Homocysteine and Stroke Risk: Modifying Effect of Methylenetetrahydrofolate Reductase C677T Polymorphism and Folic Acid Intervention

Min Zhao; Xiaobin Wang; Mingli He; Xianhui Qin; Genfu Tang; Yong Huo; Jianping Li; Jia Fu; Xiao Huang; Xiaoshu Cheng; Binyan Wang; Fan Fan Hou; Ningling Sun; Yefeng Cai

doi:10.1161/STROKEAHA.116.015324

Homocysteine and Stroke Risk: Modifying Effect of Methylenetetrahydrofolate Reductase C677T Polymorphism and Folic Acid Intervention

Stroke. 2017 May;48(5):1183-1190. doi: 10.1161/STROKEAHA.116.015324. Epub 2017 Mar 30.

Authors

Min Zhao¹, Xiaobin Wang¹, Mingli He¹, Xianhui Qin¹, Genfu Tang¹, Yong Huo¹, Jianping Li¹, Jia Fu¹, Xiao Huang¹, Xiaoshu Cheng¹, Binyan Wang¹, Fan Fan Hou¹, Ningling Sun², Yefeng Cai²

Affiliations

¹ 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.).
² 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.

PMID: 28360116
DOI: 10.1161/STROKEAHA.116.015324

Abstract

Background and purpose: 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.

Methods: 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.

Results: 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).

Conclusions: 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.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00794885.

Keywords: folic acid; homocysteine; methylenetetrahydrofolate reductase (MTHFR); polymorphism, genetic; stroke.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Antihypertensive Agents / administration & dosage
Antihypertensive Agents / pharmacology
China / epidemiology
Double-Blind Method
Drug Therapy, Combination
Enalapril / administration & dosage
Enalapril / pharmacology
Female
Folic Acid / administration & dosage
Folic Acid / pharmacology*
Follow-Up Studies
Genotype
Homocysteine / blood*
Humans
Hypertension* / blood
Hypertension* / drug therapy
Hypertension* / epidemiology
Hypertension* / genetics
Male
Methylenetetrahydrofolate Reductase (NADPH2) / genetics*
Middle Aged
Polymorphism, Genetic
Stroke* / blood
Stroke* / epidemiology
Stroke* / genetics
Stroke* / prevention & control
Treatment Outcome
Vitamin B Complex / administration & dosage
Vitamin B Complex / pharmacology*

Substances

Antihypertensive Agents
Homocysteine
Vitamin B Complex
Enalapril
Folic Acid
MTHFR protein, human
Methylenetetrahydrofolate Reductase (NADPH2)

Associated data

ClinicalTrials.gov/NCT00794885