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

LifeLines Cohort study group, UCLEB consortium

Research output: Contribution to journalArticle

120 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)97-105
Number of pages9
JournalThe Lancet Diabetes and Endocrinology
Volume5
Issue number2
DOIs
StatePublished - Feb 1 2017

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Random Allocation
LDL Cholesterol
Type 2 Diabetes Mellitus
Fasting
Waist-Hip Ratio
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Insulin
Hydroxymethylglutaryl CoA Reductases
Glucose
National Institutes of Health (U.S.)
Hyperglycemia
Genes
Coronary Disease
Blood Glucose
Meta-Analysis
Case-Control Studies
Biomedical Research
Cohort Studies
Randomized Controlled Trials
Biomarkers

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

LifeLines Cohort study group ; UCLEB consortium. / PCSK9 genetic variants and risk of type 2 diabetes : a mendelian randomisation study. In: The Lancet Diabetes and Endocrinology. 2017 ; Vol. 5, No. 2. pp. 97-105.
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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.",
author = "{LifeLines Cohort study group} and {UCLEB consortium} and 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 Pająk",
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PCSK9 genetic variants and risk of type 2 diabetes : a mendelian randomisation study. / LifeLines Cohort study group; UCLEB consortium.

In: The Lancet Diabetes and Endocrinology, Vol. 5, No. 2, 01.02.2017, p. 97-105.

Research output: Contribution to journalArticle

TY - JOUR

T1 - PCSK9 genetic variants and risk of type 2 diabetes

T2 - a mendelian randomisation study

AU - LifeLines Cohort study group

AU - UCLEB consortium

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

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 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.

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