Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Amand F. Schmidt; Michael V. Holmes; David Preiss; Daniel I. Swerdlow; Spiros Denaxas; Ghazaleh Fatemifar; Rupert Faraway; Chris Finan; Dennis Valentine; Zammy Fairhurst-Hunter; Fernando Pires Hartwig; Bernardo Lessa Horta; Elina Hypponen; Christine Power; Max Moldovan; Erik Van Iperen; Kees Hovingh; Ilja Demuth; Kristina Norman; Elisabeth Steinhagen-Thiessen; Juri Demuth; Lars Bertram; Christina M. Lill; Stefan Coassin; Johann Willeit; Stefan Kiechl; Karin Willeit; Dan Mason; John Wright; Richard Morris; Goya Wanamethee; Peter Whincup; Yoav Ben-Shlomo; Stela McLachlan; Jackie F. Price; Mika Kivimaki; Catherine Welch; Adelaida Sanchez-Galvez; Pedro Marques-Vidal; Andrew Nicolaides; Andrie G. Panayiotou; N. Charlotte Onland-Moret; Yvonne T. Van Der Schouw; Giuseppe Matullo; Giovanni Fiorito; Simonetta Guarrera; Carlotta Sacerdote; Nicholas J. Wareham; Claudia Langenberg; Robert A. Scott; Jian'An Luan; Martin Bobak; Sofia Malyutina; Andrzej Pajak; Ruzena Kubinova; Abdonas Tamosiunas; Hynek Pikhart; Niels Grarup; Oluf Pedersen; Torben Hansen; Allan Linneberg; Tine Jess; Jackie Cooper; Steve E. Humphries; Murray Brilliant; Terrie Kitchner; Hakon Hakonarson; David S. Carrell; Catherine A. McCarty; Kirchner H. Lester; Eric B. Larson; David R. Crosslin; Mariza De Andrade; Dan M. Roden; Joshua C. Denny; Cara Carty; Stephen Hancock; John Attia; Elizabeth Holliday; Rodney Scott; Peter Schofield; Martin O'Donnell; Salim Yusuf; Michael Chong; Guillaume Pare; Pim Van Der Harst; M. Abdullah Said; Ruben N. Eppinga; Niek Verweij; Harold Snieder; Tim Christen; D. O. Mook-Kanamori; Stefan Gustafsson; Lars Lind; Erik Ingelsson; Raha Pazoki; Oscar Franco; Albert Hofman; Andre Uitterlinden; Abbas Dehghan; Alexander Teumer; Sebastian Baumeister; Marcus Dörr; Markus M. Lerch; Uwe Völker; Henry Völzke; Joey Ward; Jill P. Pell; Tom Meade; Ingrid E. Christophersen; Anke H. Maitland-Van Der Zee; Ekaterina V. Baranova; Robin Young; Ian Ford; Archie Campbell; Sandosh Padmanabhan; Michiel L. Bots; Diederick E. Grobbee; Philippe Froguel; Dorothée Thuillier; Ronan Roussel; Amélie Bonnefond; Bertrand Cariou; Melissa Smart; Yanchun Bao; Meena Kumari; Anubha Mahajan; Jemma C. Hopewell; Sudha Seshadri; Caroline Dale; Rui Providencia E. Costa; Paul M. Ridker; Daniel I. Chasman; Alex P. Reiner; Marylyn D. Ritchie; Leslie A. Lange; Alex J. Cornish; Sara E. Dobbins; Kari Hemminki; Ben Kinnersley; Marc Sanson; Karim Labreche; Matthias Simon; Melissa Bondy; Philip Law; Helen Speedy; James Allan; Ni Li; Molly Went; Niels Weinhold; Gareth Morgan; Pieter Sonneveld; Björn Nilsson; Hartmut Goldschmidt; Amit Sud; Andreas Engert; Markus Hansson; Harry Hemingway; Folkert W. Asselbergs; Riyaz S. Patel; Brendan J. Keating; Naveed Sattar; Richard Houlston; Juan P. Casas; Aroon D. Hingorani

