PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study: a mendelian randomisation study

Amand F. Schmidt; Daniel I. Swerdlow; Michael V. Holmes; Riyaz S. Patel; Zammy Fairhurst-Hunter; Donald M. Lyall; Fernando Pires Hartwig; Bernardo Lessa Horta; Elina Hyppönen; Christine Power; Max Moldovan; Erik van Iperen; G. Kees Hovingh; Ilja Demuth; Kristina Norman; Elisabeth Steinhagen-Thiessen; Juri Demuth; Lars Bertram; Tian Liu; 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 Scott; Jian'an Luan; Martin Bobak; Sofia Malyutina; Andrzej Pająk; Ruzena Kubinova; Abdonas Tamosiunas; Hynek Pikhart; Lise Lotte Nystrup Husemoen; Niels Grarup; Oluf Pedersen; Torben Hansen; Allan Linneberg; Kenneth Starup Simonsen; Jackie Cooper; Steve E. Humphries; Murray Brilliant; Terrie Kitchner; Hakon Hakonarson; David S. Carrell; Catherine A. McCarty; H. Lester Kirchner; Eric B. Larson; David R. Crosslin; Mariza de Andrade; Dan M. Roden; Joshua C. Denny; Cara Carty; Stephen Hancock; John Attia; Elizabeth Holliday; 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; Dennis 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; Daniel J. Smith; Tom Meade; 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; Beverley Balkau; Amélie Bonnefond; Bertrand Cariou; Melissa Smart; Yanchun Bao; Meena Kumari; Anubha Mahajan; Paul M. Ridker; Daniel I. Chasman; Alex P. Reiner; Leslie A. Lange; Marylyn D. Ritchie; Folkert W. Asselbergs; Juan-Pablo Casas; Brendan J. Keating; David Preiss; Aroon D. Hingorani; Naveed Sattar

doi:10.1016/S2213-8587(16)30396-5

PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study: a mendelian randomisation study

Amand F. Schmidt
, Daniel I. Swerdlow
, Michael V. Holmes
, Riyaz S. Patel
, Zammy Fairhurst-Hunter
, Donald M. Lyall
, Fernando Pires Hartwig
, Bernardo Lessa Horta
, Elina Hyppönen
, Christine Power
, Max Moldovan
, Erik van Iperen
, G. Kees Hovingh
, Ilja Demuth
, Kristina Norman
, Elisabeth Steinhagen-Thiessen
, Juri Demuth
, Lars Bertram
, Tian Liu
, 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 Scott, Jian'an Luan, Martin Bobak, Sofia Malyutina, Andrzej Pająk, Ruzena Kubinova, Abdonas Tamosiunas, Hynek Pikhart, Lise Lotte Nystrup Husemoen, Niels Grarup, Oluf Pedersen, Torben Hansen, Allan Linneberg, Kenneth Starup Simonsen, Jackie Cooper, Steve E. Humphries, Murray Brilliant, Terrie Kitchner, Hakon Hakonarson, David S. Carrell, Catherine A. McCarty, H. Lester Kirchner, Eric B. Larson, David R. Crosslin, Mariza de Andrade, Dan M. Roden, Joshua C. Denny, Cara Carty, Stephen Hancock, John Attia, Elizabeth Holliday, 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, Dennis 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, Daniel J. Smith, Tom Meade, 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, Beverley Balkau, Amélie Bonnefond, Bertrand Cariou, Melissa Smart, Yanchun Bao, Meena Kumari, Anubha Mahajan, Paul M. Ridker, Daniel I. Chasman, Alex P. Reiner, Leslie A. Lange, Marylyn D. Ritchie, Folkert W. Asselbergs, Juan-Pablo Casas, Brendan J. Keating, David Preiss, Aroon D. Hingorani, Naveed Sattar

University College London

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

BACKGROUND: Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk.

METHODS: In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores.

FINDINGS: Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m2, -0·09 to 0·30).

INTERPRETATION: PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins.

FUNDING: British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.

