Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias

Title: Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias
Authors: Clarke, R
Bennett, DA
Parish, S
Verhoef, P
Dotsch-Klerk, M
Lathrop, M
Xu, P
Nordestgaard, BG
Holm, H
Hopewell, JC
Saleheen, D
Tanaka, T
Anand, SS
Chambers, JC
Kleber, ME
Ouwehand, WH
Yamada, Y
Elbers, C
Peters, B
Stewart, AFR
Reilly, MM
Thorand, B
Yusuf, S
Engert, JC
Assimes, TL
Kooner, J
Danesh, J
Watkins, H
Samani, NJ
Collins, R
Peto, R
Item Type: Journal Article
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 Methods and Findings Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T.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 In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 1.02 (0.98–1.07; p = 0.28) overall, and 1.01 (0.95–1.07) in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CHD cases and 41,857 controls), the OR was 1.15 (1.09–1.21), significantly discrepant (p = 0.001) with the OR in the unpublished datasets.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 Conclusions The CI for the overall result from large unpublished datasets shows lifelong moderate homocysteine elevation has little or no effect on CHD.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.
Issue Date: 21-Feb-2012
Date of Acceptance: 11-Jan-2012
URI: http://hdl.handle.net/10044/1/72540
DOI: https://doi.org/10.1371/journal.pmed.1001177
ISSN: 1549-1277
Publisher: Public Library of Science (PLoS)
Start Page: 1
End Page: 12
Journal / Book Title: PLoS Medicine
Volume: 9
Issue: 2
Copyright Statement: © 2012 Clarke et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Sponsor/Funder: Medical Research Council (MRC)
Medical Research Council (MRC)
Medical Research Council (MRC)
Funder's Grant Number: G0601966
G0700931
G0801056B
Keywords: Science & Technology
Life Sciences & Biomedicine
Medicine, General & Internal
General & Internal Medicine
METHYLENETETRAHYDROFOLATE REDUCTASE GENE
PLACEBO-CONTROLLED TRIAL
CARDIOVASCULAR-DISEASE
MENDELIAN RANDOMIZATION
MYOCARDIAL-INFARCTION
VASCULAR-DISEASE
COMMON MUTATION
B VITAMINS
FOLIC-ACID
ETHNIC-GROUPS
Bias
Coronary Disease
Folic Acid
Genotype
Homocysteine
Humans
Methylenetetrahydrofolate Reductase (NADPH2)
Polymorphism, Genetic
Risk Factors
MTHFR Studies Collaborative Group
Humans
Coronary Disease
Folic Acid
Methylenetetrahydrofolate Reductase (NADPH2)
Homocysteine
Risk Factors
Genotype
Polymorphism, Genetic
Bias
Science & Technology
Life Sciences & Biomedicine
Medicine, General & Internal
General & Internal Medicine
METHYLENETETRAHYDROFOLATE REDUCTASE GENE
PLACEBO-CONTROLLED TRIAL
CARDIOVASCULAR-DISEASE
MENDELIAN RANDOMIZATION
MYOCARDIAL-INFARCTION
VASCULAR-DISEASE
COMMON MUTATION
B VITAMINS
FOLIC-ACID
ETHNIC-GROUPS
11 Medical and Health Sciences
General & Internal Medicine
Publication Status: Published
Article Number: ARTN e1001177
Online Publication Date: 2012-02-21
Appears in Collections:National Heart and Lung Institute
Epidemiology, Public Health and Primary Care



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