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

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Gregson , J M , Freitag , D F , Surendran , P , Stitziel , N O , Chowdhury , R , Burgess , S , Kaptoge , S , Gao , P , Staley , J R , Willeit , P , Nielsen , S F , Caslake , M , Trompet , S , Polfus , L M , Kuulasmaa , K , Kontto , J , Perola , M , Blankenberg , S , Veronesi , G , Gianfagna , F , Mannisto , S , Kimura , A , Lin , H , Reilly , D F , Gorski , M , Mijatovic , V , Munroe , P B , Ehret , G B , Thompson , A , Uria-Nickelsen , M , Malarstig , A , Dehghan , A , Vogt , T F , Sasaoka , T , Takeuchi , F , Kato , N , Yamada , Y , Kee , F , Mueller-Nurasyid , M , Ferrieres , J , Arveiler , D , Amouyel , P , Salomaa , V , Boerwinkle , E , Thompson , S G , Ford , I , Jukema , J W , Sattar , N , Packard , C J , Majumder , A A S , CKDGen Consortium , Int Consortium Blood Pressure , CHARGE Inflammation Working Grp , MICAD Exome Consortium , EPIC-CVD Consortium & CHD Exome Consortium 2017 , ' Genetic invalidation of Lp-PLA(2) as a therapeutic target : Large-scale study of five functional Lp-PLA(2)-lowering alleles ' , European journal of preventive cardiology , vol. 24 , no. 5 , pp. 492-504 .

Title: Genetic invalidation of Lp-PLA(2) as a therapeutic target : Large-scale study of five functional Lp-PLA(2)-lowering alleles
Author: Gregson, John M.; Freitag, Daniel F.; Surendran, Praveen; Stitziel, Nathan O.; Chowdhury, Rajiv; Burgess, Stephen; Kaptoge, Stephen; Gao, Pei; Staley, James R.; Willeit, Peter; Nielsen, Sune F.; Caslake, Muriel; Trompet, Stella; Polfus, Linda M.; Kuulasmaa, Kari; Kontto, Jukka; Perola, Markus; Blankenberg, Stefan; Veronesi, Giovanni; Gianfagna, Francesco; Mannisto, Satu; Kimura, Akinori; Lin, Honghuang; Reilly, Dermot F.; Gorski, Mathias; Mijatovic, Vladan; Munroe, Patricia B.; Ehret, Georg B.; Thompson, Alex; Uria-Nickelsen, Maria; Malarstig, Anders; Dehghan, Abbas; Vogt, Thomas F.; Sasaoka, Taishi; Takeuchi, Fumihiko; Kato, Norihiro; Yamada, Yoshiji; Kee, Frank; Mueller-Nurasyid, Martina; Ferrieres, Jean; Arveiler, Dominique; Amouyel, Philippe; Salomaa, Veikko; Boerwinkle, Eric; Thompson, Simon G.; Ford, Ian; Jukema, J. Wouter; Sattar, Naveed; Packard, Chris J.; Majumder, Abdulla al Shafi; CKDGen Consortium; Int Consortium Blood Pressure; CHARGE Inflammation Working Grp; MICAD Exome Consortium; EPIC-CVD Consortium; CHD Exome Consortium
Contributor organization: Institute for Molecular Medicine Finland
University of Helsinki
Quantitative Genetics
Date: 2017-03
Language: eng
Number of pages: 13
Belongs to series: European journal of preventive cardiology
ISSN: 2047-4873
Abstract: 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 x 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 x 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.
Subject: Human genetics
target validation
coronary heart disease
lipoprotein-associated phospholipase A(2)
3111 Biomedicine
1184 Genetics, developmental biology, physiology
3121 General medicine, internal medicine and other clinical medicine
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

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