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

<h4>Background</h4>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 re...

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Autores principales: Robert Clarke, Derrick A Bennett, Sarah Parish, Petra Verhoef, Mariska Dötsch-Klerk, Mark Lathrop, Peng Xu, Børge G Nordestgaard, Hilma Holm, Jemma C Hopewell, Danish Saleheen, Toshihiro Tanaka, Sonia S Anand, John C Chambers, Marcus E Kleber, Willem H Ouwehand, Yoshiji Yamada, Clara Elbers, Bas Peters, Alexandre F R Stewart, Muredach M Reilly, Barbara Thorand, Salim Yusuf, James C Engert, Themistocles L Assimes, Jaspal Kooner, John Danesh, Hugh Watkins, Nilesh J Samani, Rory Collins, Richard Peto, MTHFR Studies Collaborative Group
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Publicado: Public Library of Science (PLoS) 2012
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spelling oai:doaj.org-article:7f5a426f397543f1857ef493ad0d882a2021-11-18T05:42:21ZHomocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias.1549-12771549-167610.1371/journal.pmed.1001177https://doaj.org/article/7f5a426f397543f1857ef493ad0d882a2012-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22363213/?tool=EBIhttps://doaj.org/toc/1549-1277https://doaj.org/toc/1549-1676<h4>Background</h4>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.<h4>Methods and findings</h4>Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T.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 In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 1.02 (0.98-1.07; p = 0.28) overall, and 1.01 (0.95-1.07) in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).<h4>Conclusions</h4>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.Robert ClarkeDerrick A BennettSarah ParishPetra VerhoefMariska Dötsch-KlerkMark LathropPeng XuBørge G NordestgaardHilma HolmJemma C HopewellDanish SaleheenToshihiro TanakaSonia S AnandJohn C ChambersMarcus E KleberWillem H OuwehandYoshiji YamadaClara ElbersBas PetersAlexandre F R StewartMuredach M ReillyBarbara ThorandSalim YusufJames C EngertThemistocles L AssimesJaspal KoonerJohn DaneshHugh WatkinsNilesh J SamaniRory CollinsRichard PetoMTHFR Studies Collaborative GroupPublic Library of Science (PLoS)articleMedicineRENPLoS Medicine, Vol 9, Iss 2, p e1001177 (2012)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
spellingShingle Medicine
R
Robert Clarke
Derrick A Bennett
Sarah Parish
Petra Verhoef
Mariska Dötsch-Klerk
Mark Lathrop
Peng Xu
Børge G Nordestgaard
Hilma Holm
Jemma C Hopewell
Danish Saleheen
Toshihiro Tanaka
Sonia S Anand
John C Chambers
Marcus E Kleber
Willem H Ouwehand
Yoshiji Yamada
Clara Elbers
Bas Peters
Alexandre F R Stewart
Muredach M Reilly
Barbara Thorand
Salim Yusuf
James C Engert
Themistocles L Assimes
Jaspal Kooner
John Danesh
Hugh Watkins
Nilesh J Samani
Rory Collins
Richard Peto
MTHFR Studies Collaborative Group
Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias.
description <h4>Background</h4>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.<h4>Methods and findings</h4>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).<h4>Conclusions</h4>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.
format article
author Robert Clarke
Derrick A Bennett
Sarah Parish
Petra Verhoef
Mariska Dötsch-Klerk
Mark Lathrop
Peng Xu
Børge G Nordestgaard
Hilma Holm
Jemma C Hopewell
Danish Saleheen
Toshihiro Tanaka
Sonia S Anand
John C Chambers
Marcus E Kleber
Willem H Ouwehand
Yoshiji Yamada
Clara Elbers
Bas Peters
Alexandre F R Stewart
Muredach M Reilly
Barbara Thorand
Salim Yusuf
James C Engert
Themistocles L Assimes
Jaspal Kooner
John Danesh
Hugh Watkins
Nilesh J Samani
Rory Collins
Richard Peto
MTHFR Studies Collaborative Group
author_facet Robert Clarke
Derrick A Bennett
Sarah Parish
Petra Verhoef
Mariska Dötsch-Klerk
Mark Lathrop
Peng Xu
Børge G Nordestgaard
Hilma Holm
Jemma C Hopewell
Danish Saleheen
Toshihiro Tanaka
Sonia S Anand
John C Chambers
Marcus E Kleber
Willem H Ouwehand
Yoshiji Yamada
Clara Elbers
Bas Peters
Alexandre F R Stewart
Muredach M Reilly
Barbara Thorand
Salim Yusuf
James C Engert
Themistocles L Assimes
Jaspal Kooner
John Danesh
Hugh Watkins
Nilesh J Samani
Rory Collins
Richard Peto
MTHFR Studies Collaborative Group
author_sort Robert Clarke
title Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias.
title_short Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias.
title_full Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias.
title_fullStr Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias.
title_full_unstemmed Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias.
title_sort homocysteine and coronary heart disease: meta-analysis of mthfr case-control studies, avoiding publication bias.
publisher Public Library of Science (PLoS)
publishDate 2012
url https://doaj.org/article/7f5a426f397543f1857ef493ad0d882a
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