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

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PCSK9 genetic variants and risk of type 2 diabetes : a mendelian randomisation study. / Schmidt, Amand F; Swerdlow, Daniel I; Holmes, Michael V; Patel, Riyaz S; Fairhurst-Hunter, Zammy; Lyall, Donald M; Hartwig, Fernando Pires; Horta, Bernardo Lessa; Hyppönen, Elina; Power, Christine; Moldovan, Max; van Iperen, Erik; Hovingh, G Kees; Demuth, Ilja; Norman, Kristina; Steinhagen-Thiessen, Elisabeth; Demuth, Juri; Bertram, Lars; Liu, Tian; 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; Grarup, Niels; Pedersen, Oluf; Hansen, Torben; Linneberg, Allan; LifeLines Cohort study group.

In: The Lancet Diabetes & Endocrinology, Vol. 5, No. 2, 02.2017, p. 97–105.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

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, Grarup, N, Pedersen, O, Hansen, T, Linneberg, A & LifeLines Cohort study group 2017, 'PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study', The Lancet Diabetes & Endocrinology, vol. 5, no. 2, pp. 97–105. https://doi.org/10.1016/S2213-8587(16)30396-5

APA

Schmidt, A. F., Swerdlow, D. I., Holmes, M. V., Patel, R. S., Fairhurst-Hunter, Z., Lyall, D. M., ... LifeLines Cohort study group (2017). PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study. The Lancet Diabetes & Endocrinology, 5(2), 97–105. https://doi.org/10.1016/S2213-8587(16)30396-5

Vancouver

Schmidt AF, Swerdlow DI, Holmes MV, Patel RS, Fairhurst-Hunter Z, Lyall DM et al. PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study. The Lancet Diabetes & Endocrinology. 2017 Feb;5(2):97–105. https://doi.org/10.1016/S2213-8587(16)30396-5

Author

Schmidt, Amand F ; Swerdlow, Daniel I ; Holmes, Michael V ; Patel, Riyaz S ; Fairhurst-Hunter, Zammy ; Lyall, Donald M ; Hartwig, Fernando Pires ; Horta, Bernardo Lessa ; Hyppönen, Elina ; Power, Christine ; Moldovan, Max ; van Iperen, Erik ; Hovingh, G Kees ; Demuth, Ilja ; Norman, Kristina ; Steinhagen-Thiessen, Elisabeth ; Demuth, Juri ; Bertram, Lars ; Liu, Tian ; 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 ; Grarup, Niels ; Pedersen, Oluf ; Hansen, Torben ; Linneberg, Allan ; LifeLines Cohort study group. / PCSK9 genetic variants and risk of type 2 diabetes : a mendelian randomisation study. In: The Lancet Diabetes & Endocrinology. 2017 ; Vol. 5, No. 2. pp. 97–105.

Bibtex

@article{fb030f454bfe47959130969aaa64ef88,
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 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/m(2), -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.",
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 Niels Grarup and Oluf Pedersen and Torben Hansen and Allan Linneberg and {LifeLines Cohort study group}",
note = "Copyright {\^A}{\circledC} 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.",
year = "2017",
month = "2",
doi = "10.1016/S2213-8587(16)30396-5",
language = "English",
volume = "5",
pages = "97–105",
journal = "The Lancet Diabetes & Endocrinology",
issn = "2213-8587",
publisher = "The Lancet Publishing Group",
number = "2",

}

RIS

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 - Grarup, Niels

AU - Pedersen, Oluf

AU - Hansen, Torben

AU - Linneberg, Allan

AU - LifeLines Cohort study group

N1 - Copyright © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY license. Published by Elsevier Ltd.. All rights reserved.

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/m(2), -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/m(2), -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.

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

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

M3 - Journal article

VL - 5

SP - 97

EP - 105

JO - The Lancet Diabetes & Endocrinology

JF - The Lancet Diabetes & Endocrinology

SN - 2213-8587

IS - 2

ER -

ID: 172434808