doi:10.1186/s12872-019-1187-z

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Amand F. Schmidt^*, Michael V. Holmes, David Preiss, Daniel I. Swerdlow, Spiros Denaxas, Ghazaleh Fatemifar, Rupert Faraway, Chris Finan, Dennis Valentine, Zammy Fairhurst-Hunter, Fernando Pires Hartwig, Bernardo Lessa Horta, Elina Hypponen, Christine Power, Max Moldovan, Erik Van Iperen, Kees Hovingh, Ilja Demuth, Kristina Norman, Elisabeth Steinhagen-ThiessenJuri Demuth, Lars Bertram, Christina M. Lill, Stefan Coassin, Johann Willeit, Stefan Kiechl, Karin Willeit, Dan Mason, John Wright, Richard Morris, Goya Wanamethee, Peter Whincup, Yoav Ben-Shlomo, Stela McLachlan, Jackie F. Price, Mika Kivimaki, Catherine Welch, Adelaida Sanchez-Galvez, Pedro Marques-Vidal, Andrew Nicolaides, Andrie G. Panayiotou, N. Charlotte Onland-Moret, Yvonne T. Van Der Schouw, Giuseppe Matullo, Giovanni Fiorito, Simonetta Guarrera, Carlotta Sacerdote, Nicholas J. Wareham, Claudia Langenberg, Robert A. Scott, Jian'An Luan, Martin Bobak, Sofia Malyutina, Andrzej Pajak, Ruzena Kubinova, Abdonas Tamosiunas, Hynek Pikhart, Niels Grarup, Oluf Pedersen, Torben Hansen, Allan Linneberg, Tine Jess, Jackie Cooper, Steve E. Humphries, Murray Brilliant, Terrie Kitchner, Hakon Hakonarson, David S. Carrell, Catherine A. McCarty, Kirchner H. Lester, Eric B. Larson, David R. Crosslin, Mariza De Andrade, Dan M. Roden, Joshua C. Denny, Cara Carty, Stephen Hancock, John Attia, Elizabeth Holliday, Rodney Scott, Peter Schofield, Martin O'Donnell, Salim Yusuf, Michael Chong, Guillaume Pare, Pim Van Der Harst, M. Abdullah Said, Ruben N. Eppinga, Niek Verweij, Harold Snieder, Tim Christen, D. O. Mook-Kanamori, Stefan Gustafsson, Lars Lind, Erik Ingelsson, Raha Pazoki, Oscar Franco, Albert Hofman, Andre Uitterlinden, Abbas Dehghan, Alexander Teumer, Sebastian Baumeister, Marcus Dörr, Markus M. Lerch, Uwe Völker, Henry Völzke, Joey Ward, Jill P. Pell, Tom Meade, Ingrid E. Christophersen, Anke H. Maitland-Van Der Zee, Ekaterina V. Baranova, Robin Young, Ian Ford, Archie Campbell, Sandosh Padmanabhan, Michiel L. Bots, Diederick E. Grobbee, Philippe Froguel, Dorothée Thuillier, Ronan Roussel, Amélie Bonnefond, Bertrand Cariou, Melissa Smart, Yanchun Bao, Meena Kumari, Anubha Mahajan, Jemma C. Hopewell, Sudha Seshadri, Caroline Dale, Rui Providencia E. Costa, Paul M. Ridker, Daniel I. Chasman, Alex P. Reiner, Marylyn D. Ritchie, Leslie A. Lange, Alex J. Cornish, Sara E. Dobbins, Kari Hemminki, Ben Kinnersley, Marc Sanson, Karim Labreche, Matthias Simon, Melissa Bondy, Philip Law, Helen Speedy, James Allan, Ni Li, Molly Went, Niels Weinhold, Gareth Morgan, Pieter Sonneveld, Björn Nilsson, Hartmut Goldschmidt, Amit Sud, Andreas Engert, Markus Hansson, Harry Hemingway, Folkert W. Asselbergs, Riyaz S. Patel, Brendan J. Keating, Naveed Sattar, Richard Houlston, Juan P. Casas, Aroon D. Hingorani

^*Corresponding author af dette arbejde

2 Citationer (Scopus)

Abstract

Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

Originalsprog	Engelsk
Artikelnummer	240
Tidsskrift	BMC Cardiovascular Disorders
Vol/bind	19
Udgave nummer	1
Antal sider	10
ISSN	1471-2261
DOI	https://doi.org/10.1186/s12872-019-1187-z
Status	Udgivet - 2019

