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

被引：291

作者：

Holmes, Michael V. ^{[1
]}

Newcombe, Paul ^{[6
,7
]}

Hubacek, Jaroslav A. ^{[8
,9
]}

Sofat, Reecha ^{[2
]}

Ricketts, Sally L. ^{[10
]}

Cooper, Jackie ^{[3
]}

Breteler, Monique M. B. ^{[14
,15
]}

Bautista, Leonelo E. ^{[16
]}

Sharma, Pankaj ^{[17
]}

Whittaker, John C. ^{[6
,7
]}

Smeeth, Liam ^{[6
]}

Fowkes, F. Gerald R. ^{[18
]}

Algra, Ale ^{[19
,22
,23
]}

Shmeleva, Veronika ^{[20
]}

Szolnoki, Zoltan ^{[21
]}

Roest, Mark ^{[24
]}

Linnebank, Michael ^{[25
]}

Zacho, Jeppe ^{[26
]}

Nalls, Michael A. ^{[27
]}

Singleton, Andrew B. ^{[27
]}

Ferrucci, Luigi ^{[28
]}

Hardy, John ^{[5
]}

Worrall, Bradford B. ^{[29
]}

Rich, Stephen S. ^{[30
]}

Matarin, Mar ^{[4
]}

Norman, Paul E. ^{[31
]}

Flicker, Leon ^{[32
,35
]}

Almeida, Osvaldo P. ^{[33
,35
,36
]}

van Bockxmeer, Frank M. ^{[34
,37
]}

Shimokata, Hiroshi ^{[38
]}

Khaw, Kay-Tee ^{[11
]}

Wareham, Nicholas J. ^{[12
]}

Bobak, Martin ^{[1
]}

Sterne, Jonathan A. C. ^{[40
]}

Smith, George Davey ^{[39
]}

Talmud, Philippa J. ^{[3
]}

van Duijn, Cornelia ^{[14
]}

Humphries, Steve E. ^{[3
]}

Price, Jackie F. ^{[18
]}

Ebrahim, Shah ^{[6
]}

Lawlor, Debbie A. ^{[39
]}

Hankey, Graeme J. ^{[32
]}

Meschia, James F. ^{[41
]}

Sandhu, Manjinder S. ^{[13
]}

Hingorani, Aroon D. ^{[1
,2
]}

Casas, Juan P. ^{[1
,6
]}

机构：

[1] UCL, Res Dept Epidemiol & Publ Hlth, London, England

[2] UCL, Dept Clin Pharmacol, London, England

[3] UCL, Inst Cardiovasc Sci, Ctr Cardiovasc Genet, London, England

[4] UCL, Dept Clin & Expt Epilepsy, London, England

[5] UCL, Inst Neurol, London, England

[6] London Sch Hyg & Trop Med, Fac Epidemiol & Publ Hlth, London WC1E 7HT, England

[7] GlaxoSmithKline, Genet, R&D, Stevenage, Herts, England

[8] Inst Clin & Expt Med, Prague, Czech Republic

[9] Cardiovasc Res Ctr, Prague, Czech Republic

[10] Univ Cambridge, Dept Publ Hlth & Primary Care, Strangeways Res Lab, Cambridge, England

