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PLoS Med. 2012 Feb;9(2):e1001177. doi: 10.1371/journal.pmed.1001177. Epub 2012 Feb 21.

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

Collaborators (157)

Holm H, Thorsteinsdottir U, Gretarsdottir S, Gulcher JR, Thorgeirsson G, Andersen K, Stefansson K, Parish S, Bennett DA, Clarke R, Peto R, Sleight P, Collins R, Hopewell JC, Clarke R, Collins R, Watkins H, Saleheen D, Danesh J, Rasheed A, Zaidi M, Frossard P, Shah N, Samuel M, Tanaka T, Ozaki K, Sato H, Sakata Y, Komuro I, Anand SS, Yusuf S, Engert JC, Chambers J, Kooner J, Hopewell JC, Parish S, Clarke R, Peto R, Armitage J, Collins R, Samani NJ, Braund PS, Nelson CP, Hall AS, Balmforth A, Ball SG, Kleber ME, Hoffmann MM, März WA, Bugert P, Winkelmann B, Böhm BO, Ouwehand WH, Sivapalaratnam S, Kastelein JJ, Trip MD, Bezzina CR, Ouwehand W, Yamada Y, Elbers CC, Onland-Moret NC, Bauer F, van der Schouw YT, Verschuren WM, de Boer JM, Wijmenga C, Hofker MH, de Bakker PI, Peters BJ, Maitland-van der Zee AH, de Boer A, Klungel OH, Grobbee DE, Stewart AF, Roberts R, McPherson R, Chen L, Wells GA, Reilly MM, Li M, Qu I, Rader DJ, Thorand B, Illig T, Peters A, Koenig W, Assimes TL, Fortmann S, Iribarren C, Abbate R, Marcucci R, Anderson JL, Zebrack JS, Ardissino D, Merlini FM, Bonomi AB, Ashfield-Watt PA, Clark ZE, van Bockxmeer FM, Brownrigg L, Chambers J, Kooner JS, Ferrer-Antunes C, Palmeiro A, Fernandez-Arcas N, Reyes-Engel A, Folsom AR, Fowkes FG, Lee AJ, Gaziano JM, Gemmati D, Scapoli GL, Genest J, Rozen R, Girelli D, Corrocher R, Rossi GB, Meleady R, Graham IM, Gulec S, Hopkins PN, Inbal A, Selighson U, Jukema JW, Litynsky P, Kluijtmans LA, Kozich V, Janosikova B, Ma J, Stampfer MJ, Malinow MR, Meisel C, Stangl K, Morita H, Nagai R, Nakai K, Nordestgaard BG, Zacho J, Rimm EB, Samani NJ, Schwartz SM, Siscovick DS, Silberberg JS, Szczeklik A, Domagala BT, Tanis BC, Rosendaal FM, Thogersen AM, Nilsson TK, Todesco L, Tokgozoglu SL, Tsai MY, Hanson NQ, Verhoeff BJ, Trip MD, Yamakawa-Kobayashi K, Hamaguchi H.

Author information

Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), University of Oxford, Oxford, UK.



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.


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).


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.

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