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Schmidt, A. F., Holmes, M. V., Preiss, D., Swerdlow, D. I., Denaxas, S., Fatemifar, G., Faraway, R., Finan, C., Valentine, D., Fairhurst-Hunter, Z., Hartwig, F. P., Horta, B. L., Hypponen, E., Power, C., Moldovan, M., Van Iperen, E., Hovingh, K., Demuth, I., Norman, K., ... Hingorani, A. D. (2019). Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9. BMC Cardiovascular Disorders, 19(1), Artikel 240. https://doi.org/10.1186/s12872-019-1187-z

Schmidt, AF, Holmes, MV, Preiss, D, Swerdlow, DI, Denaxas, S, Fatemifar, G, Faraway, R, Finan, C, Valentine, D, Fairhurst-Hunter, Z, Hartwig, FP, Horta, BL, Hypponen, E, Power, C, Moldovan, M, Van Iperen, E, Hovingh, K, Demuth, I, Norman, K, Steinhagen-Thiessen, E, Demuth, J, Bertram, L, Lill, CM, Coassin, S, Willeit, J, Kiechl, S, Willeit, K, Mason, D, Wright, J, Morris, R, Wanamethee, G, Whincup, P, Ben-Shlomo, Y, McLachlan, S, Price, JF, Kivimaki, M, Welch, C, Sanchez-Galvez, A, Marques-Vidal, P, Nicolaides, A, Panayiotou, AG, Onland-Moret, NC, Van Der Schouw, YT, Matullo, G, Fiorito, G, Guarrera, S, Sacerdote, C, Wareham, NJ, Langenberg, C, Scott, RA, Luan, JA, Bobak, M, Malyutina, S, Pajak, A, Kubinova, R, Tamosiunas, A, Pikhart, H, Grarup, N , Pedersen, O , Hansen, T , Linneberg, A, Jess, T, Cooper, J, Humphries, SE, Brilliant, M, Kitchner, T, Hakonarson, H, Carrell, DS, McCarty, CA, Lester, KH, Larson, EB, Crosslin, DR, De Andrade, M, Roden, DM, Denny, JC, Carty, C, Hancock, S, Attia, J, Holliday, E, Scott, R, Schofield, P, O'Donnell, M, Yusuf, S, Chong, M, Pare, G, Van Der Harst, P, Said, MA, Eppinga, RN, Verweij, N, Snieder, H, Christen, T, Mook-Kanamori, DO, Gustafsson, S, Lind, L, Ingelsson, E, Pazoki, R, Franco, O, Hofman, A, Uitterlinden, A, Dehghan, A, Teumer, A, Baumeister, S, Dörr, M, Lerch, MM, Völker, U, Völzke, H, Ward, J, Pell, JP, Meade, T, Christophersen, IE, Maitland-Van Der Zee, AH, Baranova, EV, Young, R, Ford, I, Campbell, A, Padmanabhan, S, Bots, ML, Grobbee, DE, Froguel, P, Thuillier, D, Roussel, R, Bonnefond, A, Cariou, B, Smart, M, Bao, Y, Kumari, M, Mahajan, A, Hopewell, JC, Seshadri, S, Dale, C, Costa, RPE, Ridker, PM, Chasman, DI, Reiner, AP, Ritchie, MD, Lange, LA, Cornish, AJ, Dobbins, SE, Hemminki, K, Kinnersley, B, Sanson, M, Labreche, K, Simon, M, Bondy, M, Law, P, Speedy, H, Allan, J, Li, N, Went, M, Weinhold, N, Morgan, G, Sonneveld, P, Nilsson, B, Goldschmidt, H, Sud, A, Engert, A, Hansson, M, Hemingway, H, Asselbergs, FW, Patel, RS, Keating, BJ, Sattar, N, Houlston, R, Casas, JP & Hingorani, AD 2019, 'Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9', BMC Cardiovascular Disorders, bind 19, nr. 1, 240. https://doi.org/10.1186/s12872-019-1187-z