Original language	English
Pages (from-to)	97-105
Number of pages	9
Journal	Lancet. Diabetes and endocrinology
Volume	5
Issue number	2
Early online date	2016
DOIs	https://doi.org/10.1016/S2213-8587(16)30396-5
Publication status	Published - Feb 2017

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Blood Glucose/metabolism
Case-Control Studies
Cholesterol, LDL/blood
Cohort Studies
Diabetes Mellitus, Type 2/blood
Genetic Predisposition to Disease/genetics
Genetic Variation/genetics
Humans
Mendelian Randomization Analysis/methods
Proprotein Convertase 9/genetics
Randomized Controlled Trials as Topic/methods

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10.1016/S2213-8587(16)30396-5

Cite this

Schmidt, A. F., Swerdlow, D. I., Holmes, M. V., Patel, R. S., Fairhurst-Hunter, Z., Lyall, D. M., Hartwig, F. P., Horta, B. L., Hyppönen, E., Power, C., Moldovan, M., van Iperen, E., Hovingh, G. K., Demuth, I., Norman, K., Steinhagen-Thiessen, E., Demuth, J., Bertram, L., Liu, T., ... Sattar, N. (2017). PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study: a mendelian randomisation study. Lancet. Diabetes and endocrinology, 5(2), 97-105. https://doi.org/10.1016/S2213-8587(16)30396-5

@article{a19c734b1dbf40399ad817f65568078a,

title = "PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study: a mendelian randomisation study",

abstract = "BACKGROUND: Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk.METHODS: In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores.FINDINGS: Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95\% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03\%, -0·01 to 0·08), fasting insulin (0·00\%, -0·06 to 0·07), and BMI (0·11 kg/m2, -0·09 to 0·30).INTERPRETATION: PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins.FUNDING: British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.",

keywords = "Blood Glucose/metabolism, Case-Control Studies, Cholesterol, LDL/blood, Cohort Studies, Diabetes Mellitus, Type 2/blood, Genetic Predisposition to Disease/genetics, Genetic Variation/genetics, Humans, Mendelian Randomization Analysis/methods, Proprotein Convertase 9/genetics, Randomized Controlled Trials as Topic/methods",

author = "Schmidt, \{Amand F.\} and Swerdlow, \{Daniel I.\} and Holmes, \{Michael V.\} and Patel, \{Riyaz S.\} and Zammy Fairhurst-Hunter and Lyall, \{Donald M.\} and Hartwig, \{Fernando Pires\} and Horta, \{Bernardo Lessa\} and Elina Hypp{\"o}nen and Christine Power and Max Moldovan and \{van Iperen\}, Erik and Hovingh, \{G. Kees\} and Ilja Demuth and Kristina Norman and Elisabeth Steinhagen-Thiessen and Juri Demuth and Lars Bertram and Tian Liu 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 Robert Scott and Jian'an Luan and Martin Bobak and Sofia Malyutina and Andrzej Paj{\c a}k and Ruzena Kubinova and Abdonas Tamosiunas and Hynek Pikhart and Husemoen, \{Lise Lotte Nystrup\} and Niels Grarup and Oluf Pedersen and Torben Hansen and Allan Linneberg and Simonsen, \{Kenneth Starup\} 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 Kirchner, \{H. Lester\} 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 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, \{Dennis 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 Smith, \{Daniel J.\} and Tom Meade 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 Beverley Balkau and Am{\'e}lie Bonnefond and Bertrand Cariou and Melissa Smart and Yanchun Bao and Meena Kumari and Anubha Mahajan and Ridker, \{Paul M.\} and Chasman, \{Daniel I.\} and Reiner, \{Alex P.\} and Lange, \{Leslie A.\} and Ritchie, \{Marylyn D.\} and Asselbergs, \{Folkert W.\} and Juan-Pablo Casas and Keating, \{Brendan J.\} and David Preiss and Hingorani, \{Aroon D.\} and Naveed Sattar",

