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Title: Homocysteine and Coronary Heart Disease: Meta-analysis of MTHFR Case-Control Studies, Avoiding Publication Bias
Authors: Clarke, Robert
Bennett, Derrick A.
Parish, Sarah
Verhoef, Petra
Dotsch-Klerk, Mariska
Lathrop, Mark
Xu, Peng
Nordestgaard, Børge G.
Holm, Hilma
Hopewell, Jemma C.
Saleheen, Danish
Tanaka, Toshihiro
Anand, Sonia S.
Chambers, John C.
Kleber, Marcus E.
Ouwehand, Willem H.
Yamada, Yoshiji
Elbers, Clara
Peters, Bas
Stewart, Alexandre F.R.
Reilly, Muredach M.
Thorand, Barbara
Yusuf, Salim
Engert, James C.
Assimes, Themistocles L.
Kooner, Jaspal
Danesh, John
Watkins, Hugh
Samani, Nilesh J.
Collins, Rory
Peto, Richard
First Published: 21-Feb-2012
Publisher: Public Library of Science
Citation: PLoS Medicine, 2012, 9 (2), e1001177 (12)
Abstract: Background: Moderately elevated blood levels of homocysteine are weakly correlated with coronary heart disease (CHD) risk, but causality remains uncertain. When folate levels are low, the TT genotype of the common C677T polymorphism (rs1801133) of the methylene tetrahydrofolate reductase gene (MTHFR) appreciably increases homocysteine levels, so “Mendelian randomization” studies using this variant as an instrumental variable could help test causality. Methods and Findings: Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T. These datasets did not include measurements of blood homocysteine, but homocysteine levels would be expected to be about 20% higher with TT than with CC genotype in the populations studied. In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 1.02 (0.98–1.07; p = 0.28) overall, and 1.01 (0.95–1.07) in unsupplemented low-folate populations. By contrast, in a slightly updated meta-analysis of the 86 published studies (28,617 CHD cases and 41,857 controls), the OR was 1.15 (1.09–1.21), significantly discrepant (p = 0.001) with the OR in the unpublished datasets. Within the meta-analysis of published studies, the OR was 1.12 (1.04–1.21) in the 14 larger studies (those with variance of log OR<0.05; total 13,119 cases) and 1.18 (1.09–1.28) in the 72 smaller ones (total 15,498 cases). Conclusions: The CI for the overall result from large unpublished datasets shows lifelong moderate homocysteine elevation has little or no effect on CHD. The discrepant overall result from previously published studies reflects publication bias or methodological problems.
DOI Link: 10.1371/journal.pmed.1001177
ISSN: 1549-1277
eISSN: 1549-1676
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright: © 2012 Clarke et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Appears in Collections:Published Articles, Dept. of Cardiovascular Sciences

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