title: Homocysteine and Stroke Risk: Modifying Effect of Methylenetetrahydrofolate Reductase C677T Polymorphism and Folic Acid Intervention.
abstract: Elevated blood homocysteine concentration increases the risk of stroke, especially among hypertensive individuals. Homocysteine is largely affected by the methylenetetrahydrofolate reductase C677T polymorphism and folate status. Among hypertensive patients, we aimed to test the hypothesis that the association between homocysteine and stroke can be modified by the methylenetetrahydrofolate reductase C677T polymorphism and folic acid intervention.
  
  
  
  We analyzed the data of 20 424 hypertensive adults enrolled in the China Stroke Primary Prevention Trial. The participants, first stratified by methylenetetrahydrofolate reductase genotype, were randomly assigned to receive double-blind treatments of 10-mg enalapril and 0.8-mg folic acid or 10-mg enalapril only. The participants were followed up for a median of 4.5 years.
  
  
  
  In the control group, baseline log-transformed homocysteine was associated with an increased risk of first stroke among participants with the CC/CT genotype (hazard ratio, 3.1; 1.1-9.2), but not among participants with the TT genotype (hazard ratio, 0.7; 0.2-2.1), indicating a significant gene-homocysteine interaction (P=0.008). In the folic acid intervention group, homocysteine showed no significant effect on stroke regardless of genotype. Consistently, folic acid intervention significantly reduced stroke risk in participants with CC/CT genotypes and high homocysteine levels (tertile 3; hazard ratio, 0.73; 0.55-0.97).
  
  
  
  In Chinese hypertensive patients, the effect of homocysteine on the first stroke was significantly modified by the methylenetetrahydrofolate reductase C677T genotype and folic acid supplementation. Such information may help to more precisely predict stroke risk and develop folic acid interventions tailored to individual genetic background and nutritional status.
  
  
  
