PCSK9 genetic variants and risk of type 2 diabetes: 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 Pajak; 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

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 CoassinJohann 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 Pajak, 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

^*Corresponding author for this work

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

306 Citations (Scopus)

319 Downloads (Pure)

Abstract

Background Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of low-density lipoprotein cholesterol (LDL-C) and the risk of coronary heart disease, but also with modest hyperglycemia, higher weight and risk of type 2 diabetes mellitus (T2DM). We sought to clarify the associations of LDL-C-lowering PCSK9 variants with T2DM and related biomarkers to gauge likely effects of PCSK9 inhibitors.
Methods Associations of PCSK9 variants with LDL-C, fasting blood glucose, HbA_1c, fasting insulin, weight and T2DM risk, available for over 550,000 individuals and 51,623 T2DM cases, were estimated using a standardised analysis plan, meta-analyses and weighted gene-centric scores (GS).
Findings Combined analysis of four independent PCSK9 variants scaled to 1 mmol/L lower LDL-C resulted in the following associations: fasting glucose (0·09 mmol/L; 95%CI 0·02; 0·15), HbA1c (0·03%; 95%CI -0·01; 0·08), fasting insulin (0·00% 95%CI -0·06; 0·07), body weight (1·03 kg; 95%CI 0·24; 1·82), waist-to-hip ratio (0·006; 95%CI 0·003; 0·010), body mass index (0·11 kg/m²; 95%CI -0·09; 0·30), and an odds ratio of 1·29 for T2DM (95%CI 1·11; 1·50).
Interpretation PCSK9 variants associated with lower LDL-C were also associated with higher levels of glucose, weight, waist-to-hip ratio and increased T2DM risk. Trials of PCSK9 inhibitor drugs should carefully evaluate these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment as previously done for statins.

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	29 Nov 2016
DOIs	https://doi.org/10.1016/S2213-8587(16)30396-5
Publication status	Published - 1 Feb 2017

Keywords

Diabetes Mellitus
Genetic Association Studies
Mendelian randomisation
LDL-cholesterol
PCSK9 inhibition

UN SDGs

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

Access to Document

10.1016/S2213-8587(16)30396-5

Full-text PDF (final published version)
This is the final published version of the article (version of record). It first appeared online via Elsevier at http://www.sciencedirect.com/science/article/pii/S2213858716303965. Please refer to any applicable terms of use of the publisher.
Final published version, 590 KBLicence: CC BY

Handle.net

Persistent link

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. Lancet Diabetes and Endocrinology, 5(2), 97-105. https://doi.org/10.1016/S2213-8587(16)30396-5

@article{b842e1d8febc49c98b9ba3f34a94e1df,

title = "PCSK9 genetic variants and risk of type 2 diabetes: 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 low-density lipoprotein cholesterol (LDL-C) and the risk of coronary heart disease, but also with modest hyperglycemia, higher weight and risk of type 2 diabetes mellitus (T2DM). We sought to clarify the associations of LDL-C-lowering PCSK9 variants with T2DM and related biomarkers to gauge likely effects of PCSK9 inhibitors. Methods Associations of PCSK9 variants with LDL-C, fasting blood glucose, HbA1c, fasting insulin, weight and T2DM risk, available for over 550,000 individuals and 51,623 T2DM cases, were estimated using a standardised analysis plan, meta-analyses and weighted gene-centric scores (GS).Findings Combined analysis of four independent PCSK9 variants scaled to 1 mmol/L lower LDL-C resulted in the following associations: fasting glucose (0·09 mmol/L; 95%CI 0·02; 0·15), HbA1c (0·03%; 95%CI -0·01; 0·08), fasting insulin (0·00% 95%CI -0·06; 0·07), body weight (1·03 kg; 95%CI 0·24; 1·82), waist-to-hip ratio (0·006; 95%CI 0·003; 0·010), body mass index (0·11 kg/m2; 95%CI -0·09; 0·30), and an odds ratio of 1·29 for T2DM (95%CI 1·11; 1·50).Interpretation PCSK9 variants associated with lower LDL-C were also associated with higher levels of glucose, weight, waist-to-hip ratio and increased T2DM risk. Trials of PCSK9 inhibitor drugs should carefully evaluate these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment as previously done for statins.",

keywords = "Diabetes Mellitus, Genetic Association Studies, Mendelian randomisation, LDL-cholesterol, PCSK9 inhibition",

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 Pajak 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 Donnell, {Martin O.} 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 Casas, {Juan Pablo} and Keating, {Brendan J.} and David Preiss and Hingorani, {Aroon D.} and Naveed Sattar",

year = "2017",

month = feb,

day = "1",

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

language = "English",

volume = "5",

pages = "97--105",

journal = "Lancet Diabetes and Endocrinology",

issn = "2213-8587",

publisher = "Lancet Publishing Group",

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, Pajak, 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, Donnell, MO, 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, JP, Keating, BJ, Preiss, D, Hingorani, AD & Sattar, N 2017, 'PCSK9 genetic variants and risk of type 2 diabetes: 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

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 - Pajak, 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 - Donnell, Martin O.

