Polfus, LM; Kuulasmaa, K; Kontto, J; Perola, M; Blankenberg, S; Veronesi, G; Gianfagna, F; Männistö, S; Kimura, A; Lin, H; Reilly, DF; Gorski, M; Mijatovic, V; CKDGen consortium; Munroe, PB; Ehret, GB; International Consortium for Blood Pressure; Thompson, A; Uria-Nickelsen, M; Malarstig, A; Dehghan, A; CHARGE inflammation working group; Vogt, TF; Sasaoka, T; Takeuchi, F; Kato, N; Yamada, Y; Kee, F; Müller-Nurasyid, M; Ferrières, J; Arveiler, D; Amouyel, P; Salomaa, V; Boerwinkle, E; Thompson, SG; Ford, I; Wouter Jukema, J; Sattar, N; Packard, CJ; Shafi Majumder, AA; Alam, DS; Deloukas, P; Schunkert, H; Samani, NJ; Kathiresan, S; MICAD Exome consortium; Nordestgaard, BG; Saleheen, D; Howson, JM; Di Angelantonio, E; Butterworth, AS; Danesh, J; EPIC-CVD consortium and the CHD Exome+ consortium
- Cardiovascular 
Showing items related by title, author, creator and subject.
Investigating the Causal Relationship of C-Reactive Protein with 32 Complex Somatic and Psychiatric Outcomes: A Large-Scale Cross-Consortium Mendelian Randomization Study. Prins, BP; Abbasi, A; Wong, A; Vaez, A; Nolte, I; Franceschini, N; Stuart, PE; Guterriez Achury, J; Mistry, V; Bradfield, JP;... (2016-06-21)BACKGROUND: C-reactive protein (CRP) is associated with immune, cardiometabolic, and psychiatric traits and diseases. Yet it is inconclusive whether these associations are causal. METHODS AND FINDINGS: We performed Mendelian ...
Trans-ancestry meta-analyses identify rare and common variants associated with blood pressure and hypertension. Surendran, P; Drenos, F; Young, R; Warren, H; Cook, JP; Manning, AK; Grarup, N; Sim, X; Barnes, DR; Witkowska, K;... (2016-07-26)High blood pressure is a major risk factor for cardiovascular disease and premature death. However, there is limited knowledge on specific causal genes and pathways. To better understand the genetics of blood pressure, we ...
Genome-wide association analysis identifies novel blood pressure loci and offers biological insights into cardiovascular risk. Warren, HR; Evangelou, E; Cabrera, CP; Gao, H; Ren, M; Mifsud, B; Ntalla, I; Surendran, P; Liu, C; Cook, JP;... (2017-01-30)Elevated blood pressure is the leading heritable risk factor for cardiovascular disease worldwide. We report genetic association of blood pressure (systolic, diastolic, pulse pressure) among UK Biobank participants of ...