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 Hypponen; Christine Power; Max Moldovan; Erik P. A. 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 N. Nicolaides; Andrie G. Panayiotou; Charlotte N. Onland-Moret; Yvonne T. van der Schouw; Giuseppe Matullo; Giovanni Fiorito; Simonetta Guarrera; Carlotta Sacerdote; Nicholas J. Wareham; Pim van der Harst; M. Abdullah Said; Ruben N. Eppinga; Niek Verweij; Harold Snieder; Folkert W. Asselbergs; LifeLines Cohort Study Grp; UCLEB Consortium

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 Hypponen, Christine Power, Max Moldovan, Erik P. A. 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 N. Nicolaides, Andrie G. Panayiotou, Charlotte N. Onland-Moret, Yvonne T. van der Schouw, Giuseppe Matullo, Giovanni Fiorito, Simonetta Guarrera, Carlotta Sacerdote, Nicholas J. Wareham, Pim van der Harst, M. Abdullah Said, Ruben N. Eppinga, Niek Verweij, Harold Snieder, Folkert W. Asselbergs, LifeLines Cohort Study Grp, UCLEB Consortium

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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 off sets their substantial benefi ts. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely eff ects 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, HbA 1c, 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 HbA 1c (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 benefi ts of PCSK9 inhibitor treatment, as was previously done for statins.

Originele taal-2	English
Pagina's (van-tot)	97-105
Aantal pagina's	9
Tijdschrift	Lancet Diabetes & Endocrinology
Volume	5
Nummer van het tijdschrift	2
DOI's	https://doi.org/10.1016/S2213-8587(16)30396-5
Status	Published - feb.-2017

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

@article{a7eb47c22b0c46a38419d8eea8571279,

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 off sets their substantial benefi ts. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely eff ects 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, HbA 1c, 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 HbA 1c (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 benefi ts of PCSK9 inhibitor treatment, as was previously done for statins.",

keywords = "STATIN THERAPY, HEART-DISEASE, ASSOCIATION, HYPERCHOLESTEROLEMIA, METAANALYSIS, CHOLESTEROL, COMMON, ARCHITECTURE, PATHWAYS, INSIGHTS",

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 Hypponen and Christine Power and Max Moldovan and {van Iperen}, {Erik P. A.} 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 Nicolaides, {Andrew N.} and Panayiotou, {Andrie G.} and Onland-Moret, {Charlotte N.} and {van der Schouw}, {Yvonne T.} and Giuseppe Matullo and Giovanni Fiorito and Simonetta Guarrera and Carlotta Sacerdote and Wareham, {Nicholas J.} and {van der Harst}, Pim and Said, {M. Abdullah} and Eppinga, {Ruben N.} and Niek Verweij and Harold Snieder and Asselbergs, {Folkert W.} and {LifeLines Cohort Study Grp} and {UCLEB Consortium}",

year = "2017",

month = feb,

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

language = "English",

volume = "5",

pages = "97--105",

journal = "Lancet Diabetes & Endocrinology",

issn = "2213-8587",

publisher = "ELSEVIER SCIENCE INC",

number = "2",

}

Schmidt, AF, Swerdlow, DI, Holmes, MV, Patel, RS, Fairhurst-Hunter, Z, Lyall, DM, Hartwig, FP, Horta, BL, Hypponen, E, Power, C, Moldovan, M, van Iperen, EPA, 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, AN, Panayiotou, AG, Onland-Moret, CN, van der Schouw, YT, Matullo, G, Fiorito, G, Guarrera, S, Sacerdote, C, Wareham, NJ, van der Harst, P , Said, MA, Eppinga, RN, Verweij, N, Snieder, H, Asselbergs, FW, LifeLines Cohort Study Grp & UCLEB Consortium 2017, 'PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study', Lancet Diabetes & Endocrinology, vol. 5, nr. 2, blz. 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 - Hypponen, Elina

AU - Power, Christine

AU - Moldovan, Max

AU - van Iperen, Erik P. A.

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 N.

AU - Panayiotou, Andrie G.

AU - Onland-Moret, Charlotte N.

AU - van der Schouw, Yvonne T.

AU - Matullo, Giuseppe

AU - Fiorito, Giovanni

AU - Guarrera, Simonetta

AU - Sacerdote, Carlotta

AU - Wareham, Nicholas J.

AU - van der Harst, Pim

AU - Said, M. Abdullah

AU - Eppinga, Ruben N.

AU - Verweij, Niek

AU - Snieder, Harold

AU - Asselbergs, Folkert W.

AU - LifeLines Cohort Study Grp

AU - UCLEB Consortium

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 off sets their substantial benefi ts. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely eff ects 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, HbA 1c, 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 HbA 1c (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 benefi ts of PCSK9 inhibitor treatment, as was 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 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 off sets their substantial benefi ts. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely eff ects 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, HbA 1c, 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 HbA 1c (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 benefi ts of PCSK9 inhibitor treatment, as was previously done for statins.

KW - STATIN THERAPY

KW - HEART-DISEASE

KW - ASSOCIATION

KW - HYPERCHOLESTEROLEMIA

KW - METAANALYSIS

KW - CHOLESTEROL

KW - COMMON

KW - ARCHITECTURE

KW - PATHWAYS

KW - INSIGHTS

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

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

M3 - Article

SN - 2213-8587

VL - 5

SP - 97

EP - 105

JO - Lancet Diabetes & Endocrinology

JF - Lancet Diabetes & Endocrinology

IS - 2

ER -

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

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