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 - 2017/2/1

Y1 - 2017/2/1

N2 - Background Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of low-density lipoprotein cholesterol (LDL-C) and the risk of coronary heart disease, but also with modest hyperglycemia, higher weight and risk of type 2 diabetes mellitus (T2DM). We sought to clarify the associations of LDL-C-lowering PCSK9 variants with T2DM and related biomarkers to gauge likely effects of PCSK9 inhibitors. Methods Associations of PCSK9 variants with LDL-C, fasting blood glucose, HbA1c, fasting insulin, weight and T2DM risk, available for over 550,000 individuals and 51,623 T2DM cases, were estimated using a standardised analysis plan, meta-analyses and weighted gene-centric scores (GS).Findings Combined analysis of four independent PCSK9 variants scaled to 1 mmol/L lower LDL-C resulted in the following associations: fasting glucose (0·09 mmol/L; 95%CI 0·02; 0·15), HbA1c (0·03%; 95%CI -0·01; 0·08), fasting insulin (0·00% 95%CI -0·06; 0·07), body weight (1·03 kg; 95%CI 0·24; 1·82), waist-to-hip ratio (0·006; 95%CI 0·003; 0·010), body mass index (0·11 kg/m2; 95%CI -0·09; 0·30), and an odds ratio of 1·29 for T2DM (95%CI 1·11; 1·50).Interpretation PCSK9 variants associated with lower LDL-C were also associated with higher levels of glucose, weight, waist-to-hip ratio and increased T2DM risk. Trials of PCSK9 inhibitor drugs should carefully evaluate these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment as previously done for statins.

AB - Background Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of low-density lipoprotein cholesterol (LDL-C) and the risk of coronary heart disease, but also with modest hyperglycemia, higher weight and risk of type 2 diabetes mellitus (T2DM). We sought to clarify the associations of LDL-C-lowering PCSK9 variants with T2DM and related biomarkers to gauge likely effects of PCSK9 inhibitors. Methods Associations of PCSK9 variants with LDL-C, fasting blood glucose, HbA1c, fasting insulin, weight and T2DM risk, available for over 550,000 individuals and 51,623 T2DM cases, were estimated using a standardised analysis plan, meta-analyses and weighted gene-centric scores (GS).Findings Combined analysis of four independent PCSK9 variants scaled to 1 mmol/L lower LDL-C resulted in the following associations: fasting glucose (0·09 mmol/L; 95%CI 0·02; 0·15), HbA1c (0·03%; 95%CI -0·01; 0·08), fasting insulin (0·00% 95%CI -0·06; 0·07), body weight (1·03 kg; 95%CI 0·24; 1·82), waist-to-hip ratio (0·006; 95%CI 0·003; 0·010), body mass index (0·11 kg/m2; 95%CI -0·09; 0·30), and an odds ratio of 1·29 for T2DM (95%CI 1·11; 1·50).Interpretation PCSK9 variants associated with lower LDL-C were also associated with higher levels of glucose, weight, waist-to-hip ratio and increased T2DM risk. Trials of PCSK9 inhibitor drugs should carefully evaluate these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment as previously done for statins.

KW - Diabetes Mellitus

KW - Genetic Association Studies

KW - Mendelian randomisation

KW - LDL-cholesterol

KW - PCSK9 inhibition

UR - http://www.scopus.com/inward/record.url?scp=85007330927&partnerID=8YFLogxK

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

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

M3 - Article (Academic Journal)

C2 - 27908689

AN - SCOPUS:85007330927

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

Abstract

Keywords

UN SDGs

Access to Document

Handle.net

Other files and links

Embargoed Document

Fingerprint

MRC UoB UNITE Unit - Programme 1

Professor Yoav Ben-Shlomo

Cite this

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

Abstract

Keywords

UN SDGs

Access to Document

Handle.net

Other files and links

Embargoed Document

Fingerprint

Projects

MRC UoB UNITE Unit - Programme 1

Profiles

Professor Yoav Ben-Shlomo

Cite this