Mendelian randomization of blood lipids for coronary heart disease

Michael V. Holmes; Folkert W. Asselbergs; Tom M. Palmer; Fotios Drenos; Matthew B. Lanktree; Christopher P. Nelson; Caroline E. Dale; Sandosh Padmanabhan; Chris Finan; Daniel I. Swerdlow; Vinicius Tragante; Erik P A Van Iperen; Suthesh Sivapalaratnam; Sonia Shah; Clara C. Elbers; Tina Shah; Jorgen Engmann; Claudia Giambartolomei; Jon White; Delilah Zabaneh; Reecha Sofat; Stela McLachlan; Pieter A. Doevendans; Anthony J. Balmforth; Alistair S. Hall; Kari E. North; Berta Almoguera; Ron C. Hoogeveen; Mary Cushman; Myriam Fornage; Sanjay R. Patel; Susan Redline; David S. Siscovick; Michael Y. Tsai; Konrad J. Karczewski; Marten H. Hofker; W. Monique Verschuren; Michiel L. Bots; Yvonne T. Van Der Schouw; Olle Melander; Anna F. Dominiczak; Richard Morris; Yoav Ben-Shlomo; Jackie Price; Meena Kumari; Jens Baumert; Annette Peters; Barbara Thorand; Wolfgang Koenig; Tom R. Gaunt; Steve E. Humphries; Robert Clarke; Hugh Watkins; Martin Farrall; James G. Wilson; Stephen S. Rich; Paul I W De Bakker; Leslie A. Lange; George Davey Smith; Alex P. Reiner; Philippa J. Talmud; Mika Kivimäki; Debbie A. Lawlor; Frank Dudbridge; Nilesh J. Samani; Brendan J. Keating; Aroon D. Hingorani; Juan P. Casas

doi:10.1093/eurheartj/eht571

Mendelian randomization of blood lipids for coronary heart disease

Michael V. Holmes^*, Folkert W. Asselbergs, Tom M. Palmer, Fotios Drenos, Matthew B. Lanktree, Christopher P. Nelson, Caroline E. Dale, Sandosh Padmanabhan, Chris Finan, Daniel I. Swerdlow, Vinicius Tragante, Erik P A Van Iperen, Suthesh Sivapalaratnam, Sonia Shah, Clara C. Elbers, Tina Shah, Jorgen Engmann, Claudia Giambartolomei, Jon White, Delilah ZabanehReecha Sofat, Stela McLachlan, Pieter A. Doevendans, Anthony J. Balmforth, Alistair S. Hall, Kari E. North, Berta Almoguera, Ron C. Hoogeveen, Mary Cushman, Myriam Fornage, Sanjay R. Patel, Susan Redline, David S. Siscovick, Michael Y. Tsai, Konrad J. Karczewski, Marten H. Hofker, W. Monique Verschuren, Michiel L. Bots, Yvonne T. Van Der Schouw, Olle Melander, Anna F. Dominiczak, Richard Morris, Yoav Ben-Shlomo, Jackie Price, Meena Kumari, Jens Baumert, Annette Peters, Barbara Thorand, Wolfgang Koenig, Tom R. Gaunt, Steve E. Humphries, Robert Clarke, Hugh Watkins, Martin Farrall, James G. Wilson, Stephen S. Rich, Paul I W De Bakker, Leslie A. Lange, George Davey Smith, Alex P. Reiner, Philippa J. Talmud, Mika Kivimäki, Debbie A. Lawlor, Frank Dudbridge, Nilesh J. Samani, Brendan J. Keating, Aroon D. Hingorani, Juan P. Casas

^*Corresponding author for this work

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

4 Citations (Scopus)

Abstract

Aims To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization.

Methods and results We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10^-6); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75).

Conclusion The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.

