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

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

doi:10.1371/journal.pmed.1001177

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

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 StewartMuredach 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

132 Citations (Scopus)

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 Methods and Findings: Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T.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 In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 1.02 (0.98-1.07; p = 0.28) overall, and 1.01 (0.95-1.07) in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. Please see later in the article for the Editors' Summary.

Original language	English
Journal	P L o S Medicine
Volume	9
Issue number	2
Pages (from-to)	e1001177
ISSN	1549-1277
DOIs	https://doi.org/10.1371/journal.pmed.1001177
Publication status	Published - Feb 2012

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10.1371/journal.pmed.1001177

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Clarke, R., Bennett, D. A., Parish, S., Verhoef, P., Dötsch-Klerk, M., Lathrop, M., Xu, P., Nordestgaard, B. G., Holm, H., Hopewell, J. C., Saleheen, D., Tanaka, T., Anand, S. S., Chambers, J. C., Kleber, M. E., Ouwehand, W. H., Yamada, Y., Elbers, C., Peters, B., ... MTHFR Studies Collaborative Group (2012). Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias. P L o S Medicine, 9(2), e1001177. https://doi.org/10.1371/journal.pmed.1001177

Clarke, R, Bennett, DA, Parish, S, Verhoef, P, Dötsch-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 & MTHFR Studies Collaborative Group 2012, 'Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias', P L o S Medicine, vol. 9, no. 2, pp. e1001177. https://doi.org/10.1371/journal.pmed.1001177

@article{5b27ffd583f94b0c954b92e35214a026,

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. 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. Please see later in the article for the Editors' Summary.",

author = "Robert Clarke and Bennett, {Derrick A} and Sarah Parish and Petra Verhoef and Mariska D{\"o}tsch-Klerk and Mark Lathrop and Peng Xu and Nordestgaard, {B{\o}rge G} and Hilma Holm and Hopewell, {Jemma C} and Danish Saleheen and Toshihiro Tanaka and Anand, {Sonia S} and Chambers, {John C} and Kleber, {Marcus E} and Ouwehand, {Willem H} and Yoshiji Yamada and Clara Elbers and Bas Peters and Stewart, {Alexandre F R} and Reilly, {Muredach M} and Barbara Thorand and Salim Yusuf and Engert, {James C} and Assimes, {Themistocles L} and Jaspal Kooner and John Danesh and Hugh Watkins and Samani, {Nilesh J} and Rory Collins and Richard Peto and B{\o}rge Nordestgaard",

year = "2012",

month = feb,

doi = "10.1371/journal.pmed.1001177",

language = "English",

volume = "9",

pages = "e1001177",

journal = "P L o S Medicine (Online)",

issn = "1549-1277",

publisher = "Public Library of Science",

number = "2",

}

TY - JOUR

T1 - Homocysteine and coronary heart disease

T2 - meta-analysis of MTHFR case-control studies, avoiding publication bias

AU - Clarke, Robert

AU - Bennett, Derrick A

AU - Parish, Sarah

AU - Verhoef, Petra

AU - Dötsch-Klerk, Mariska

AU - Lathrop, Mark

AU - Xu, Peng

AU - Nordestgaard, Børge G

AU - Holm, Hilma

AU - Hopewell, Jemma C

AU - Saleheen, Danish

AU - Tanaka, Toshihiro

AU - Anand, Sonia S

AU - Chambers, John C

AU - Kleber, Marcus E

AU - Ouwehand, Willem H

AU - Yamada, Yoshiji

AU - Elbers, Clara

AU - Peters, Bas

AU - Stewart, Alexandre F R

AU - Reilly, Muredach M

AU - Thorand, Barbara

AU - Yusuf, Salim

AU - Engert, James C

AU - Assimes, Themistocles L

AU - Kooner, Jaspal

AU - Danesh, John

AU - Watkins, Hugh

AU - Samani, Nilesh J

AU - Collins, Rory

AU - Peto, Richard

AU - MTHFR Studies Collaborative Group

PY - 2012/2

Y1 - 2012/2

N2 - 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. Please see later in the article for the Editors' Summary.

AB - 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. Please see later in the article for the Editors' Summary.

U2 - 10.1371/journal.pmed.1001177

DO - 10.1371/journal.pmed.1001177

M3 - Journal article

C2 - 22363213

SN - 1549-1277

VL - 9

SP - e1001177

JO - P L o S Medicine (Online)

JF - P L o S Medicine (Online)

IS - 2

ER -

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

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