title: Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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).
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Full funding sources listed at end of paper (see Acknowledgments).
authors.affiliation: Research Department of Epidemiology and Public Health, University College London, London, UK.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Holmes
authors.forename: Paul
authors.initials: P
authors.lastname: Newcombe
authors.forename: Jaroslav A
authors.initials: JA
authors.lastname: Hubacek
authors.forename: Reecha
authors.initials: R
authors.lastname: Sofat
authors.forename: Sally L
authors.initials: SL
authors.lastname: Ricketts
authors.forename: Jackie
authors.initials: J
authors.lastname: Cooper
authors.forename: Monique M B
authors.initials: MM
authors.lastname: Breteler
authors.forename: Leonelo E
authors.initials: LE
authors.lastname: Bautista
authors.forename: Pankaj
authors.initials: P
authors.lastname: Sharma
authors.forename: John C
authors.initials: JC
authors.lastname: Whittaker
authors.forename: Liam
authors.initials: L
authors.lastname: Smeeth
authors.forename: F Gerald R
authors.initials: FG
authors.lastname: Fowkes
authors.forename: Ale
authors.initials: A
authors.lastname: Algra
authors.forename: Veronika
authors.initials: V
authors.lastname: Shmeleva
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Szolnoki
authors.forename: Mark
authors.initials: M
authors.lastname: Roest
authors.forename: Michael
authors.initials: M
authors.lastname: Linnebank
authors.forename: Jeppe
authors.initials: J
authors.lastname: Zacho
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nalls
authors.forename: Andrew B
authors.initials: AB
authors.lastname: Singleton
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.forename: John
authors.initials: J
authors.lastname: Hardy
authors.forename: Bradford B
authors.initials: BB
authors.lastname: Worrall
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.forename: Mar
authors.initials: M
authors.lastname: Matarin
authors.forename: Paul E
authors.initials: PE
authors.lastname: Norman
authors.forename: Leon
authors.initials: L
authors.lastname: Flicker
authors.forename: Osvaldo P
authors.initials: OP
authors.lastname: Almeida
authors.forename: Frank M
authors.initials: FM
authors.lastname: van Bockxmeer
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimokata
authors.forename: Kay-Tee
authors.initials: KT
authors.lastname: Khaw
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: Martin
authors.initials: M
authors.lastname: Bobak
authors.forename: Jonathan A C
authors.initials: JA
authors.lastname: Sterne
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Talmud
authors.forename: Cornelia
authors.initials: C
authors.lastname: van Duijn
authors.forename: Steve E
authors.initials: SE
authors.lastname: Humphries
authors.forename: Jackie F
authors.initials: JF
authors.lastname: Price
authors.forename: Shah
authors.initials: S
authors.lastname: Ebrahim
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Lawlor
authors.forename: Graeme J
authors.initials: GJ
authors.lastname: Hankey
authors.forename: James F
authors.initials: JF
authors.lastname: Meschia
authors.forename: Manjinder S
authors.initials: MS
authors.lastname: Sandhu
authors.forename: Aroon D
authors.initials: AD
authors.lastname: Hingorani
authors.forename: Juan P
authors.initials: JP
authors.lastname: Casas
mesh_terms: D019587:Dietary Supplements; D005492:Folic Acid / Q000008:administration & dosage*; D006710:Homocysteine / Q000097:blood* / Q000235:genetics; D006801:Humans; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D011110:Polymorphism, Genetic; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D020521:Stroke / Q000097:blood / Q000235:genetics / Q000517:prevention & control*; D014803:Vitamin B Complex / Q000008:administration & dosage*
chemical_list: D006710:Homocysteine; D014803:Vitamin B Complex; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2)