Original language	English
Pages (from-to)	539-550
Number of pages	12
Journal	European Heart Journal
Volume	36
Issue number	9
DOIs	https://doi.org/10.1093/eurheartj/eht571
Publication status	Published - 1 Jan 2015

Keywords

Aetiology
Epidemiology
Heart disease
Lipids
Mendelian randomization

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Holmes, M. V., Asselbergs, F. W., Palmer, T. M., Drenos, F., Lanktree, M. B., Nelson, C. P., Dale, C. E., Padmanabhan, S., Finan, C., Swerdlow, D. I., Tragante, V., Van Iperen, E. P. A., Sivapalaratnam, S., Shah, S., Elbers, C. C., Shah, T., Engmann, J., Giambartolomei, C., White, J., ... Casas, J. P. (2015). Mendelian randomization of blood lipids for coronary heart disease. European Heart Journal, 36(9), 539-550. https://doi.org/10.1093/eurheartj/eht571

@article{81008cb6c759475790e1a8909637627d,

title = "Mendelian randomization of blood lipids for coronary heart disease",

abstract = "Aims To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization. Methods and results We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10-6); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75). Conclusion The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.",

keywords = "Aetiology, Epidemiology, Heart disease, Lipids, Mendelian randomization",

author = "Holmes, {Michael V.} and Asselbergs, {Folkert W.} and Palmer, {Tom M.} and Fotios Drenos and Lanktree, {Matthew B.} and Nelson, {Christopher P.} and Dale, {Caroline E.} and Sandosh Padmanabhan and Chris Finan and Swerdlow, {Daniel I.} and Vinicius Tragante and {Van Iperen}, {Erik P A} and Suthesh Sivapalaratnam and Sonia Shah and Elbers, {Clara C.} and Tina Shah and Jorgen Engmann and Claudia Giambartolomei and Jon White and Delilah Zabaneh and Reecha Sofat and Stela McLachlan and Doevendans, {Pieter A.} and Balmforth, {Anthony J.} and Hall, {Alistair S.} and North, {Kari E.} and Berta Almoguera and Hoogeveen, {Ron C.} and Mary Cushman and Myriam Fornage and Patel, {Sanjay R.} and Susan Redline and Siscovick, {David S.} and Tsai, {Michael Y.} and Karczewski, {Konrad J.} and Hofker, {Marten H.} and Verschuren, {W. Monique} and Bots, {Michiel L.} and {Van Der Schouw}, {Yvonne T.} and Olle Melander and Dominiczak, {Anna F.} and Richard Morris and Yoav Ben-Shlomo and Jackie Price and Meena Kumari and Jens Baumert and Annette Peters and Barbara Thorand and Wolfgang Koenig and Gaunt, {Tom R.} and Humphries, {Steve E.} and Robert Clarke and Hugh Watkins and Martin Farrall and Wilson, {James G.} and Rich, {Stephen S.} and {De Bakker}, {Paul I W} and Lange, {Leslie A.} and Smith, {George Davey} and Reiner, {Alex P.} and Talmud, {Philippa J.} and Mika Kivim{\"a}ki and Lawlor, {Debbie A.} and Frank Dudbridge and Samani, {Nilesh J.} and Keating, {Brendan J.} and Hingorani, {Aroon D.} and Casas, {Juan P.}",

year = "2015",

month = jan,

day = "1",

doi = "10.1093/eurheartj/eht571",

language = "English",

volume = "36",

pages = "539--550",

number = "9",

}

Holmes, MV, Asselbergs, FW, Palmer, TM, Drenos, F, Lanktree, MB, Nelson, CP, Dale, CE, Padmanabhan, S, Finan, C, Swerdlow, DI, Tragante, V, Van Iperen, EPA, Sivapalaratnam, S, Shah, S, Elbers, CC, Shah, T, Engmann, J, Giambartolomei, C, White, J, Zabaneh, D, Sofat, R, McLachlan, S, Doevendans, PA, Balmforth, AJ, Hall, AS, North, KE, Almoguera, B, Hoogeveen, RC, Cushman, M, Fornage, M, Patel, SR, Redline, S, Siscovick, DS, Tsai, MY, Karczewski, KJ, Hofker, MH, Verschuren, WM , Bots, ML , Van Der Schouw, YT, Melander, O, Dominiczak, AF, Morris, R, Ben-Shlomo, Y, Price, J, Kumari, M, Baumert, J, Peters, A, Thorand, B, Koenig, W, Gaunt, TR, Humphries, SE, Clarke, R, Watkins, H, Farrall, M, Wilson, JG, Rich, SS, De Bakker, PIW, Lange, LA, Smith, GD, Reiner, AP, Talmud, PJ, Kivimäki, M, Lawlor, DA, Dudbridge, F, Samani, NJ, Keating, BJ, Hingorani, AD & Casas, JP 2015, 'Mendelian randomization of blood lipids for coronary heart disease', European Heart Journal, vol. 36, no. 9, pp. 539-550. https://doi.org/10.1093/eurheartj/eht571