@article{8bcf44285e5c4db5baa8f6ae04367149,

title = "Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9",

abstract = "Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.",

keywords = "Genetic association studies, LDL-cholesterol, Mendelian randomisation, Phenome-wide association scan",

author = "Schmidt, {Amand F.} and Holmes, {Michael V.} and David Preiss and Swerdlow, {Daniel I.} and Spiros Denaxas and Ghazaleh Fatemifar and Rupert Faraway and Chris Finan and Dennis Valentine and Zammy Fairhurst-Hunter and Hartwig, {Fernando Pires} and Horta, {Bernardo Lessa} and Elina Hypponen and Christine Power and Max Moldovan and {Van Iperen}, Erik and Kees Hovingh and Ilja Demuth and Kristina Norman and Elisabeth Steinhagen-Thiessen and Juri Demuth and Lars Bertram and Lill, {Christina M.} and Stefan Coassin and Johann Willeit and Stefan Kiechl and Karin Willeit and Dan Mason and John Wright and Richard Morris and Goya Wanamethee and Peter Whincup and Yoav Ben-Shlomo and Stela McLachlan and Price, {Jackie F.} and Mika Kivimaki and Catherine Welch and Adelaida Sanchez-Galvez and Pedro Marques-Vidal and Andrew Nicolaides and Panayiotou, {Andrie G.} and Onland-Moret, {N. Charlotte} and {Van Der Schouw}, {Yvonne T.} and Giuseppe Matullo and Giovanni Fiorito and Simonetta Guarrera and Carlotta Sacerdote and Wareham, {Nicholas J.} and Claudia Langenberg and Scott, {Robert A.} and Jian'An Luan and Martin Bobak and Sofia Malyutina and Andrzej Pajak and Ruzena Kubinova and Abdonas Tamosiunas and Hynek Pikhart and Niels Grarup and Oluf Pedersen and Torben Hansen and Allan Linneberg and Tine Jess and Jackie Cooper and Humphries, {Steve E.} and Murray Brilliant and Terrie Kitchner and Hakon Hakonarson and Carrell, {David S.} and McCarty, {Catherine A.} and Lester, {Kirchner H.} and Larson, {Eric B.} and Crosslin, {David R.} and {De Andrade}, Mariza and Roden, {Dan M.} and Denny, {Joshua C.} and Cara Carty and Stephen Hancock and John Attia and Elizabeth Holliday and Rodney Scott and Peter Schofield and Martin O'Donnell and Salim Yusuf and Michael Chong and Guillaume Pare and {Van Der Harst}, Pim and Said, {M. Abdullah} and Eppinga, {Ruben N.} and Niek Verweij and Harold Snieder and Tim Christen and Mook-Kanamori, {D. O.} and Stefan Gustafsson and Lars Lind and Erik Ingelsson and Raha Pazoki and Oscar Franco and Albert Hofman and Andre Uitterlinden and Abbas Dehghan and Alexander Teumer and Sebastian Baumeister and Marcus D{\"o}rr and Lerch, {Markus M.} and Uwe V{\"o}lker and Henry V{\"o}lzke and Joey Ward and Pell, {Jill P.} and Tom Meade and Christophersen, {Ingrid E.} and {Maitland-Van Der Zee}, {Anke H.} and Baranova, {Ekaterina V.} and Robin Young and Ian Ford and Archie Campbell and Sandosh Padmanabhan and Bots, {Michiel L.} and Grobbee, {Diederick E.} and Philippe Froguel and Doroth{\'e}e Thuillier and Ronan Roussel and Am{\'e}lie Bonnefond and Bertrand Cariou and Melissa Smart and Yanchun Bao and Meena Kumari and Anubha Mahajan and Hopewell, {Jemma C.} and Sudha Seshadri and Caroline Dale and Costa, {Rui Providencia E.} and Ridker, {Paul M.} and Chasman, {Daniel I.} and Reiner, {Alex P.} and Ritchie, {Marylyn D.} and Lange, {Leslie A.} and Cornish, {Alex J.} and Dobbins, {Sara E.} and Kari Hemminki and Ben Kinnersley and Marc Sanson and Karim Labreche and Matthias Simon and Melissa Bondy and Philip Law and Helen Speedy and James Allan and Ni Li and Molly Went and Niels Weinhold and Gareth Morgan and Pieter Sonneveld and Bj{\"o}rn Nilsson and Hartmut Goldschmidt and Amit Sud and Andreas Engert and Markus Hansson and Harry Hemingway and Asselbergs, {Folkert W.} and Patel, {Riyaz S.} and Keating, {Brendan J.} and Naveed Sattar and Richard Houlston and Casas, {Juan P.} and Hingorani, {Aroon D.}",

year = "2019",

doi = "10.1186/s12872-019-1187-z",

language = "English",

volume = "19",

journal = "BMC Cardiovascular Disorders",

issn = "1471-2261",

publisher = "BioMed Central Ltd.",

number = "1",

}

TY - JOUR

T1 - Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

AU - Schmidt, Amand F.

