"Szolnaki, Z." . . "Singleton, A. B." . "1"^^ . "Holmes, M. V." . . "196157" . "Lancet" . "Bobak, M." . "Humphries, S. E." . "000294319500030" . "9791" . "Breteler, MMB." . "Linnebank, M." . "Meschia, J. F." . "Cooper, J." . "Hub\u00E1\u010Dek, Jaroslav" . "Rich, S. S." . "Ricketts, S. L." . "van Bockxmeer, F. M." . . . "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"@en . "Whittaker, J. C." . "Ferrucci, L." . "10.1016/S0140-6736(11)60872-6" . . . . "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). Findings 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 mu mol/L, 95% CI 2.23 to 4.01) than in areas with folate fortification (America, Australia, and New Zealand, high; 0.13 mu mol/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 085 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 (pre" . . "378" . "Shimokata, H." . . "GB - Spojen\u00E9 kr\u00E1lovstv\u00ED Velk\u00E9 Brit\u00E1nie a Severn\u00EDho Irska" . "Smeeth, L." . "Shmeleva, V." . . "Talmud, P. J." . "Roest, M." . "Fowkes, FGR." . "van Dujin, C." . . "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" . "Algra, A." . "Hingorani, A. D." . "Norman, P. E." . "RIV/00023001:_____/11:00002479" . "Worrall, BB." . "Lawlor, D. A." . "0140-6736" . "Sterne, JAC." . "Matarin, M." . . "46"^^ . . "coronary heart disease; methylenetetrahydrofolate reductase gene; folic acid supplementation; stage renal disease; cardiovascular disease; B-vitamins; ischemic stroke; plasma homocysteine; C677T polymorphism; vascular disease"@en . "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). Findings 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 mu mol/L, 95% CI 2.23 to 4.01) than in areas with folate fortification (America, Australia, and New Zealand, high; 0.13 mu mol/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 085 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 (pre"@en . . "Hardy, J." . . "Ebrahim, S." . . "Almeida, OP." . . . "11"^^ . "Wareham, N. J." . "Zacho, J." . "[BF7EA6206A7C]" . "Sofat, R." . "Z(MZ0IKEM2005)" . "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"@en . "Smith, G. D." . "RIV/00023001:_____/11:00002479!RIV12-MZ0-00023001" . . "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" . "Khaw, K-T." . "Nalls, M. A." . . "Flicker, L." . . "Bautista, L. E." . "Sharma, P." . "Sandhu, M. S." . "Newcombe, P." . . "Casas, J. P." . "Hankey, G. J." . "Price, J. F." . .