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794885.
authors.affiliation: From the National Clinical Research Study Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China (M.Z., X.Q., B.W., F.F.H.); Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD (X.W.); Department of Neurology, First People's Hospital, Lianyungang, China (M.H.); Institute for Biomedicine, Anhui Medical University, Hefei, China (G.T.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.H., J.L.); Department of Neurology, First Affiliated Hospital of Anhui Medical University, Hefei, China (J.F.); Department of Cardiovascular Medicine, Second Affiliated Hospital of Nanchang University, Jiangxi, China (X.H., X.C.); Hypertension Research Laboratory of Heart Center, Peking University People's Hospital, Beijing, China (N.S.); and Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China (M.Z., Y.C.).
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.affiliation: From the National Clinical Research Study Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China (M.Z., X.Q., B.W., F.F.H.); Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD (X.W.); Department of Neurology, First People's Hospital, Lianyungang, China (M.H.); Institute for Biomedicine, Anhui Medical University, Hefei, China (G.T.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.H., J.L.); Department of Neurology, First Affiliated Hospital of Anhui Medical University, Hefei, China (J.F.); Department of Cardiovascular Medicine, Second Affiliated Hospital of Nanchang University, Jiangxi, China (X.H., X.C.); Hypertension Research Laboratory of Heart Center, Peking University People's Hospital, Beijing, China (N.S.); and Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China (M.Z., Y.C.).
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Wang
authors.affiliation: From the National Clinical Research Study Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China (M.Z., X.Q., B.W., F.F.H.); Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD (X.W.); Department of Neurology, First People's Hospital, Lianyungang, China (M.H.); Institute for Biomedicine, Anhui Medical University, Hefei, China (G.T.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.H., J.L.); Department of Neurology, First Affiliated Hospital of Anhui Medical University, Hefei, China (J.F.); Department of Cardiovascular Medicine, Second Affiliated Hospital of Nanchang University, Jiangxi, China (X.H., X.C.); Hypertension Research Laboratory of Heart Center, Peking University People's Hospital, Beijing, China (N.S.); and Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China (M.Z., Y.C.).
authors.forename: Mingli
authors.initials: M
authors.lastname: He
authors.affiliation: From the National Clinical Research Study Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China (M.Z., X.Q., B.W., F.F.H.); Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD (X.W.); Department of Neurology, First People's Hospital, Lianyungang, China (M.H.); Institute for Biomedicine, Anhui Medical University, Hefei, China (G.T.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.H., J.L.); Department of Neurology, First Affiliated Hospital of Anhui Medical University, Hefei, China (J.F.); Department of Cardiovascular Medicine, Second Affiliated Hospital of Nanchang University, Jiangxi, China (X.H., X.C.); Hypertension Research Laboratory of Heart Center, Peking University People's Hospital, Beijing, China (N.S.); and Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China (M.Z., Y.C.).
authors.forename: Xianhui
authors.initials: X
authors.lastname: Qin
authors.affiliation: From the National Clinical Research Study Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China (M.Z., X.Q., B.W., F.F.H.); Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD (X.W.); Department of Neurology, First People's Hospital, Lianyungang, China (M.H.); Institute for Biomedicine, Anhui Medical University, Hefei, China (G.T.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.H., J.L.); Department of Neurology, First Affiliated Hospital of Anhui Medical University, Hefei, China (J.F.); Department of Cardiovascular Medicine, Second Affiliated Hospital of Nanchang University, Jiangxi, China (X.H., X.C.); Hypertension Research Laboratory of Heart Center, Peking University People's Hospital, Beijing, China (N.S.); and Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China (M.Z., Y.C.).
authors.forename: Genfu
authors.initials: G
authors.lastname: Tang
authors.affiliation: From the National Clinical Research Study Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China (M.Z., X.Q., B.W., F.F.H.); Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD (X.W.); Department of Neurology, First People's Hospital, Lianyungang, China (M.H.); Institute for Biomedicine, Anhui Medical University, Hefei, China (G.T.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.H., J.L.); Department of Neurology, First Affiliated Hospital of Anhui Medical University, Hefei, China (J.F.); Department of Cardiovascular Medicine, Second Affiliated Hospital of Nanchang University, Jiangxi, China (X.H., X.C.); Hypertension Research Laboratory of Heart Center, Peking University People's Hospital, Beijing, China (N.S.); and Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China (M.Z., Y.C.).
authors.forename: Yong
authors.initials: Y
authors.lastname: Huo
authors.affiliation: From the National Clinical Research Study Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China (M.Z., X.Q., B.W., F.F.H.); Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD (X.W.); Department of Neurology, First People's Hospital, Lianyungang, China (M.H.); Institute for Biomedicine, Anhui Medical University, Hefei, China (G.T.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.H., J.L.); Department of Neurology, First Affiliated Hospital of Anhui Medical University, Hefei, China (J.F.); Department of Cardiovascular Medicine, Second Affiliated Hospital of Nanchang University, Jiangxi, China (X.H., X.C.); Hypertension Research Laboratory of Heart Center, Peking University People's Hospital, Beijing, China (N.S.); and Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China (M.Z., Y.C.).
authors.forename: Jianping
authors.initials: J
authors.lastname: Li
authors.affiliation: From the National Clinical Research Study Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China (M.Z., X.Q., B.W., F.F.H.); Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD (X.W.); Department of Neurology, First People's Hospital, Lianyungang, China (M.H.); Institute for Biomedicine, Anhui Medical University, Hefei, China (G.T.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.H., J.L.); Department of Neurology, First Affiliated Hospital of Anhui Medical University, Hefei, China (J.F.); Department of Cardiovascular Medicine, Second Affiliated Hospital of Nanchang University, Jiangxi, China (X.H., X.C.); Hypertension Research Laboratory of Heart Center, Peking University People's Hospital, Beijing, China (N.S.); and Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China (M.Z., Y.C.).