[11] Univ Cambridge, Sch Clin Med, Clin Gerontol Unit, Cambridge, England

[12] Univ Cambridge, MRC Epidemiol Unit, Inst Metab Sci, Cambridge, England

[13] Wellcome Trust Sanger Inst, Genet Epidemiol Grp, Cambridge, England

[14] Univ Med Ctr, Dept Epidemiol, Erasmus MC, Rotterdam, Netherlands

[15] German Ctr Neurodegenerat Dis DZNE, Bonn, Germany

[16] Univ Wisconsin, Dept Populat Hlth Sci, Sch Med & Publ Hlth, Madison, WI USA

[17] Univ London Imperial Coll Sci Technol & Med, ICCRU, London, England

[18] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland

[19] Leiden Univ, Med Ctr, Dept Clin Epidemiol, Leiden, Netherlands

[20] Russian Inst Haematol & Transfus, St Petersburg, Russia

[21] Pandy Cty Hosp, Dept Neurol, Gyula, Hungary

[22] Univ Med Ctr Utrecht, Utrecht Stroke Ctr, Dept Neurol, Utrecht, Netherlands

[23] Univ Med Ctr Utrecht, Julius Ctr, Utrecht, Netherlands

[24] Univ Med Ctr Utrecht, Dept Clin Chem & Haematol, Utrecht, Netherlands

[25] Univ Zurich Hosp, Dept Neurol, CH-8091 Zurich, Switzerland

[26] Herlev Univ Hosp, Dept Clin Biochem, DK-2730 Herlev, Denmark

[27] NIA, Neurogenet Lab, US Natl Inst Hlth, Bethesda, MD 20892 USA

[28] NIA, Baltimore, MD 21224 USA

[29] Univ Virginia, Dept Neurol, Charlottesville, VA USA

[30] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA

[31] Univ Western Australia, Sch Surg, Perth, WA 6009, Australia

[32] Univ Western Australia, Sch Med & Pharmacol, Perth, WA 6009, Australia

[33] Univ Western Australia, Sch Psychiat & Clin Neurosci, Perth, WA 6009, Australia

[34] Univ Western Australia, Sch Pathol & Lab Med, Perth, WA 6009, Australia

[35] WACHA, Western Australia Inst Med Res, Perth, WA, Australia

[36] Royal Perth Hosp, Dept Psychiat, Perth, WA, Australia

[37] Royal Perth Hosp, Cardiovasc Genet Lab, Div Lab Med, Perth, WA, Australia

[38] Natl Ctr Geriatr & Gerontol, Obu City, Japan

[39] Univ Bristol, MRC Ctr Causal Anal Translat Epidemiol, Bristol, Avon, England

[40] Univ Bristol, Sch Social & Community Med, Bristol, Avon, England

[41] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA

来源：

LANCET | 2011年 / 378卷 / 9791期

基金：

英国惠康基金; 英国医学研究理事会; 美国国家卫生研究院;

关键词：

CORONARY-HEART-DISEASE; FOLIC-ACID SUPPLEMENTATION; METHYLENETETRAHYDROFOLATE-REDUCTASE; CARDIOVASCULAR-DISEASE; B-VITAMINS; C677T POLYMORPHISM; LOWERING HOMOCYSTEINE; PLASMA HOMOCYSTEINE; VASCULAR-DISEASE; ISCHEMIC-STROKE;

D O I：

10.1016/S0140-6736(11)60872-6

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 (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. Interpretation 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.

引用

页码：584 / 594

页数：11

共 62 条

[1] Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease - A randomized trial [J].

Albert, Christine M. ;

Cook, Nancy R. ;

Gaziano, J. Michael ;

Zaharris, Elaine ;

MacFadyen, Jean ;

Danielson, Eleanor ;

Buring, Julie E. ;

Manson, JoAnn E. .

JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION, 2008, 299 (17) :2027-2036

[2]

[Anonymous], HUGE REV HDB

[3]

[Anonymous], NCT00794885 CSPPT

[4]

[Anonymous], CIRCULATION

[5] Homocysteine lowering and cardiovascular events after acute myocardial infarction [J].

Bonaa, KH ;

Njolstad, I ;

Ueland, PM ;

Schirmer, H ;

Tverdal, A ;

Steigen, T ;

Wang, H ;

Nordrehaug, JE ;

Arnesen, E ;

Rasmussen, K .

NEW ENGLAND JOURNAL OF MEDICINE, 2006, 354 (15) :1578-1588

[6]

Brattström L, 2000, AM J CLIN NUTR, V72, P315

[7]

Casas JP, 2005, LANCET, V365, P224, DOI 10.1016/S0140-6736(05)70152-5

[8] Cohort profile: The Kadoorie study of chronic disease in China (KSCDC) [J].

Chen, ZM ;

Lee, L ;

Chen, JS ;

Collins, R ;

Wu, F ;

Guo, Y ;

Linksted, P ;

Peto, R .

INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, 2005, 34 (06) :1243-1249

[9] Alcohol intake and methylenetetrahydrofolate reductase polymorphism modify the relation of folate intake to plasma homocysteine [J].

Chiuve, SE ;

Giovannucci, EL ;

Hankinson, SE ;

Hunter, DJ ;

Stampfer, MJ ;

Willett, WC ;

Rimm, EB .

AMERICAN JOURNAL OF CLINICAL NUTRITION, 2005, 82 (01) :155-162

[10] Homocysteine-lowering trials for prevention of vascular disease: protocol for a collaborative meta-analysis [J].

Clarke, R. ;

Armitage, J. ;

Lewington, S. ;

Collins, R. .

CLINICAL CHEMISTRY AND LABORATORY MEDICINE, 2007, 45 (12) :1575-1581

← 1 2 3 4 5 6 7 →