TY - JOUR

T1 - Mendelian randomization of blood lipids for coronary heart disease

AU - Holmes, Michael V.

AU - Asselbergs, Folkert W.

AU - Palmer, Tom M.

AU - Drenos, Fotios

AU - Lanktree, Matthew B.

AU - Nelson, Christopher P.

AU - Dale, Caroline E.

AU - Padmanabhan, Sandosh

AU - Finan, Chris

AU - Swerdlow, Daniel I.

AU - Tragante, Vinicius

AU - Van Iperen, Erik P A

AU - Sivapalaratnam, Suthesh

AU - Shah, Sonia

AU - Elbers, Clara C.

AU - Shah, Tina

AU - Engmann, Jorgen

AU - Giambartolomei, Claudia

AU - White, Jon

AU - Zabaneh, Delilah

AU - Sofat, Reecha

AU - McLachlan, Stela

AU - Doevendans, Pieter A.

AU - Balmforth, Anthony J.

AU - Hall, Alistair S.

AU - North, Kari E.

AU - Almoguera, Berta

AU - Hoogeveen, Ron C.

AU - Cushman, Mary

AU - Fornage, Myriam

AU - Patel, Sanjay R.

AU - Redline, Susan

AU - Siscovick, David S.

AU - Tsai, Michael Y.

AU - Karczewski, Konrad J.

AU - Hofker, Marten H.

AU - Verschuren, W. Monique

AU - Bots, Michiel L.

AU - Van Der Schouw, Yvonne T.

AU - Melander, Olle

AU - Dominiczak, Anna F.

AU - Morris, Richard

AU - Ben-Shlomo, Yoav

AU - Price, Jackie

AU - Kumari, Meena

AU - Baumert, Jens

AU - Peters, Annette

AU - Thorand, Barbara

AU - Koenig, Wolfgang

AU - Gaunt, Tom R.

AU - Humphries, Steve E.

AU - Clarke, Robert

AU - Watkins, Hugh

AU - Farrall, Martin

AU - Wilson, James G.

AU - Rich, Stephen S.

AU - De Bakker, Paul I W

AU - Lange, Leslie A.

AU - Smith, George Davey

AU - Reiner, Alex P.

AU - Talmud, Philippa J.

AU - Kivimäki, Mika

AU - Lawlor, Debbie A.

AU - Dudbridge, Frank

AU - Samani, Nilesh J.

AU - Keating, Brendan J.

AU - Hingorani, Aroon D.

AU - Casas, Juan P.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Aims To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization. Methods and results We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10-6); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75). Conclusion The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.

AB - Aims To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization. Methods and results We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10-6); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75). Conclusion The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.

KW - Aetiology

KW - Epidemiology

KW - Heart disease

KW - Lipids

KW - Mendelian randomization

UR - http://www.scopus.com/inward/record.url?scp=84924420487&partnerID=8YFLogxK

U2 - 10.1093/eurheartj/eht571

DO - 10.1093/eurheartj/eht571

M3 - Article

C2 - 24474739

AN - SCOPUS:84924420487

SN - 0195-668X

VL - 36

SP - 539

EP - 550

JO - European Heart Journal

JF - European Heart Journal

IS - 9

ER -

Mendelian randomization of blood lipids for coronary heart disease

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