title: Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias.
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.
  
  
  RESULTS
  Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T.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 In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 1.02 (0.98-1.07; p = 0.28) overall, and 1.01 (0.95-1.07) in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CHD cases and 41,857 controls), the OR was 1.15 (1.09-1.21), significantly discrepant (p = 0.001) with the OR in the unpublished datasets.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  The CI for the overall result from large unpublished datasets shows lifelong moderate homocysteine elevation has little or no effect on CHD.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.
authors.affiliation: Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK. Robert.Clarke@ctsu.ox.ac.uk
authors.forename: Robert
authors.initials: R
authors.lastname: Clarke
authors.forename: Derrick A
authors.initials: DA
authors.lastname: Bennett
authors.forename: Sarah
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authors.lastname: Parish
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authors.lastname: Dötsch-Klerk
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authors.lastname: Lathrop
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authors.lastname: Xu
authors.forename: Børge G
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authors.forename: Hilma
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authors.lastname: Holm
authors.forename: Jemma C
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authors.lastname: Hopewell
authors.forename: Danish
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authors.lastname: Saleheen
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Tanaka
authors.forename: Sonia S
authors.initials: SS
authors.lastname: Anand
authors.forename: John C
authors.initials: JC
authors.lastname: Chambers
authors.forename: Marcus E
authors.initials: ME
authors.lastname: Kleber
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.forename: Yoshiji
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authors.lastname: Yamada
authors.forename: Clara
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authors.lastname: Elbers
authors.forename: Bas
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authors.lastname: Peters
authors.forename: Alexandre F R
authors.initials: AF
authors.lastname: Stewart
authors.forename: Muredach M
authors.initials: MM
authors.lastname: Reilly
authors.forename: Barbara
authors.initials: B
authors.lastname: Thorand
authors.forename: Salim
authors.initials: S
authors.lastname: Yusuf
authors.forename: James C
authors.initials: JC
authors.lastname: Engert
authors.forename: Themistocles L
authors.initials: TL
authors.lastname: Assimes
authors.forename: Jaspal
authors.initials: J
authors.lastname: Kooner
authors.forename: John
authors.initials: J
authors.lastname: Danesh
authors.forename: Hugh
authors.initials: H
authors.lastname: Watkins
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.forename: Rory
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authors.lastname: Collins
authors.forename: Richard
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authors.lastname: Peto
mesh_terms: D015982:Bias; D003327:Coronary Disease / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D005492:Folic Acid / Q000097:blood; D005838:Genotype; D006710:Homocysteine / Q000097:blood; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D011110:Polymorphism, Genetic; D012307:Risk Factors
chemical_list: D006710:Homocysteine; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2)