year = "2017",

month = feb,

doi = "10.1016/S2213-8587(16)30396-5",

language = "English",

volume = "5",

pages = "97--105",

journal = "Lancet. Diabetes and endocrinology",

issn = "2213-8587",

publisher = "Elsevier BV",

number = "2",

}

Schmidt, AF, Swerdlow, DI, Holmes, MV, Patel, RS, Fairhurst-Hunter, Z, Lyall, DM, Hartwig, FP, Horta, BL, Hyppönen, E, Power, C, Moldovan, M, van Iperen, E, Hovingh, GK, Demuth, I, Norman, K, Steinhagen-Thiessen, E, Demuth, J, Bertram, L, Liu, T, 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, R, Luan, J, Bobak, M, Malyutina, S, Pająk, A, Kubinova, R, Tamosiunas, A, Pikhart, H, Husemoen, LLN, Grarup, N, Pedersen, O, Hansen, T, Linneberg, A, Simonsen, KS, Cooper, J, Humphries, SE, Brilliant, M, Kitchner, T, Hakonarson, H, Carrell, DS, McCarty, CA, Kirchner, HL, Larson, EB, Crosslin, DR, de Andrade, M, Roden, DM, Denny, JC, Carty, C, Hancock, S, Attia, J, Holliday, E, 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, Smith, DJ, Meade, T, Maitland-van der Zee, AH, Baranova, EV, Young, R, Ford, I, Campbell, A, Padmanabhan, S, Bots, ML, Grobbee, DE, Froguel, P, Thuillier, D, Balkau, B, Bonnefond, A, Cariou, B, Smart, M, Bao, Y, Kumari, M, Mahajan, A, Ridker, PM, Chasman, DI, Reiner, AP, Lange, LA, Ritchie, MD, Asselbergs, FW, Casas, J-P, Keating, BJ, Preiss, D, Hingorani, AD & Sattar, N 2017, 'PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study: a mendelian randomisation study', Lancet. Diabetes and endocrinology, vol. 5, no. 2, pp. 97-105. https://doi.org/10.1016/S2213-8587(16)30396-5

TY - JOUR

T1 - PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study

T2 - a mendelian randomisation study

AU - Schmidt, Amand F.

AU - Swerdlow, Daniel I.

AU - Holmes, Michael V.

AU - Patel, Riyaz S.

AU - Fairhurst-Hunter, Zammy

AU - Lyall, Donald M.

AU - Hartwig, Fernando Pires

AU - Horta, Bernardo Lessa

AU - Hyppönen, Elina

AU - Power, Christine

AU - Moldovan, Max

AU - van Iperen, Erik

AU - Hovingh, G. Kees

AU - Demuth, Ilja

AU - Norman, Kristina

AU - Steinhagen-Thiessen, Elisabeth

AU - Demuth, Juri

AU - Bertram, Lars

AU - Liu, Tian

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

AU - Luan, Jian'an

AU - Bobak, Martin

AU - Malyutina, Sofia

AU - Pająk, Andrzej

AU - Kubinova, Ruzena

AU - Tamosiunas, Abdonas

AU - Pikhart, Hynek

AU - Husemoen, Lise Lotte Nystrup

AU - Grarup, Niels

AU - Pedersen, Oluf

AU - Hansen, Torben

AU - Linneberg, Allan

AU - Simonsen, Kenneth Starup

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 - Kirchner, H. Lester

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 - 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, Dennis 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 - Smith, Daniel J.

AU - Meade, Tom

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 - Balkau, Beverley

AU - Bonnefond, Amélie

AU - Cariou, Bertrand

AU - Smart, Melissa

AU - Bao, Yanchun

AU - Kumari, Meena

AU - Mahajan, Anubha

AU - Ridker, Paul M.

AU - Chasman, Daniel I.

AU - Reiner, Alex P.

AU - Lange, Leslie A.

AU - Ritchie, Marylyn D.

AU - Asselbergs, Folkert W.

AU - Casas, Juan-Pablo

AU - Keating, Brendan J.

AU - Preiss, David

AU - Hingorani, Aroon D.

AU - Sattar, Naveed

PY - 2017/2

Y1 - 2017/2

N2 - BACKGROUND: Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk.METHODS: In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores.FINDINGS: Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m2, -0·09 to 0·30).INTERPRETATION: PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins.FUNDING: British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.

AB - BACKGROUND: Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk.METHODS: In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores.FINDINGS: Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m2, -0·09 to 0·30).INTERPRETATION: PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins.FUNDING: British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.

KW - Blood Glucose/metabolism

KW - Case-Control Studies

KW - Cholesterol, LDL/blood

KW - Cohort Studies

KW - Diabetes Mellitus, Type 2/blood

KW - Genetic Predisposition to Disease/genetics

KW - Genetic Variation/genetics

KW - Humans

KW - Mendelian Randomization Analysis/methods

KW - Proprotein Convertase 9/genetics

KW - Randomized Controlled Trials as Topic/methods

U2 - 10.1016/S2213-8587(16)30396-5

DO - 10.1016/S2213-8587(16)30396-5

M3 - Article

C2 - 27908689

SN - 2213-8587

VL - 5

SP - 97

EP - 105

JO - Lancet. Diabetes and endocrinology

JF - Lancet. Diabetes and endocrinology

IS - 2

ER -

PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study: a mendelian randomisation study

Abstract

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Keywords

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