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

John M. Gregson, Daniel F. Freitag, Praveen Surendran, Nathan O. Stitziel, Rajiv Chowdhury, Stephen Burgess, Stephen Kaptoge, Pei Gao, James R. Staley, Peter Willeit, Sune F. Nielsen, Muriel Caslake, Stella Trompet, Linda M. Polfus, Kari Kuulasmaa, Jukka Kontto, Markus Perola, Stefan Blankenberg, Giovanni Veronesi, Francesco GianfagnaSatu Männistö, Akinori Kimura, Honghuang Lin, Dermot F. Reilly, Mathias Gorski, Vladan Mijatovic, Patricia B. Munroe, Georg B. Ehret, Alex Thompson, Maria Uria-Nickelsen, Anders Malarstig, Abbas Dehghan, Thomas F. Vogt, Taishi Sasaoka, Fumihiko Takeuchi, Norihiro Kato, Yoshiji Yamada, Frank Kee, Martina Müller-Nurasyid, Jean Ferrières, Dominique Arveiler, Philippe Amouyel, Veikko Salomaa, Eric Boerwinkle, Simon G. Thompson, Ian Ford, J. Wouter Jukema, Naveed Sattar, Chris J. Packard, Abdulla Al Shafi Majumder, Dewan S. Alam, Panos Deloukas, Heribert Schunkert, Nilesh J. Samani, Sekar Kathiresan, Børge G. Nordestgaard, Danish Saleheen, Joanna M M Howson, Emanuele Di Angelantonio, Adam S. Butterworth, John Danesh

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)492-504
Number of pages13
JournalEuropean Journal of Preventive Cardiology
Volume24
Issue number5
DOIs
StatePublished - Mar 1 2017

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1-Alkyl-2-acetylglycerophosphocholine Esterase
Alleles
Coronary Disease
Therapeutics
Medical Genetics
Epidemiologic Studies
Cardiovascular Diseases

Keywords

  • coronary heart disease
  • darapladib
  • Human genetics
  • lipoprotein-associated phospholipase A
  • target validation

ASJC Scopus subject areas

  • Epidemiology
  • Cardiology and Cardiovascular Medicine

Cite this

Gregson, J. M., Freitag, D. F., Surendran, P., Stitziel, N. O., Chowdhury, R., Burgess, S., ... Danesh, J. (2017). Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles. European Journal of Preventive Cardiology, 24(5), 492-504. https://doi.org/10.1177/2047487316682186

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 M M; Di Angelantonio, Emanuele; Butterworth, Adam S.; Danesh, John.

In: European Journal of Preventive Cardiology, Vol. 24, No. 5, 01.03.2017, p. 492-504.

Research output: Contribution to journalArticle

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, JMM, Di Angelantonio, E, Butterworth, AS & Danesh, J 2017, 'Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles', European Journal of Preventive Cardiology, vol. 24, no. 5, pp. 492-504. https://doi.org/10.1177/2047487316682186
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 M M ; Di Angelantonio, Emanuele ; Butterworth, Adam S. ; Danesh, John. / Genetic invalidation of Lp-PLA2 as a therapeutic target : Large-scale study of five functional Lp-PLA2-lowering alleles. In: European Journal of Preventive Cardiology. 2017 ; Vol. 24, No. 5. pp. 492-504.
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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 = "coronary heart disease, darapladib, Human genetics, lipoprotein-associated phospholipase A, target validation",
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 M M} and {Di Angelantonio}, Emanuele and Butterworth, {Adam S.} and John Danesh",
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month = "3",
day = "1",
doi = "10.1177/2047487316682186",
language = "English (US)",
volume = "24",
pages = "492--504",
journal = "European Journal of Preventive Cardiology",
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TY - JOUR

T1 - Genetic invalidation of Lp-PLA2 as a therapeutic target

T2 - 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 M M

AU - Di Angelantonio, Emanuele

AU - Butterworth, Adam S.

AU - Danesh, John

PY - 2017/3/1

Y1 - 2017/3/1

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 - coronary heart disease

KW - darapladib

KW - Human genetics

KW - lipoprotein-associated phospholipase A

KW - target validation

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JF - European Journal of Preventive Cardiology

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