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March 17, 2020; 94 (11) Article

Interaction of serum vitamin B12 and folate with MTHFR genotypes on risk of ischemic stroke

Xianhui Qin, J. David Spence, Jianping Li, Yan Zhang, Youbao Li, Ningling Sun, Min Liang, Yun Song, Yuanyuan Zhang, Binyan Wang, Xiaoshu Cheng, Lianyou Zhao, Xiaobin Wang, Xiping Xu, Yong Huo
First published January 13, 2020, DOI: https://doi.org/10.1212/WNL.0000000000008932
Xianhui Qin
From Renal Division (X.Q., Y.L., M.L., Y.Z., X.X.), Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease (X.Q., Y.L., M.L., Y.Z., X.X.); State Key Laboratory for Organ Failure Research (X.Q., Y.L., M.L., Y.Z., X.X.), Guangzhou, China; Stroke Prevention and Atherosclerosis Research Centre (J.D.S.), Robarts Research Institute, University of Western Ontario, London, Canada; Department of Cardiology (J.L., Y.Z., Y.H.), Peking University First Hospital; Department of Cardiology (N.S.), Peking University People’s Hospital; Beijing Advanced Innovation Center for Food Nutrition and Human Health (Y.S.), Key Laboratory of Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing; Institute for Biomedicine (B.W.), Anhui Medical University, Hefei; Department of Cardiology (X.C.), Second Affiliated Hospital, Nanchang University; Department of Cardiology (L.Z.), Tangdu Hospital, the Fourth Military Medical University, Xi'an, China; and Department of Population, Family and Reproductive Health (X.W.), Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD.
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J. David Spence
From Renal Division (X.Q., Y.L., M.L., Y.Z., X.X.), Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease (X.Q., Y.L., M.L., Y.Z., X.X.); State Key Laboratory for Organ Failure Research (X.Q., Y.L., M.L., Y.Z., X.X.), Guangzhou, China; Stroke Prevention and Atherosclerosis Research Centre (J.D.S.), Robarts Research Institute, University of Western Ontario, London, Canada; Department of Cardiology (J.L., Y.Z., Y.H.), Peking University First Hospital; Department of Cardiology (N.S.), Peking University People’s Hospital; Beijing Advanced Innovation Center for Food Nutrition and Human Health (Y.S.), Key Laboratory of Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing; Institute for Biomedicine (B.W.), Anhui Medical University, Hefei; Department of Cardiology (X.C.), Second Affiliated Hospital, Nanchang University; Department of Cardiology (L.Z.), Tangdu Hospital, the Fourth Military Medical University, Xi'an, China; and Department of Population, Family and Reproductive Health (X.W.), Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD.
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Jianping Li
From Renal Division (X.Q., Y.L., M.L., Y.Z., X.X.), Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease (X.Q., Y.L., M.L., Y.Z., X.X.); State Key Laboratory for Organ Failure Research (X.Q., Y.L., M.L., Y.Z., X.X.), Guangzhou, China; Stroke Prevention and Atherosclerosis Research Centre (J.D.S.), Robarts Research Institute, University of Western Ontario, London, Canada; Department of Cardiology (J.L., Y.Z., Y.H.), Peking University First Hospital; Department of Cardiology (N.S.), Peking University People’s Hospital; Beijing Advanced Innovation Center for Food Nutrition and Human Health (Y.S.), Key Laboratory of Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing; Institute for Biomedicine (B.W.), Anhui Medical University, Hefei; Department of Cardiology (X.C.), Second Affiliated Hospital, Nanchang University; Department of Cardiology (L.Z.), Tangdu Hospital, the Fourth Military Medical University, Xi'an, China; and Department of Population, Family and Reproductive Health (X.W.), Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD.
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Yan Zhang
From Renal Division (X.Q., Y.L., M.L., Y.Z., X.X.), Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease (X.Q., Y.L., M.L., Y.Z., X.X.); State Key Laboratory for Organ Failure Research (X.Q., Y.L., M.L., Y.Z., X.X.), Guangzhou, China; Stroke Prevention and Atherosclerosis Research Centre (J.D.S.), Robarts Research Institute, University of Western Ontario, London, Canada; Department of Cardiology (J.L., Y.Z., Y.H.), Peking University First Hospital; Department of Cardiology (N.S.), Peking University People’s Hospital; Beijing Advanced Innovation Center for Food Nutrition and Human Health (Y.S.), Key Laboratory of Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing; Institute for Biomedicine (B.W.), Anhui Medical University, Hefei; Department of Cardiology (X.C.), Second Affiliated Hospital, Nanchang University; Department of Cardiology (L.Z.), Tangdu Hospital, the Fourth Military Medical University, Xi'an, China; and Department of Population, Family and Reproductive Health (X.W.), Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD.
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Youbao Li
From Renal Division (X.Q., Y.L., M.L., Y.Z., X.X.), Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease (X.Q., Y.L., M.L., Y.Z., X.X.); State Key Laboratory for Organ Failure Research (X.Q., Y.L., M.L., Y.Z., X.X.), Guangzhou, China; Stroke Prevention and Atherosclerosis Research Centre (J.D.S.), Robarts Research Institute, University of Western Ontario, London, Canada; Department of Cardiology (J.L., Y.Z., Y.H.), Peking University First Hospital; Department of Cardiology (N.S.), Peking University People’s Hospital; Beijing Advanced Innovation Center for Food Nutrition and Human Health (Y.S.), Key Laboratory of Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing; Institute for Biomedicine (B.W.), Anhui Medical University, Hefei; Department of Cardiology (X.C.), Second Affiliated Hospital, Nanchang University; Department of Cardiology (L.Z.), Tangdu Hospital, the Fourth Military Medical University, Xi'an, China; and Department of Population, Family and Reproductive Health (X.W.), Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD.
