| 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 |
| Contributors: |
Medical Research Council (MRC) |
| Source: |
12 ; 1 |
| Publisher Information: |
Public Library of Science (PLoS) |
| Publication Year: |
2012 |
| Collection: |
Imperial College London: Spiral |
| Subject Terms: |
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 |
| Description: |
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 Methods and Findings Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T.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 In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 1.02 (0.98–1.07; p = 0.28) overall, and 1.01 (0.95–1.07) in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 |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
PLoS Medicine; http://hdl.handle.net/10044/1/72540; https://doi.org/10.1371/journal.pmed.1001177; G0601966; G0700931; G0801056B |
| DOI: |
10.1371/journal.pmed.1001177 |
| Availability: |
http://hdl.handle.net/10044/1/72540; https://doi.org/10.1371/journal.pmed.1001177 |
| Rights: |
© 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. |
| Accession Number: |
edsbas.631E5502 |
| Database: |
BASE |