Standard
Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9. / Schmidt, Amand F.; Holmes, Michael V.; Preiss, David; Swerdlow, Daniel I.; Denaxas, Spiros; Fatemifar, Ghazaleh; Faraway, Rupert; Finan, Chris; Valentine, Dennis; Fairhurst-Hunter, Zammy; Hartwig, Fernando Pires; Horta, Bernardo Lessa; Hypponen, Elina; Power, Christine; Moldovan, Max; Van Iperen, Erik; Hovingh, Kees; Demuth, Ilja; Norman, Kristina; Steinhagen-Thiessen, Elisabeth; Demuth, Juri; Bertram, Lars; Lill, Christina M.; Coassin, Stefan; Willeit, Johann; Kiechl, Stefan; Willeit, Karin; Mason, Dan; Wright, John; Morris, Richard; Wanamethee, Goya; Whincup, Peter; Ben-Shlomo, Yoav; McLachlan, Stela; Price, Jackie F.; Kivimaki, Mika; Welch, Catherine; Sanchez-Galvez, Adelaida; Marques-Vidal, Pedro; Nicolaides, Andrew; Panayiotou, Andrie G.; Onland-Moret, N. Charlotte; Van Der Schouw, Yvonne T.; Matullo, Giuseppe; Fiorito, Giovanni; Guarrera, Simonetta; Sacerdote, Carlotta; Wareham, Nicholas J.; Langenberg, Claudia; Scott, Robert A.; Luan, Jian'An; Bobak, Martin; Malyutina, Sofia; Pajak, Andrzej; Kubinova, Ruzena; Tamosiunas, Abdonas; Pikhart, Hynek; Grarup, Niels; Pedersen, Oluf; Hansen, Torben; Linneberg, Allan; Jess, Tine; Cooper, Jackie; Humphries, Steve E.; Brilliant, Murray; Kitchner, Terrie; Hakonarson, Hakon; Carrell, David S.; McCarty, Catherine A.; Lester, Kirchner H.; Larson, Eric B.; Crosslin, David R.; De Andrade, Mariza; Roden, Dan M.; Denny, Joshua C.; Carty, Cara; Hancock, Stephen; Attia, John; Holliday, Elizabeth; Scott, Rodney; Schofield, Peter; O'Donnell, Martin; Yusuf, Salim; Chong, Michael; Pare, Guillaume; Van Der Harst, Pim; Said, M. Abdullah; Eppinga, Ruben N.; Verweij, Niek; Snieder, Harold; Christen, Tim; Mook-Kanamori, D. O.; Gustafsson, Stefan; Lind, Lars; Ingelsson, Erik; Pazoki, Raha; Franco, Oscar; Hofman, Albert; Uitterlinden, Andre; Dehghan, Abbas; Teumer, Alexander; Baumeister, Sebastian; Dörr, Marcus; Lerch, Markus M.; Völker, Uwe; Völzke, Henry; Ward, Joey; Pell, Jill P.; Meade, Tom; Christophersen, Ingrid E.; Maitland-Van Der Zee, Anke H.; Baranova, Ekaterina V.; Young, Robin; Ford, Ian; Campbell, Archie; Padmanabhan, Sandosh; Bots, Michiel L.; Grobbee, Diederick E.; Froguel, Philippe; Thuillier, Dorothée; Roussel, Ronan; Bonnefond, Amélie; Cariou, Bertrand; Smart, Melissa; Bao, Yanchun; Kumari, Meena; Mahajan, Anubha; Hopewell, Jemma C.; Seshadri, Sudha; Dale, Caroline; Costa, Rui Providencia E.; Ridker, Paul M.; Chasman, Daniel I.; Reiner, Alex P.; Ritchie, Marylyn D.; Lange, Leslie A.; Cornish, Alex J.; Dobbins, Sara E.; Hemminki, Kari; Kinnersley, Ben; Sanson, Marc; Labreche, Karim; Simon, Matthias; Bondy, Melissa; Law, Philip; Speedy, Helen; Allan, James; Li, Ni; Went, Molly; Weinhold, Niels; Morgan, Gareth; Sonneveld, Pieter; Nilsson, Björn; Goldschmidt, Hartmut; Sud, Amit; Engert, Andreas; Hansson, Markus; Hemingway, Harry; Asselbergs, Folkert W.; Patel, Riyaz S.; Keating, Brendan J.; Sattar, Naveed; Houlston, Richard; Casas, Juan P.; Hingorani, Aroon D.
In:
BMC Cardiovascular Disorders, Vol. 19, No. 1, 240, 2019.
Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
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, vol. 19, no. 1, 240.
https://doi.org/10.1186/s12872-019-1187-zAPA
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), [240].
https://doi.org/10.1186/s12872-019-1187-zVancouver
Schmidt AF, Holmes MV, Preiss D, Swerdlow DI, Denaxas S, Fatemifar G et al.
Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9.