AU - Holmes, Michael V.

AU - Preiss, David

AU - Swerdlow, Daniel I.

AU - Denaxas, Spiros

AU - Fatemifar, Ghazaleh

AU - Faraway, Rupert

AU - Finan, Chris

AU - Valentine, Dennis

AU - Fairhurst-Hunter, Zammy

AU - Hartwig, Fernando Pires

AU - Horta, Bernardo Lessa

AU - Hypponen, Elina

AU - Power, Christine

AU - Moldovan, Max

AU - Van Iperen, Erik

AU - Hovingh, Kees

AU - Demuth, Ilja

AU - Norman, Kristina

AU - Steinhagen-Thiessen, Elisabeth

AU - Demuth, Juri

AU - Bertram, Lars

AU - Lill, Christina M.

AU - Coassin, Stefan

AU - Willeit, Johann

AU - Kiechl, Stefan

AU - Willeit, Karin

AU - Mason, Dan

AU - Wright, John

AU - Morris, Richard

AU - Wanamethee, Goya

AU - Whincup, Peter

AU - Ben-Shlomo, Yoav

AU - McLachlan, Stela

AU - Price, Jackie F.

AU - Kivimaki, Mika

AU - Welch, Catherine

AU - Sanchez-Galvez, Adelaida

AU - Marques-Vidal, Pedro

AU - Nicolaides, Andrew

AU - Panayiotou, Andrie G.

AU - Onland-Moret, N. Charlotte

AU - Van Der Schouw, Yvonne T.

AU - Matullo, Giuseppe

AU - Fiorito, Giovanni

AU - Guarrera, Simonetta

AU - Sacerdote, Carlotta

AU - Wareham, Nicholas J.

AU - Langenberg, Claudia

AU - Scott, Robert A.

AU - Luan, Jian'An

AU - Bobak, Martin

AU - Malyutina, Sofia

AU - Pajak, Andrzej

AU - Kubinova, Ruzena

AU - Tamosiunas, Abdonas

AU - Pikhart, Hynek

AU - Grarup, Niels

AU - Pedersen, Oluf

AU - Hansen, Torben

AU - Linneberg, Allan

AU - Jess, Tine

AU - Cooper, Jackie

AU - Humphries, Steve E.

AU - Brilliant, Murray

AU - Kitchner, Terrie

AU - Hakonarson, Hakon

AU - Carrell, David S.

AU - McCarty, Catherine A.

AU - Lester, Kirchner H.

AU - Larson, Eric B.

AU - Crosslin, David R.

AU - De Andrade, Mariza

AU - Roden, Dan M.

AU - Denny, Joshua C.

AU - Carty, Cara

AU - Hancock, Stephen

AU - Attia, John

AU - Holliday, Elizabeth

AU - Scott, Rodney

AU - Schofield, Peter

AU - O'Donnell, Martin

AU - Yusuf, Salim

AU - Chong, Michael

AU - Pare, Guillaume

AU - Van Der Harst, Pim

AU - Said, M. Abdullah

AU - Eppinga, Ruben N.

AU - Verweij, Niek

AU - Snieder, Harold

AU - Christen, Tim

AU - Mook-Kanamori, D. O.

AU - Gustafsson, Stefan

AU - Lind, Lars

AU - Ingelsson, Erik

AU - Pazoki, Raha

AU - Franco, Oscar

AU - Hofman, Albert

AU - Uitterlinden, Andre

AU - Dehghan, Abbas

AU - Teumer, Alexander

AU - Baumeister, Sebastian

AU - Dörr, Marcus

AU - Lerch, Markus M.

AU - Völker, Uwe

AU - Völzke, Henry

AU - Ward, Joey

AU - Pell, Jill P.