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Ningling Sun
From Renal Division (X.Q., Y.L., M.L., Y.Z., X.X.), Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease (X.Q., Y.L., M.L., Y.Z., X.X.); State Key Laboratory for Organ Failure Research (X.Q., Y.L., M.L., Y.Z., X.X.), Guangzhou, China; Stroke Prevention and Atherosclerosis Research Centre (J.D.S.), Robarts Research Institute, University of Western Ontario, London, Canada; Department of Cardiology (J.L., Y.Z., Y.H.), Peking University First Hospital; Department of Cardiology (N.S.), Peking University People’s Hospital; Beijing Advanced Innovation Center for Food Nutrition and Human Health (Y.S.), Key Laboratory of Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing; Institute for Biomedicine (B.W.), Anhui Medical University, Hefei; Department of Cardiology (X.C.), Second Affiliated Hospital, Nanchang University; Department of Cardiology (L.Z.), Tangdu Hospital, the Fourth Military Medical University, Xi'an, China; and Department of Population, Family and Reproductive Health (X.W.), Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD.
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Min Liang
From Renal Division (X.Q., Y.L., M.L., Y.Z., X.X.), Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease (X.Q., Y.L., M.L., Y.Z., X.X.); State Key Laboratory for Organ Failure Research (X.Q., Y.L., M.L., Y.Z., X.X.), Guangzhou, China; Stroke Prevention and Atherosclerosis Research Centre (J.D.S.), Robarts Research Institute, University of Western Ontario, London, Canada; Department of Cardiology (J.L., Y.Z., Y.H.), Peking University First Hospital; Department of Cardiology (N.S.), Peking University People’s Hospital; Beijing Advanced Innovation Center for Food Nutrition and Human Health (Y.S.), Key Laboratory of Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing; Institute for Biomedicine (B.W.), Anhui Medical University, Hefei; Department of Cardiology (X.C.), Second Affiliated Hospital, Nanchang University; Department of Cardiology (L.Z.), Tangdu Hospital, the Fourth Military Medical University, Xi'an, China; and Department of Population, Family and Reproductive Health (X.W.), Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD.
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Yun Song
From Renal Division (X.Q., Y.L., M.L., Y.Z., X.X.), Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease (X.Q., Y.L., M.L., Y.Z., X.X.); State Key Laboratory for Organ Failure Research (X.Q., Y.L., M.L., Y.Z., X.X.), Guangzhou, China; Stroke Prevention and Atherosclerosis Research Centre (J.D.S.), Robarts Research Institute, University of Western Ontario, London, Canada; Department of Cardiology (J.L., Y.Z., Y.H.), Peking University First Hospital; Department of Cardiology (N.S.), Peking University People’s Hospital; Beijing Advanced Innovation Center for Food Nutrition and Human Health (Y.S.), Key Laboratory of Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing; Institute for Biomedicine (B.W.), Anhui Medical University, Hefei; Department of Cardiology (X.C.), Second Affiliated Hospital, Nanchang University; Department of Cardiology (L.Z.), Tangdu Hospital, the Fourth Military Medical University, Xi'an, China; and Department of Population, Family and Reproductive Health (X.W.), Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD.
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Yuanyuan Zhang
From Renal Division (X.Q., Y.L., M.L., Y.Z., X.X.), Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease (X.Q., Y.L., M.L., Y.Z., X.X.); State Key Laboratory for Organ Failure Research (X.Q., Y.L., M.L., Y.Z., X.X.), Guangzhou, China; Stroke Prevention and Atherosclerosis Research Centre (J.D.S.), Robarts Research Institute, University of Western Ontario, London, Canada; Department of Cardiology (J.L., Y.Z., Y.H.), Peking University First Hospital; Department of Cardiology (N.S.), Peking University People’s Hospital; Beijing Advanced Innovation Center for Food Nutrition and Human Health (Y.S.), Key Laboratory of Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing; Institute for Biomedicine (B.W.), Anhui Medical University, Hefei; Department of Cardiology (X.C.), Second Affiliated Hospital, Nanchang University; Department of Cardiology (L.Z.), Tangdu Hospital, the Fourth Military Medical University, Xi'an, China; and Department of Population, Family and Reproductive Health (X.W.), Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD.
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Binyan Wang
From Renal Division (X.Q., Y.L., M.L., Y.Z., X.X.), Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease (X.Q., Y.L., M.L., Y.Z., X.X.); State Key Laboratory for Organ Failure Research (X.Q., Y.L., M.L., Y.Z., X.X.), Guangzhou, China; Stroke Prevention and Atherosclerosis Research Centre (J.D.S.), Robarts Research Institute, University of Western Ontario, London, Canada; Department of Cardiology (J.L., Y.Z., Y.H.), Peking University First Hospital; Department of Cardiology (N.S.), Peking University People’s Hospital; Beijing Advanced Innovation Center for Food Nutrition and Human Health (Y.S.), Key Laboratory of Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing; Institute for Biomedicine (B.W.), Anhui Medical University, Hefei; Department of Cardiology (X.C.), Second Affiliated Hospital, Nanchang University; Department of Cardiology (L.Z.), Tangdu Hospital, the Fourth Military Medical University, Xi'an, China; and Department of Population, Family and Reproductive Health (X.W.), Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD.
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Xiaoshu Cheng