BMC Cardiovascular Disorders. 2019;19(1). 240.
https://doi.org/10.1186/s12872-019-1187-zAuthor
Schmidt, Amand F. ; Holmes, Michael V. ; Preiss, David ; Swerdlow, Daniel I. ; Denaxas, Spiros ; Fatemifar, Ghazaleh ; Faraway, Rupert ; Finan, Chris ; Valentine, Dennis ; Fairhurst-Hunter, Zammy ; Hartwig, Fernando Pires ; Horta, Bernardo Lessa ; Hypponen, Elina ; Power, Christine ; Moldovan, Max ; Van Iperen, Erik ; Hovingh, Kees ; Demuth, Ilja ; Norman, Kristina ; Steinhagen-Thiessen, Elisabeth ; Demuth, Juri ; Bertram, Lars ; Lill, Christina M. ; Coassin, Stefan ; Willeit, Johann ; Kiechl, Stefan ; Willeit, Karin ; Mason, Dan ; Wright, John ; Morris, Richard ; Wanamethee, Goya ; Whincup, Peter ; Ben-Shlomo, Yoav ; McLachlan, Stela ; Price, Jackie F. ; Kivimaki, Mika ; Welch, Catherine ; Sanchez-Galvez, Adelaida ; Marques-Vidal, Pedro ; Nicolaides, Andrew ; Panayiotou, Andrie G. ; Onland-Moret, N. Charlotte ; Van Der Schouw, Yvonne T. ; Matullo, Giuseppe ; Fiorito, Giovanni ; Guarrera, Simonetta ; Sacerdote, Carlotta ; Wareham, Nicholas J. ; Langenberg, Claudia ; Scott, Robert A. ; Luan, Jian'An ; Bobak, Martin ; Malyutina, Sofia ; Pajak, Andrzej ; Kubinova, Ruzena ; Tamosiunas, Abdonas ; Pikhart, Hynek ; Grarup, Niels ; Pedersen, Oluf ; Hansen, Torben ; Linneberg, Allan ; Jess, Tine ; Cooper, Jackie ; Humphries, Steve E. ; Brilliant, Murray ; Kitchner, Terrie ; Hakonarson, Hakon ; Carrell, David S. ; McCarty, Catherine A. ; Lester, Kirchner H. ; Larson, Eric B. ; Crosslin, David R. ; De Andrade, Mariza ; Roden, Dan M. ; Denny, Joshua C. ; Carty, Cara ; Hancock, Stephen ; Attia, John ; Holliday, Elizabeth ; Scott, Rodney ; Schofield, Peter ; O'Donnell, Martin ; Yusuf, Salim ; Chong, Michael ; Pare, Guillaume ; Van Der Harst, Pim ; Said, M. Abdullah ; Eppinga, Ruben N. ; Verweij, Niek ; Snieder, Harold ; Christen, Tim ; Mook-Kanamori, D. O. ; Gustafsson, Stefan ; Lind, Lars ; Ingelsson, Erik ; Pazoki, Raha ; Franco, Oscar ; Hofman, Albert ; Uitterlinden, Andre ; Dehghan, Abbas ; Teumer, Alexander ; Baumeister, Sebastian ; Dörr, Marcus ; Lerch, Markus M. ; Völker, Uwe ; Völzke, Henry ; Ward, Joey ; Pell, Jill P. ; Meade, Tom ; Christophersen, Ingrid E. ; Maitland-Van Der Zee, Anke H. ; Baranova, Ekaterina V. ; Young, Robin ; Ford, Ian ; Campbell, Archie ; Padmanabhan, Sandosh ; Bots, Michiel L. ; Grobbee, Diederick E. ; Froguel, Philippe ; Thuillier, Dorothée ; Roussel, Ronan ; Bonnefond, Amélie ; Cariou, Bertrand ; Smart, Melissa ; Bao, Yanchun ; Kumari, Meena ; Mahajan, Anubha ; Hopewell, Jemma C. ; Seshadri, Sudha ; Dale, Caroline ; Costa, Rui Providencia E. ; Ridker, Paul M. ; Chasman, Daniel I. ; Reiner, Alex P. ; Ritchie, Marylyn D. ; Lange, Leslie A. ; Cornish, Alex J. ; Dobbins, Sara E. ; Hemminki, Kari ; Kinnersley, Ben ; Sanson, Marc ; Labreche, Karim ; Simon, Matthias ; Bondy, Melissa ; Law, Philip ; Speedy, Helen ; Allan, James ; Li, Ni ; Went, Molly ; Weinhold, Niels ; Morgan, Gareth ; Sonneveld, Pieter ; Nilsson, Björn ; Goldschmidt, Hartmut ; Sud, Amit ; Engert, Andreas ; Hansson, Markus ; Hemingway, Harry ; Asselbergs, Folkert W. ; Patel, Riyaz S. ; Keating, Brendan J. ; Sattar, Naveed ; Houlston, Richard ; Casas, Juan P. ; Hingorani, Aroon D. / Phenome-wide association analysis of LDL-cholesterol lowering genetic variants in PCSK9. In: BMC Cardiovascular Disorders. 2019 ; Vol. 19, No. 1.
Bibtex
@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 = "B M C Cardiovascular Disorders",
issn = "1471-2261",
publisher = "BioMed Central Ltd.",
number = "1",
}
RIS
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
U2 - 10.1186/s12872-019-1187-z
DO - 10.1186/s12872-019-1187-z
M3 - Journal article
C2 - 31664920
AN - SCOPUS:85074350493
VL - 19
JO - B M C Cardiovascular Disorders
JF - B M C Cardiovascular Disorders
SN - 1471-2261
IS - 1
M1 - 240
ER -