authors.forename: Jia
authors.initials: J
authors.lastname: Fu
authors.affiliation: From the National Clinical Research Study Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China (M.Z., X.Q., B.W., F.F.H.); Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD (X.W.); Department of Neurology, First People's Hospital, Lianyungang, China (M.H.); Institute for Biomedicine, Anhui Medical University, Hefei, China (G.T.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.H., J.L.); Department of Neurology, First Affiliated Hospital of Anhui Medical University, Hefei, China (J.F.); Department of Cardiovascular Medicine, Second Affiliated Hospital of Nanchang University, Jiangxi, China (X.H., X.C.); Hypertension Research Laboratory of Heart Center, Peking University People's Hospital, Beijing, China (N.S.); and Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China (M.Z., Y.C.).
authors.forename: Xiao
authors.initials: X
authors.lastname: Huang
authors.affiliation: From the National Clinical Research Study Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China (M.Z., X.Q., B.W., F.F.H.); Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD (X.W.); Department of Neurology, First People's Hospital, Lianyungang, China (M.H.); Institute for Biomedicine, Anhui Medical University, Hefei, China (G.T.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.H., J.L.); Department of Neurology, First Affiliated Hospital of Anhui Medical University, Hefei, China (J.F.); Department of Cardiovascular Medicine, Second Affiliated Hospital of Nanchang University, Jiangxi, China (X.H., X.C.); Hypertension Research Laboratory of Heart Center, Peking University People's Hospital, Beijing, China (N.S.); and Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China (M.Z., Y.C.).
authors.forename: Xiaoshu
authors.initials: X
authors.lastname: Cheng
authors.affiliation: From the National Clinical Research Study Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China (M.Z., X.Q., B.W., F.F.H.); Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD (X.W.); Department of Neurology, First People's Hospital, Lianyungang, China (M.H.); Institute for Biomedicine, Anhui Medical University, Hefei, China (G.T.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.H., J.L.); Department of Neurology, First Affiliated Hospital of Anhui Medical University, Hefei, China (J.F.); Department of Cardiovascular Medicine, Second Affiliated Hospital of Nanchang University, Jiangxi, China (X.H., X.C.); Hypertension Research Laboratory of Heart Center, Peking University People's Hospital, Beijing, China (N.S.); and Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China (M.Z., Y.C.).
authors.forename: Binyan
authors.initials: B
authors.lastname: Wang
authors.affiliation: From the National Clinical Research Study Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China (M.Z., X.Q., B.W., F.F.H.); Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD (X.W.); Department of Neurology, First People's Hospital, Lianyungang, China (M.H.); Institute for Biomedicine, Anhui Medical University, Hefei, China (G.T.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.H., J.L.); Department of Neurology, First Affiliated Hospital of Anhui Medical University, Hefei, China (J.F.); Department of Cardiovascular Medicine, Second Affiliated Hospital of Nanchang University, Jiangxi, China (X.H., X.C.); Hypertension Research Laboratory of Heart Center, Peking University People's Hospital, Beijing, China (N.S.); and Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China (M.Z., Y.C.).
authors.forename: Fan Fan
authors.initials: FF
authors.lastname: Hou
authors.affiliation: From the National Clinical Research Study Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China (M.Z., X.Q., B.W., F.F.H.); Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD (X.W.); Department of Neurology, First People's Hospital, Lianyungang, China (M.H.); Institute for Biomedicine, Anhui Medical University, Hefei, China (G.T.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.H., J.L.); Department of Neurology, First Affiliated Hospital of Anhui Medical University, Hefei, China (J.F.); Department of Cardiovascular Medicine, Second Affiliated Hospital of Nanchang University, Jiangxi, China (X.H., X.C.); Hypertension Research Laboratory of Heart Center, Peking University People's Hospital, Beijing, China (N.S.); and Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China (M.Z., Y.C.). sunnl@263.net caiyefeng@126.com.
authors.forename: Ningling
authors.initials: N
authors.lastname: Sun
authors.affiliation: From the National Clinical Research Study Center for Kidney Disease, State Key Laboratory for Organ Failure Research, Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China (M.Z., X.Q., B.W., F.F.H.); Department of Population, Family and Reproductive Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD (X.W.); Department of Neurology, First People's Hospital, Lianyungang, China (M.H.); Institute for Biomedicine, Anhui Medical University, Hefei, China (G.T.); Department of Cardiology, Peking University First Hospital, Beijing, China (Y.H., J.L.); Department of Neurology, First Affiliated Hospital of Anhui Medical University, Hefei, China (J.F.); Department of Cardiovascular Medicine, Second Affiliated Hospital of Nanchang University, Jiangxi, China (X.H., X.C.); Hypertension Research Laboratory of Heart Center, Peking University People's Hospital, Beijing, China (N.S.); and Department of Neurology, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China (M.Z., Y.C.). sunnl@263.net caiyefeng@126.com.
authors.forename: Yefeng
authors.initials: Y
authors.lastname: Cai
mesh_terms: D000368:Aged; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology; D002681:China / Q000453:epidemiology; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004656:Enalapril / Q000008:administration & dosage / Q000494:pharmacology; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D005500:Follow-Up Studies; D005838:Genotype; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020521:Stroke / Q000097:blood / Q000453:epidemiology / Q000235:genetics / Q000517:prevention & control; D016896:Treatment Outcome; D014803:Vitamin B Complex / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000959:Antihypertensive Agents; D006710:Homocysteine; D014803:Vitamin B Complex; D004656:Enalapril; D005492:Folic Acid; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2)
keywords: folic acid; homocysteine; methylenetetrahydrofolate reductase (MTHFR); polymorphism, genetic; stroke