From Renal Division (X.Q., Y.L., M.L., Y.Z., X.X.), Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease (X.Q., Y.L., M.L., Y.Z., X.X.); State Key Laboratory for Organ Failure Research (X.Q., Y.L., M.L., Y.Z., X.X.), Guangzhou, China; Stroke Prevention and Atherosclerosis Research Centre (J.D.S.), Robarts Research Institute, University of Western Ontario, London, Canada; Department of Cardiology (J.L., Y.Z., Y.H.), Peking University First Hospital; Department of Cardiology (N.S.), Peking University People’s Hospital; Beijing Advanced Innovation Center for Food Nutrition and Human Health (Y.S.), Key Laboratory of Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing; Institute for Biomedicine (B.W.), Anhui Medical University, Hefei; Department of Cardiology (X.C.), Second Affiliated Hospital, Nanchang University; Department of Cardiology (L.Z.), Tangdu Hospital, the Fourth Military Medical University, Xi'an, China; and Department of Population, Family and Reproductive Health (X.W.), Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD.
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Lianyou Zhao
From Renal Division (X.Q., Y.L., M.L., Y.Z., X.X.), Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease (X.Q., Y.L., M.L., Y.Z., X.X.); State Key Laboratory for Organ Failure Research (X.Q., Y.L., M.L., Y.Z., X.X.), Guangzhou, China; Stroke Prevention and Atherosclerosis Research Centre (J.D.S.), Robarts Research Institute, University of Western Ontario, London, Canada; Department of Cardiology (J.L., Y.Z., Y.H.), Peking University First Hospital; Department of Cardiology (N.S.), Peking University People’s Hospital; Beijing Advanced Innovation Center for Food Nutrition and Human Health (Y.S.), Key Laboratory of Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing; Institute for Biomedicine (B.W.), Anhui Medical University, Hefei; Department of Cardiology (X.C.), Second Affiliated Hospital, Nanchang University; Department of Cardiology (L.Z.), Tangdu Hospital, the Fourth Military Medical University, Xi'an, China; and Department of Population, Family and Reproductive Health (X.W.), Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD.
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Xiaobin Wang
From Renal Division (X.Q., Y.L., M.L., Y.Z., X.X.), Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease (X.Q., Y.L., M.L., Y.Z., X.X.); State Key Laboratory for Organ Failure Research (X.Q., Y.L., M.L., Y.Z., X.X.), Guangzhou, China; Stroke Prevention and Atherosclerosis Research Centre (J.D.S.), Robarts Research Institute, University of Western Ontario, London, Canada; Department of Cardiology (J.L., Y.Z., Y.H.), Peking University First Hospital; Department of Cardiology (N.S.), Peking University People’s Hospital; Beijing Advanced Innovation Center for Food Nutrition and Human Health (Y.S.), Key Laboratory of Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing; Institute for Biomedicine (B.W.), Anhui Medical University, Hefei; Department of Cardiology (X.C.), Second Affiliated Hospital, Nanchang University; Department of Cardiology (L.Z.), Tangdu Hospital, the Fourth Military Medical University, Xi'an, China; and Department of Population, Family and Reproductive Health (X.W.), Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD.
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Xiping Xu
From Renal Division (X.Q., Y.L., M.L., Y.Z., X.X.), Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease (X.Q., Y.L., M.L., Y.Z., X.X.); State Key Laboratory for Organ Failure Research (X.Q., Y.L., M.L., Y.Z., X.X.), Guangzhou, China; Stroke Prevention and Atherosclerosis Research Centre (J.D.S.), Robarts Research Institute, University of Western Ontario, London, Canada; Department of Cardiology (J.L., Y.Z., Y.H.), Peking University First Hospital; Department of Cardiology (N.S.), Peking University People’s Hospital; Beijing Advanced Innovation Center for Food Nutrition and Human Health (Y.S.), Key Laboratory of Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing; Institute for Biomedicine (B.W.), Anhui Medical University, Hefei; Department of Cardiology (X.C.), Second Affiliated Hospital, Nanchang University; Department of Cardiology (L.Z.), Tangdu Hospital, the Fourth Military Medical University, Xi'an, China; and Department of Population, Family and Reproductive Health (X.W.), Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD.
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Yong Huo
From Renal Division (X.Q., Y.L., M.L., Y.Z., X.X.), Nanfang Hospital, Southern Medical University; National Clinical Research Center for Kidney Disease (X.Q., Y.L., M.L., Y.Z., X.X.); State Key Laboratory for Organ Failure Research (X.Q., Y.L., M.L., Y.Z., X.X.), Guangzhou, China; Stroke Prevention and Atherosclerosis Research Centre (J.D.S.), Robarts Research Institute, University of Western Ontario, London, Canada; Department of Cardiology (J.L., Y.Z., Y.H.), Peking University First Hospital; Department of Cardiology (N.S.), Peking University People’s Hospital; Beijing Advanced Innovation Center for Food Nutrition and Human Health (Y.S.), Key Laboratory of Functional Dairy, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing; Institute for Biomedicine (B.W.), Anhui Medical University, Hefei; Department of Cardiology (X.C.), Second Affiliated Hospital, Nanchang University; Department of Cardiology (L.Z.), Tangdu Hospital, the Fourth Military Medical University, Xi'an, China; and Department of Population, Family and Reproductive Health (X.W.), Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD.
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Citation
Interaction of serum vitamin B12 and folate with MTHFR genotypes on risk of ischemic stroke
Xianhui Qin, J. David Spence, Jianping Li, Yan Zhang, Youbao Li, Ningling Sun, Min Liang, Yun Song, Yuanyuan Zhang, Binyan Wang, Xiaoshu Cheng, Lianyou Zhao, Xiaobin Wang, Xiping Xu, Yong Huo
Neurology Mar 2020, 94 (11) e1126-e1136; DOI: 10.1212/WNL.0000000000008932