AU - Meade, Tom

AU - Christophersen, Ingrid E.

AU - Maitland-Van Der Zee, Anke H.

AU - Baranova, Ekaterina V.

AU - Young, Robin

AU - Ford, Ian

AU - Campbell, Archie

AU - Padmanabhan, Sandosh

AU - Bots, Michiel L.

AU - Grobbee, Diederick E.

AU - Froguel, Philippe

AU - Thuillier, Dorothée

AU - Roussel, Ronan

AU - Bonnefond, Amélie

AU - Cariou, Bertrand

AU - Smart, Melissa

AU - Bao, Yanchun

AU - Kumari, Meena

AU - Mahajan, Anubha

AU - Hopewell, Jemma C.

AU - Seshadri, Sudha

AU - Dale, Caroline

AU - Costa, Rui Providencia E.

AU - Ridker, Paul M.

AU - Chasman, Daniel I.

AU - Reiner, Alex P.

AU - Ritchie, Marylyn D.

AU - Lange, Leslie A.

AU - Cornish, Alex J.

AU - Dobbins, Sara E.

AU - Hemminki, Kari

AU - Kinnersley, Ben

AU - Sanson, Marc

AU - Labreche, Karim

AU - Simon, Matthias

AU - Bondy, Melissa

AU - Law, Philip

AU - Speedy, Helen

AU - Allan, James

AU - Li, Ni

AU - Went, Molly

AU - Weinhold, Niels

AU - Morgan, Gareth

AU - Sonneveld, Pieter

AU - Nilsson, Björn

AU - Goldschmidt, Hartmut

AU - Sud, Amit

AU - Engert, Andreas

AU - Hansson, Markus

AU - Hemingway, Harry

AU - Asselbergs, Folkert W.

AU - Patel, Riyaz S.

AU - Keating, Brendan J.

AU - Sattar, Naveed

AU - Houlston, Richard

AU - Casas, Juan P.

AU - Hingorani, Aroon D.

PY - 2019

Y1 - 2019

N2 - Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

AB - Background: We characterised the phenotypic consequence of genetic variation at the PCSK9 locus and compared findings with recent trials of pharmacological inhibitors of PCSK9. Methods: Published and individual participant level data (300,000+ participants) were combined to construct a weighted PCSK9 gene-centric score (GS). Seventeen randomized placebo controlled PCSK9 inhibitor trials were included, providing data on 79,578 participants. Results were scaled to a one mmol/L lower LDL-C concentration. Results: The PCSK9 GS (comprising 4 SNPs) associations with plasma lipid and apolipoprotein levels were consistent in direction with treatment effects. The GS odds ratio (OR) for myocardial infarction (MI) was 0.53 (95% CI 0.42; 0.68), compared to a PCSK9 inhibitor effect of 0.90 (95% CI 0.86; 0.93). For ischemic stroke ORs were 0.84 (95% CI 0.57; 1.22) for the GS, compared to 0.85 (95% CI 0.78; 0.93) in the drug trials. ORs with type 2 diabetes mellitus (T2DM) were 1.29 (95% CI 1.11; 1.50) for the GS, as compared to 1.00 (95% CI 0.96; 1.04) for incident T2DM in PCSK9 inhibitor trials. No genetic associations were observed for cancer, heart failure, atrial fibrillation, chronic obstructive pulmonary disease, or Alzheimer's disease - outcomes for which large-scale trial data were unavailable. Conclusions: Genetic variation at the PCSK9 locus recapitulates the effects of therapeutic inhibition of PCSK9 on major blood lipid fractions and MI. While indicating an increased risk of T2DM, no other possible safety concerns were shown; although precision was moderate.

KW - Genetic association studies

KW - LDL-cholesterol

KW - Mendelian randomisation

KW - Phenome-wide association scan

UR - http://www.scopus.com/inward/record.url?scp=85074350493&partnerID=8YFLogxK

U2 - 10.1186/s12872-019-1187-z

DO - 10.1186/s12872-019-1187-z

M3 - Journal article

C2 - 31664920

AN - SCOPUS:85074350493

SN - 1471-2261

VL - 19

JO - BMC Cardiovascular Disorders

JF - BMC Cardiovascular Disorders

IS - 1

M1 - 240

ER -

Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9

Abstract

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