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Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles

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Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles. / 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; Männistö, 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; Müller-Nurasyid, Martina; Ferrières, Jean; Arveiler, Dominique; Amouyel, Philippe; Salomaa, Veikko; Boerwinkle, Eric; Thompson, Simon G; Ford, Ian; Wouter Jukema, J; Sattar, Naveed; Packard, Chris J; Shafi Majumder, Abdulla Al; Alam, Dewan S; Deloukas, Panos; Schunkert, Heribert; Samani, Nilesh J; Kathiresan, Sekar; Nordestgaard, Børge G; Saleheen, Danish; Howson, Joanna Mm; Di Angelantonio, Emanuele; Butterworth, Adam S; Danesh, John; CKDGen Consortium.

In: EUR J PREV CARDIOL, Vol. 24, No. 5, 03.2017, p. 492-504.

Research output: SCORING: Contribution to journal › SCORING: Review article › Research

Harvard

Gregson, 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, Munroe, PB, Ehret, GB, Thompson, A, Uria-Nickelsen, M, Malarstig, A, Dehghan, A, 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, Nordestgaard, BG, Saleheen, D, Howson, JM, Di Angelantonio, E, Butterworth, AS, Danesh, J & CKDGen Consortium 2017, 'Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles', EUR J PREV CARDIOL, vol. 24, no. 5, pp. 492-504. https://doi.org/10.1177/2047487316682186

APA

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., ... CKDGen Consortium (2017). Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles. EUR J PREV CARDIOL, 24(5), 492-504. https://doi.org/10.1177/2047487316682186

Vancouver

Gregson JM, Freitag DF, Surendran P, Stitziel NO, Chowdhury R, Burgess S et al. Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles. EUR J PREV CARDIOL. 2017 Mar;24(5):492-504. https://doi.org/10.1177/2047487316682186

Bibtex

@article{4b528a0cc460456f9e7ff76087f4aa02,
title = "Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles",
abstract = "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.",
keywords = "1-Alkyl-2-acetylglycerophosphocholine Esterase/drug effects, Adult, Aged, Alleles, Benzaldehydes/therapeutic use, Case-Control Studies, Coronary Disease/diagnosis, Female, Gene Expression Regulation, Genotype, Humans, Male, Middle Aged, Molecular Targeted Therapy, Oximes/therapeutic use, Phospholipase A2 Inhibitors/therapeutic use, Polymorphism, Single Nucleotide, Randomized Controlled Trials as Topic, Reference Values, Reproducibility of Results, Risk Assessment, Treatment Outcome",
author = "Gregson, {John M} and Freitag, {Daniel F} and Praveen Surendran and Stitziel, {Nathan O} and Rajiv Chowdhury and Stephen Burgess and Stephen Kaptoge and Pei Gao and Staley, {James R} and Peter Willeit and Nielsen, {Sune F} and Muriel Caslake and Stella Trompet and Polfus, {Linda M} and Kari Kuulasmaa and Jukka Kontto and Markus Perola and Stefan Blankenberg and Giovanni Veronesi and Francesco Gianfagna and Satu M{\"a}nnist{\"o} and Akinori Kimura and Honghuang Lin and Reilly, {Dermot F} and Mathias Gorski and Vladan Mijatovic and Munroe, {Patricia B} and Ehret, {Georg B} and Alex Thompson and Maria Uria-Nickelsen and Anders Malarstig and Abbas Dehghan and Vogt, {Thomas F} and Taishi Sasaoka and Fumihiko Takeuchi and Norihiro Kato and Yoshiji Yamada and Frank Kee and Martina M{\"u}ller-Nurasyid and Jean Ferri{\`e}res and Dominique Arveiler and Philippe Amouyel and Veikko Salomaa and Eric Boerwinkle and Thompson, {Simon G} and Ian Ford and {Wouter Jukema}, J and Naveed Sattar and Packard, {Chris J} and {Shafi Majumder}, {Abdulla Al} and Alam, {Dewan S} and Panos Deloukas and Heribert Schunkert and Samani, {Nilesh J} and Sekar Kathiresan and Nordestgaard, {B{\o}rge G} and Danish Saleheen and Howson, {Joanna Mm} and {Di Angelantonio}, Emanuele and Butterworth, {Adam S} and John Danesh and {CKDGen Consortium}",
year = "2017",
month = mar,
doi = "10.1177/2047487316682186",
language = "English",
volume = "24",
pages = "492--504",
journal = "EUR J PREV CARDIOL",
issn = "2047-4873",
publisher = "SAGE Publications",
number = "5",

