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Mendelian randomization of blood lipids for coronary heart disease. 2015
Michael V Holmes, and
Folkert W Asselbergs, and
Tom M Palmer, and
Fotios Drenos, and
Matthew B Lanktree, and
Christopher P Nelson, and
Caroline E Dale, and
Sandosh Padmanabhan, and
Chris Finan, and
Daniel I Swerdlow, and
Vinicius Tragante, and
Erik P A van Iperen, and
Suthesh Sivapalaratnam, and
Sonia Shah, and
Clara C Elbers, and
Tina Shah, and
Jorgen Engmann, and
Claudia Giambartolomei, and
Jon White, and
Delilah Zabaneh, and
Reecha Sofat, and
Stela McLachlan, and
, and
Pieter A Doevendans, and
Anthony J Balmforth, and
Alistair S Hall, and
Kari E North, and
Berta Almoguera, and
Ron C Hoogeveen, and
Mary Cushman, and
Myriam Fornage, and
Sanjay R Patel, and
Susan Redline, and
David S Siscovick, and
Michael Y Tsai, and
Konrad J Karczewski, and
Marten H Hofker, and
W Monique Verschuren, and
Michiel L Bots, and
Yvonne T van der Schouw, and
Olle Melander, and
Anna F Dominiczak, 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
Tom R Gaunt, and
Steve E Humphries, and
Robert Clarke, and
Hugh Watkins, and
Martin Farrall, and
James G Wilson, and
Stephen S Rich, and
Paul I W de Bakker, and
Leslie A Lange, and
George Davey Smith, and
Alex P Reiner, and
Philippa J Talmud, and
Mika Kivimäki, and
Debbie A Lawlor, and
Frank Dudbridge, and
Nilesh J Samani, and
Brendan J Keating, and
Aroon D Hingorani, and
Juan P Casas
Genetic Epidemiology Group, Institute of Cardiovacular Science, Faculty of Population Healh Sciences, University College London, 1-19 Torrington Place, London WC1E 6BT, UK Division of Transplant Surgery, Perelman School of Medicine, University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104, USA mvholmes@gmail.com.
OBJECTIVE 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. 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). CONCLUSIONS The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.
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Annette Peters, and
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Steve E Humphries, and
Robert Clarke, and
Hugh Watkins, and
Martin Farrall, and
James G Wilson, and
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Sandosh Padmanabhan, and
Chris Finan, and
Daniel I Swerdlow, and
Vinicius Tragante, and
Erik P A van Iperen, and
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Clara C Elbers, and
Tina Shah, and
Jorgen Engmann, and
Claudia Giambartolomei, and
Jon White, and
Delilah Zabaneh, and
Reecha Sofat, and
Stela McLachlan, and
, and
Pieter A Doevendans, and
Anthony J Balmforth, and
Alistair S Hall, and
Kari E North, and
Berta Almoguera, and
Ron C Hoogeveen, and
Mary Cushman, and
Myriam Fornage, and
Sanjay R Patel, and
Susan Redline, and
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Michael Y Tsai, and
Konrad J Karczewski, and
Marten H Hofker, and
W Monique Verschuren, and
Michiel L Bots, and
Yvonne T van der Schouw, and
Olle Melander, and
Anna F Dominiczak, 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
Tom R Gaunt, and
Steve E Humphries, and
Robert Clarke, and
Hugh Watkins, and
Martin Farrall, and
James G Wilson, and
Stephen S Rich, and
Paul I W de Bakker, and
Leslie A Lange, and
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Alex P Reiner, and
Philippa J Talmud, and
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Yoav Ben-Shlomo, and
Jackie Price, and
Meena Kumari, and
Jens Baumert, and
Annette Peters, and
Barbara Thorand, and
Wolfgang Koenig, and
Tom R Gaunt, and
Steve E Humphries, and
Robert Clarke, and
Hugh Watkins, and
Martin Farrall, and
James G Wilson, and
Stephen S Rich, and
Paul I W de Bakker, and
Leslie A Lange, and
George Davey Smith, and
Alex P Reiner, and
Philippa J Talmud, and
Mika Kivimäki, and
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Daniel I Swerdlow, and
Vinicius Tragante, and
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Clara C Elbers, and
Tina Shah, and
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Claudia Giambartolomei, and
Jon White, and
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Stela McLachlan, and
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Pieter A Doevendans, and
Anthony J Balmforth, and
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Ron C Hoogeveen, and
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Sanjay R Patel, and
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Marten H Hofker, and
W Monique Verschuren, and
Michiel L Bots, and
Yvonne T van der Schouw, and
Olle Melander, and
Anna F Dominiczak, 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
Tom R Gaunt, and
Steve E Humphries, and
Robert Clarke, and
Hugh Watkins, and
Martin Farrall, and
James G Wilson, and
Stephen S Rich, and
Paul I W de Bakker, and
Leslie A Lange, and
George Davey Smith, and
Alex P Reiner, and
Philippa J Talmud, and
Mika Kivimäki, and
Debbie A Lawlor, and
Frank Dudbridge, and
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October 2023,
The Journal of clinical endocrinology and metabolism,