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Abstract

Objective We evaluated the interaction of serum folate and vitamin B12 with methylenetetrahydrofolate reductase (MTHFR) C677T genotypes on the risk of first ischemic stroke and on the efficacy of folic acid treatment in prevention of first ischemic stroke.

Methods A total of 20,702 hypertensive adults were randomized to a double-blind treatment of daily enalapril 10 mg and folic acid 0.8 mg or enalapril 10 mg alone. Participants were followed up every 3 months.

Results Median values of folate and B12 concentrations at baseline were 8.1 ng/mL and 280.2 pmol/L, respectively. Over a median of 4.5 years, among those not receiving folic acid, participants with baseline serum B12 or serum folate above the median had a significantly lower risk of first ischemic stroke (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.57–0.96), especially in those with MTHFR 677 CC genotype (wild-type) (HR, 0.49; 95% CI, 0.31–0.78). Folic acid treatment significantly reduced the risk of first ischemic stroke in participants with both folate and B12 below the median (2.3% in enalapril-folic acid group vs 3.6% in enalapril-only group; HR, 0.62; 95% CI, 0.46–0.86), particularly in MTHFR 677 CC carriers (1.6% vs 4.9%; HR, 0.24; 95% CI, 0.11–0.55). However, TT homozygotes responded better with both folate and B12 levels above the median (HR, 0.28; 95% CI, 0.10–0.75).

Conclusions The risk of first ischemic stroke was significantly higher in hypertensive patients with low levels of both folate and B12. Effect of folic acid treatment was greatest in patients with low folate and B12 with the CC genotype, and with high folate and B12 with the TT genotype.

Glossary

CI=
confidence interval;
CSPPT=
China Stroke Primary Prevention Trial;
HR=
hazard ratio;
IQR=
interquartile range;
MI=
myocardial infarction;
MTHFR=
methylenetetrahydrofolate reductase;
tHcy=
total homocysteine

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Received June 8, 2020.
  • Accepted in final form September 19, 2020.
  • © 2020 American Academy of Neurology
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