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.
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.
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DOI：
10.1016/s0140-6736(11)60872-6
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发表时间：
2011-08-13
期刊：
影响因子：
168.9
通讯作者：
Casas, Juan P.
中科院分区：
文献类型：
--
作者：
Holmes, Michael V.;Newcombe, Paul;Hubacek, Jaroslav A.;Sofat, Reecha;Ricketts, Sally L.;Cooper, Jackie;Breteler, Monique M. B.;Bautista, Leonelo E.;Sharma, Pankaj;Whittaker, John C.;Smeeth, Liam;Fowkes, F. Gerald R.;Algra, Ale;Shmeleva, Veronika;Szolnoki, Zoltan;Roest, Mark;Linnebank, Michael;Zacho, Jeppe;Nalls, Michael A.;Singleton, Andrew B.;Ferrucci, Luigi;Hardy, John;Worrall, Bradford B.;Rich, Stephen S.;Matarin, Mar;Norman, Paul E.;Flicker, Leon;Almeida, Osvaldo P.;van Bockxmeer, Frank M.;Shimokata, Hiroshi;Khaw, Kay-Tee;Wareham, Nicholas J.;Bobak, Martin;Sterne, Jonathan A. C.;Smith, George Davey;Talmud, Philippa J.;van Duijn, Cornelia;Humphries, Steve E.;Price, Jackie F.;Ebrahim, Shah;Lawlor, Debbie A.;Hankey, Graeme J.;Meschia, James F.;Sandhu, Manjinder S.;Hingorani, Aroon D.;Casas, Juan P.
MTHFR 677 C →T多态性与同型半胱氨酸浓度升高和卒中风险增加相关。先前的综述表明，在膳食叶酸摄入量低的地区，这种影响最大，但很难区分叶酸的影响和小型研究偏倚。对降低同型半胱氨酸干预措施的随机试验的荟萃分析显示，冠心病事件或中风没有减少，但这些试验通常设置在叶酸摄入量高的人群中。我们的目的是减少小型研究偏倚的影响，并在随机对照试验的遗传分析和荟萃分析中研究叶酸状态是否改变MTHFR 677 C →T与卒中之间的关联。我们建立了一个由237个数据集组成的遗传学研究合作，包括59995名个体的同型半胱氨酸数据和20885起卒中事件。 我们将遗传学结果与13项降低同型半胱氨酸治疗和卒中风险的随机试验（45549例患者，2314例卒中事件，269例短暂性脑缺血发作）的荟萃分析进行了比较。 MTHFR 677 C →T变异体对同型半胱氨酸浓度的影响在低叶酸地区（亚洲; TT与CC基因型个体之间的差异，3.12 μmol/L，95% CI 2.23至4.01）比在叶酸强化地区（美国，澳大利亚和新西兰，高; 0.13 μmol/L，-0.85至1.11）更大。亚洲卒中的比值比（OR）（1.68，95%CI 1.44 ~ 1.97）也高于美国、澳大利亚和新西兰（1.03，0.84 ~ 1.25）。大多数随机试验发生在叶酸浓度高或不断增加的地区。降低同型半胱氨酸干预试验中中风的汇总相对风险（RR）（0.94，95%CI 0.85至1.04）与在具有相似叶酸状态的人群中进行的大型遗传研究中相同程度的同型半胱氨酸降低的预测结果相似（预测RR 1.00，95%CI 0.90至1.11）。虽然在低叶酸地区（亚洲）的大型遗传研究中，同型半胱氨酸降低的预测效应较大（RR 0.78，95%CI 0.68至0.90），但没有试验专门在低叶酸地区评估同型半胱氨酸降低对卒中风险的影响。在人群叶酸补充水平不断提高或已制定政策的地区，遗传学研究和随机试验的证据一致表明，降低同型半胱氨酸对预防卒中没有益处。在低叶酸水平下，MTHFR 677 C →T与中风之间的关联需要进一步的大规模遗传研究，以区分叶酸的效应修饰与小研究偏倚。如果将来进行降低同型半胱氨酸干预预防卒中的随机试验，应该在叶酸摄入量低的地区进行。完整的资金来源列在文件的末尾（见鸣谢）。
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. Full funding sources listed at end of paper (see Acknowledgments).