TY - JOUR
T1 - Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk
T2 - A meta-analysis of genetic studies and randomised trials
AU - Holmes, Michael V.
AU - Newcombe, Paul
AU - Hubacek, Jaroslav A.
AU - Sofat, Reecha
AU - Ricketts, Sally L.
AU - Cooper, Jackie
AU - Breteler, Monique Mb
AU - Bautista, Leonelo E.
AU - Sharma, Pankaj
AU - Whittaker, John C.
AU - Smeeth, Liam
AU - Fowkes, F. Gerald R.
AU - Algra, Ale
AU - Shmeleva, Veronika
AU - Szolnoki, Zoltan
AU - Roest, Mark
AU - Linnebank, Michael
AU - Zacho, Jeppe
AU - Nalls, Michael A.
AU - Singleton, Andrew B.
AU - Ferrucci, Luigi
AU - Hardy, John
AU - Worrall, Bradford B.
AU - Rich, Stephen S.
AU - Matarin, Mar
AU - Norman, Paul E.
AU - Flicker, Leon
AU - Almeida, Osvaldo P.
AU - Van Bockxmeer, Frank M.
AU - Shimokata, Hiroshi
AU - Khaw, Kay Tee
AU - Wareham, Nicholas J.
AU - Bobak, Martin
AU - Sterne, Jonathan A.C.
AU - Smith, George Davey
AU - Talmud, Philippa J.
AU - Van Duijn, Cornelia
AU - Humphries, Steve E.
AU - Price, Jackie F.
AU - Ebrahim, Shah
AU - Lawlor, Debbie A.
AU - Hankey, Graeme J.
AU - Meschia, James F.
AU - Sandhu, Manjinder S.
AU - Hingorani, Aroon D.
AU - Casas, Juan P.
N1 - Funding Information:
Funding for this study was from: a Population Health Scientist Fellowship, Medical Research Council (G0802432; MVH); the Medical Research Council (G0600580; PN); Project 00023001 (IKEM; JAH); British Heart Foundation (Schillingford) clinical training fellowship (FS/07/011; RS); British Heart Foundation (SLR, JFP); Erasmus Medical Center and Erasmus University, Rotterdam, The Netherlands Organization for Health Research and Development, The Netherlands Organisation for Scientific Research, the Research Institute for Diseases in the Elderly, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam (The Rotterdam Study; MMMB, CVD); UK Department of Health Senior Fellowship (PS); Senior Clinical Fellowship from the Wellcome Trust (082178, LS); British Heart Foundation (Edinburgh Artery Study, FGRF); the Netherlands Heart Foundation (2001.06g) and the Brain Foundation Netherlands (gF01.15; the RATIO Study; AA); the Danish Medical Research Council, the Danish Heart Foundation, and Chief Physician Johan Boserup and Lise Boserup's Fund (JZ); the US National Institute of Neurological Disorders and Stroke , grant numbers R01 NS39987 and R01 NS42733 (ISGS and SWISS: MAN, ABS, LF, JH, BBW, SR, MM, JFM); Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services (LF; project numbers Z01 AG000015-50 and Z01 AG000954-06, human subjects protocol number 2003-078; portions of this study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health); Research Funding for Longevity Sciences (23–33) from the National Center for Geriatrics and Gerontology, Japan (HS); the National Health and Medical Research Council of Australia (the Health In Men Study, project grants 279408, 379600, 403963, and 513823 ; PEN, LF, OA, FvB, GH); Wellcome Trust and the US National Institute of Aging (the HAPIEE study; MB); the UK Medical Research Council (G0600705) and the University of Bristol (GDS and DAL); British Heart Foundation Chair of Cardiovascular Genetics (SD); British Heart Foundation Senior Fellowship (FS05/125; ADH); British Heart Foundation (RG/08/008; SEH, PJT, ADH); and the Department of Health Policy Research Programme and British Heart Foundation (the British Women's Heart and Health Study; SE). The views expressed in the publication are those of the authors and not necessarily those of any funding bodies.
Funding Information:
PN is a full-time employee of GlaxoSmithKline. PS has received honoraria for lecturing in industry-sponsored meetings and has received industry funding for attending national and international meetings. He has also received research grants from pharmaceutical companies and has been a paid consultant to the biotech industry and a member of industry advisory boards. JCW owns shares in GlaxoSmithKline and is 90% employed at GlaxoSmithKline while retaining a 10% appointment at the London School of Hygiene and Tropical Medicine. LS has received consultancy fees from GlaxoSmithKline. FGRF has received funding from AstraZeneca for consultancy and grants from Bayer. AA received fees from Boehringer Ingelheim for consultancy, speaker fees, and participation in international advisory board meetings. He is a principal investigator of ESPIRIT, the European/Australian Stroke Prevention in Reversible Ischaemia Trial, a trial that was run independently of any pharmaceutical company, and in 2006, after completion and full analysis of ESPRIT, the study group accepted financial support from Boehringer Ingelheim for post-hoc exploratory analyses of the ESPRIT trial data. For this purpose a contract was signed in negotiated complete scientific freedom. ML has received money for board membership, consultancy, expert testimony, grants, and lectures from various pharmaceutical companies. JH has received consultancy fees from Merck Serono, Eisai, and Johnson & Johnson. BBW is co-principal investigator of the NIH funded GARNET, which funds genome-wide association studies of genetic samples from the Vitamin Intervention as Stroke Prevention randomised controlled trial. GH has received funds from Johnson & Johnson (executive committee for ROCKET-AF trial); Sanofi-Aventis (executive committee BOREALIS trial); Schering-Plough (steering committee TRA 2P TIMI 50 trial); Pradaxa (dabigatran) advisory board, Australia; and payment for lectures at sponsored scientific symposia by Sanofi-Aventis and Pfizer.
