PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
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 journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
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
C2 - 27908689
VL - 5
SP - 97
EP - 105
JO - The Lancet Diabetes & Endocrinology
JF - The Lancet Diabetes & Endocrinology
SN - 2213-8587
IS - 2
ER -
ID: 172434808