}

RIS

TY - JOUR

T1 - Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles

AU - Gregson, John M

AU - Freitag, Daniel F

AU - Surendran, Praveen

AU - Stitziel, Nathan O

AU - Chowdhury, Rajiv

AU - Burgess, Stephen

AU - Kaptoge, Stephen

AU - Gao, Pei

AU - Staley, James R

AU - Willeit, Peter

AU - Nielsen, Sune F

AU - Caslake, Muriel

AU - Trompet, Stella

AU - Polfus, Linda M

AU - Kuulasmaa, Kari

AU - Kontto, Jukka

AU - Perola, Markus

AU - Blankenberg, Stefan

AU - Veronesi, Giovanni

AU - Gianfagna, Francesco

AU - Männistö, Satu

AU - Kimura, Akinori

AU - Lin, Honghuang

AU - Reilly, Dermot F

AU - Gorski, Mathias

AU - Mijatovic, Vladan

AU - Munroe, Patricia B

AU - Ehret, Georg B

AU - Thompson, Alex

AU - Uria-Nickelsen, Maria

AU - Malarstig, Anders

AU - Dehghan, Abbas

AU - Vogt, Thomas F

AU - Sasaoka, Taishi

AU - Takeuchi, Fumihiko

AU - Kato, Norihiro

AU - Yamada, Yoshiji

AU - Kee, Frank

AU - Müller-Nurasyid, Martina

AU - Ferrières, Jean

AU - Arveiler, Dominique

AU - Amouyel, Philippe

AU - Salomaa, Veikko

AU - Boerwinkle, Eric

AU - Thompson, Simon G

AU - Ford, Ian

AU - Wouter Jukema, J

AU - Sattar, Naveed

AU - Packard, Chris J

AU - Shafi Majumder, Abdulla Al

AU - Alam, Dewan S

AU - Deloukas, Panos

AU - Schunkert, Heribert

AU - Samani, Nilesh J

AU - Kathiresan, Sekar

AU - Nordestgaard, Børge G

AU - Saleheen, Danish

AU - Howson, Joanna Mm

AU - Di Angelantonio, Emanuele

AU - Butterworth, Adam S

AU - Danesh, John

AU - CKDGen Consortium

PY - 2017/3

Y1 - 2017/3

N2 - 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.

AB - 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.

KW - 1-Alkyl-2-acetylglycerophosphocholine Esterase/drug effects

KW - Adult

KW - Aged

KW - Alleles

KW - Benzaldehydes/therapeutic use

KW - Case-Control Studies

KW - Coronary Disease/diagnosis

KW - Female

KW - Gene Expression Regulation

KW - Genotype

KW - Humans

KW - Male

KW - Middle Aged

KW - Molecular Targeted Therapy

KW - Oximes/therapeutic use

KW - Phospholipase A2 Inhibitors/therapeutic use

KW - Polymorphism, Single Nucleotide

KW - Randomized Controlled Trials as Topic

KW - Reference Values

KW - Reproducibility of Results

KW - Risk Assessment

KW - Treatment Outcome

U2 - 10.1177/2047487316682186

DO - 10.1177/2047487316682186

M3 - SCORING: Review article

C2 - 27940953

VL - 24

SP - 492

EP - 504

JO - EUR J PREV CARDIOL

JF - EUR J PREV CARDIOL

SN - 2047-4873

IS - 5

ER -