Mendelian randomization of blood lipids for coronary heart disease

Holmes, Michael V., Asselbergs, Folkert W., Palmer, Tom M., Drenos, Fotios, Lanktree, Matthew B., Nelson, Christopher P., Dale, Caroline E., Padmanabhan, Sandosh, Finan, Chris, Swerdlow, Daniel I., Tragante, Vinicius, van Iperen, Erik P. A., Sivapalaratnam, Suthesh, Shah, Sonia, Elbers, Clara C., Shah, Tina, Engmann, Jorgen, Giambartolomei, Claudia, White, Jon, Zabaneh, Delilah, Sofat, Reecha, McLachlan, Stela, Doevendans, Pieter A., Balmforth, Anthony J., Hall, Alistair S., North, Kari E., Almoguera, Berta, Hoogeveen, Ron C., Cushman, Mary, Fornage, Myriam, Patel, Sanjay R., Redline, Susan, Siscovick, David S., Tsai, Michael Y., Karczewski, Konrad J., Hofker, Marten H., Verschuren, W. Monique, Bots, Michiel L., van der Schouw, Yvonne T., Melander, Olle, Dominiczak, Anna F., Morris, Richard, Ben-Shlomo, Yoav, Price, Jackie, Kumari, Meena, Baumert, Jens, Peters, Annette, Thorand, Barbara, Koenig, Wolfgang, Gaunt, Tom R., Humphries, Steve E., Clarke, Robert, Watkins, Hugh, Farrall, Martin, Wilson, James G., Rich, Stephen S., de Bakker, Paul I. W., Lange, Leslie A., Smith, George Davey, Reiner, Alex P., Talmud, Philippa J., Kivimaeki, Mika, Lawlor, Debbie A., Dudbridge, Frank, Samani, Nilesh J., Keating, Brendan J., Hingorani, Aroon D. and Casas, Juan P. (2015) Mendelian randomization of blood lipids for coronary heart disease. European Heart Journal, 36 9: 539-550. doi:10.1093/eurheartj/eht571

Author Holmes, Michael V.
Asselbergs, Folkert W.
Palmer, Tom M.
Drenos, Fotios
Lanktree, Matthew B.
Nelson, Christopher P.
Dale, Caroline E.
Padmanabhan, Sandosh
Finan, Chris
Swerdlow, Daniel I.
Tragante, Vinicius
van Iperen, Erik P. A.
Sivapalaratnam, Suthesh
Shah, Sonia
Elbers, Clara C.
Shah, Tina
Engmann, Jorgen
Giambartolomei, Claudia
White, Jon
Zabaneh, Delilah
Sofat, Reecha
McLachlan, Stela
Doevendans, Pieter A.
Balmforth, Anthony J.
Hall, Alistair S.
North, Kari E.
Almoguera, Berta
Hoogeveen, Ron C.
Cushman, Mary
Fornage, Myriam
Patel, Sanjay R.
Redline, Susan
Siscovick, David S.
Tsai, Michael Y.
Karczewski, Konrad J.
Hofker, Marten H.
Verschuren, W. Monique
Bots, Michiel L.
van der Schouw, Yvonne T.
Melander, Olle
Dominiczak, Anna F.
Morris, Richard
Ben-Shlomo, Yoav
Price, Jackie
Kumari, Meena
Baumert, Jens
Peters, Annette
Thorand, Barbara
Koenig, Wolfgang
Gaunt, Tom R.
Humphries, Steve E.
Clarke, Robert
Watkins, Hugh
Farrall, Martin
Wilson, James G.
Rich, Stephen S.
de Bakker, Paul I. W.
Lange, Leslie A.
Smith, George Davey
Reiner, Alex P.
Talmud, Philippa J.
Kivimaeki, Mika
Lawlor, Debbie A.
Dudbridge, Frank
Samani, Nilesh J.
Keating, Brendan J.
Hingorani, Aroon D.
Casas, Juan P.
Title Mendelian randomization of blood lipids for coronary heart disease
Journal name European Heart Journal   Check publisher's open access policy
ISSN 1522-9645
Publication date 2015-03-01
Year available 2014
Sub-type Article (original research)
DOI 10.1093/eurheartj/eht571
Open Access Status DOI
Volume 36
Issue 9
Start page 539
End page 550
Total pages 13
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
Formatted 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.
Keyword Aetiology
Heart disease
Mendelian randomization
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID G0802432
BHF RG 08/008
NHLBI 33014
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
School of Biomedical Sciences Publications
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