PY - 2011
Y1 - 2011
N2 - The MTHFR 677C→T polymorphism has been associated with raised homocysteine concentration and increased risk of stroke. A previous overview showed that the effects were greatest in regions with low dietary folate consumption, but differentiation between the effect of folate and small-study bias was difficult. A meta-analysis of randomised trials of homocysteine- lowering interventions showed no reduction in coronary heart disease events or stroke, but the trials were generally set in populations with high folate consumption. We aimed to reduce the effect of small-study bias and investigate whether folate status modifies the association between MTHFR 677C→T and stroke in a genetic analysis and meta-analysis of randomised controlled trials. We established a collaboration of genetic studies consisting of 237 datasets including 59 995 individuals with data for homocysteine and 20 885 stroke events. We compared the genetic findings with a meta-analysis of 13 randomised trials of homocysteine-lowering treatments and stroke risk (45 549 individuals, 2314 stroke events, 269 transient ischaemic attacks). The effect of the MTHFR 677C→T variant on homocysteine concentration was larger in low folate regions (Asia; difference between individuals with TT versus CC genotype, 3·12 μmol/L, 95 CI 2·23 to 4·01) than in areas with folate fortification (America, Australia, and New Zealand, high; 0·13 μmol/L, -0·85 to 1·11). The odds ratio (OR) for stroke was also higher in Asia (1·68, 95 CI 1·44 to 1·97) than in America, Australia, and New Zealand, high (1·03, 0·84 to 1·25). Most randomised trials took place in regions with high or increasing population folate concentrations. The summary relative risk (RR) of stroke in trials of homocysteine-lowering interventions (0·94, 95 CI 0·85 to 1·04) was similar to that predicted for the same extent of homocysteine reduction in large genetic studies in populations with similar folate status (predicted RR 1·00, 95 CI 0·90 to 1·11). Although the predicted effect of homocysteine reduction from large genetic studies in low folate regions (Asia) was larger (RR 0·78, 95 CI 0·68 to 0·90), no trial has evaluated the effect of lowering of homocysteine on stroke risk exclusively in a low folate region. In regions with increasing levels or established policies of population folate supplementation, evidence from genetic studies and randomised trials is concordant in suggesting an absence of benefit from lowering of homocysteine for prevention of stroke. Further large-scale genetic studies of the association between MTHFR 677C→T and stroke in low folate settings are needed to distinguish effect modification by folate from small-study bias. If future randomised trials of homocysteine-lowering interventions for stroke prevention are undertaken, they should take place in regions with low folate consumption.
AB - The MTHFR 677C→T polymorphism has been associated with raised homocysteine concentration and increased risk of stroke. A previous overview showed that the effects were greatest in regions with low dietary folate consumption, but differentiation between the effect of folate and small-study bias was difficult. A meta-analysis of randomised trials of homocysteine- lowering interventions showed no reduction in coronary heart disease events or stroke, but the trials were generally set in populations with high folate consumption. We aimed to reduce the effect of small-study bias and investigate whether folate status modifies the association between MTHFR 677C→T and stroke in a genetic analysis and meta-analysis of randomised controlled trials. We established a collaboration of genetic studies consisting of 237 datasets including 59 995 individuals with data for homocysteine and 20 885 stroke events. We compared the genetic findings with a meta-analysis of 13 randomised trials of homocysteine-lowering treatments and stroke risk (45 549 individuals, 2314 stroke events, 269 transient ischaemic attacks). The effect of the MTHFR 677C→T variant on homocysteine concentration was larger in low folate regions (Asia; difference between individuals with TT versus CC genotype, 3·12 μmol/L, 95 CI 2·23 to 4·01) than in areas with folate fortification (America, Australia, and New Zealand, high; 0·13 μmol/L, -0·85 to 1·11). The odds ratio (OR) for stroke was also higher in Asia (1·68, 95 CI 1·44 to 1·97) than in America, Australia, and New Zealand, high (1·03, 0·84 to 1·25). Most randomised trials took place in regions with high or increasing population folate concentrations. The summary relative risk (RR) of stroke in trials of homocysteine-lowering interventions (0·94, 95 CI 0·85 to 1·04) was similar to that predicted for the same extent of homocysteine reduction in large genetic studies in populations with similar folate status (predicted RR 1·00, 95 CI 0·90 to 1·11). Although the predicted effect of homocysteine reduction from large genetic studies in low folate regions (Asia) was larger (RR 0·78, 95 CI 0·68 to 0·90), no trial has evaluated the effect of lowering of homocysteine on stroke risk exclusively in a low folate region. In regions with increasing levels or established policies of population folate supplementation, evidence from genetic studies and randomised trials is concordant in suggesting an absence of benefit from lowering of homocysteine for prevention of stroke. Further large-scale genetic studies of the association between MTHFR 677C→T and stroke in low folate settings are needed to distinguish effect modification by folate from small-study bias. If future randomised trials of homocysteine-lowering interventions for stroke prevention are undertaken, they should take place in regions with low folate consumption.
UR - http://www.scopus.com/inward/record.url?scp=80051695692&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80051695692&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(11)60872-6
DO - 10.1016/S0140-6736(11)60872-6
M3 - Article
C2 - 21803414
AN - SCOPUS:80051695692
SN - 0140-6736
VL - 378
SP - 584
EP - 594
JO - The Lancet
JF - The Lancet
IS - 9791
ER -