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 Methods and Findings: Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T.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 In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 1.02 (0.98-1.07; p = 0.28) overall, and 1.01 (0.95-1.07) in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CHD cases and 41,857 controls), the OR was 1.15 (1.09-1.21), significantly discrepant (p = 0.001) with the OR in the unpublished datasets.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 Conclusions: The CI for the overall result from large unpublished datasets shows lifelong moderate homocysteine elevation has little or no effect on CHD.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 -