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Current Neurovascular Research


ISSN (Print): 1567-2026
ISSN (Online): 1875-5739

Research Article

The U-shaped Relationship Between Serum Methylene Tetrahydrofolate Reductase and Large-artery Atherosclerotic Stroke

Author(s): Yan He, Zhengbao Zhu, Daoxia Guo, Huan Zhang, Xiaowei Zheng, Nimei Zeng, Qiu Zhang, Hao Peng, Chongke Zhong, Aili Wang, Tan Xu, Jianhua Jin, Yonghong Zhang* and Jiang He

Volume 16, Issue 1, 2019

Page: [82 - 88] Pages: 7

DOI: 10.2174/1567202616666190207161818

Price: $65


Background: Methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms have been reported to be associated with ischemic stroke. However, the association between serum MTHFR level and ischemic stroke has not yet been studied. We aimed to examine the association between them in patients with large-artery atherosclerotic stroke and community-based healthy controls.

Methods: This study includes three hundred ninety-five patients with large-artery atherosclerotic stroke from the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) and 395 age- and sex-matched healthy controls from Chinese communities. Serum MTHFR concentrations were examined and some conventional risk factors of stroke were collected. The association between serum MTHFR and large-artery atherosclerotic stroke was evaluated.

Results: A U-shaped association of serum MTHFR level with large-artery atherosclerotic stroke was observed (p for nonlinearity =0.008). After multivariate adjustment, the odds ratios (95% confidence intervals) of large-artery atherosclerotic stroke associated with the first, second, fourth, and fifth quintiles of MTHFR were 5.62 (1.10-28.87), 2.13 (0.51-8.99), 1.08 (0.21-5.56), and 2.31 (0.57-9.34), respectively, compared with the third quintiles of MTHFR. Adding MTHFR quintiles to a model containing conventional risk factors improved the predictive power for large-artery atherosclerotic stroke (continuous net reclassification improvement=63.78%, p<0.001; categorical net reclassification improvement=2.54%, p=0.012).

Conclusion: There is a significant U-shaped relationship between serum MTHFR levels and largeartery atherosclerotic stroke. Our findings raise the possibility that serum MTHFR may have a potential role in the pathogenesis of large-artery atherosclerotic stroke.

Keywords: Methylene tetrahydrofolate reductase, large-artery atherosclerotic stroke, biomarkers, case-control study ischemic stroke, hypertension, gene polymorphisms.

Strong K, Mathers C, Bonita R. Preventing stroke: saving lives around the world. Lancet Neurol 2007; 6(2): 182-7.
[ S474-4422(07)70031-5]
Shang W, Liu J. Stroke subtype classification: a comparative study of ASCO and modified TOAST. J Neurol Sci 2012; 314(1-2): 70. Epub Nov 25.
Bonita R, Mendis S, Truelsen T, et al. The global stroke initiative. Lancet Neurol 2004; 3(7): 391-3.
Shahar E, Chambless LE, Rosamond WD, et al. Plasma lipid profile and incident ischemic stroke: The Atherosclerosis Risk in Communities (ARIC) study. Stroke 2003; 34(3): 623-31. Epub 2003 Feb 20.
Mukamal KJ, Chung H, Jenny NS, et al. Alcohol use and risk of ischemic stroke among older adults: the cardiovascular health study. Stroke 2005; 36(9): 1830-4. Epub 2005 Aug 4.
[ 587.76846.89.]
Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery. Anesthesia & Analgesia 2014; 58(2): 15-26.
Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med 1998; 338(15): 1042-50.
[ 93381507.]
Zhou BS, Bu GY, Li M, et al. Tagging SNPs in the MTHFR gene and risk of ischemic stroke in a Chinese population. Int J Mol Sci 2014; 15(5): 8931-40.
Kelly PJ, Rosand J, Kistler JP, et al. Homocysteine, MTHFR 677C-->T polymorphism, and risk of ischemic stroke: results of a meta-analysis. Neurology 2002; 59(4): 529-36.
Morita H, Kurihara H, Tsubaki S, et al. Methylenetetrahydrofolate reductase gene polymorphism and ischemic stroke in Japanese. Arterioscler Thromb Vasc Biol 1998; 18(9): 1465-9.
Hou J, Zeng X, Xie Y, et al. Genetic polymorphisms of methylene-tetrahydrofolate reductase C677T and risk of ischemic stroke in a southern Chinese Hakka population. Medicine (Baltimore) 2018; 97(51): e13645.
Frosst P, Blom HJ, Milos R, et al. A candidate genetic risk factor for vascular disease: A common mutation in methylenete-trahydrofolate reductase. Nat Genet 1995; 10(1): 111-3.
Collaboration HS. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. JAMA 2002; 288(16): 2015-22.
He J, Zhang Y, Xu T, et al. Effects of immediate blood pressure reduction on death and major disability in patients with acute ischemic stroke: The CATIS randomized clinical trial. JAMA 2014; 311(5): 479-89.
Zhu Z, Zhang Q, Peng H, et al. Predictive value of serum soluble corin in the risk of hyperglycemia: A population-based prospective cohort study in China. Clin Chim Acta 2018; 479: 138-43.
Pickering TG, Hall JE, Appel LJ, et al. Recommendations for blood pressure measurement in humans: An AHA scientific statement from the Council on High Blood Pressure Research Professional and Public Education Subcommittee. J Clin Hypertens (Greenwich) 2005; 7(2): 102-9.
Durrleman S, Simon R. Flexible regression models with cubic splines. Stat Med 1989; 8(5): 551-61.
Pencina MJ, D’Agostino RB Sr, D’Agostino RB Jr, et al. Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med 2008; 27(2): 157-72.
Shi J, He W, Wang Y, et al. Tagging Functional Polymorphism in 3′ Untranslated Region of Methylene Tetrahydrofolate Reductase and Risk of Ischemic Stroke. Cell Physiol Biochem 2018; 46(3): 1019-26. Epub 2018 Apr 13
Huo Y, Li J, Qin X, et al. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial. JAMA 2015; 313(13): 1325-35.
Dardik R, Varon D, Tamarin I, et al. Homocysteine and oxidized low density lipoprotein enhanced platelet adhesion to endothelial cells under flow conditions: Distinct mechanisms of thrombogenic modulation. Thromb Haemost 2000; 83(2): 338-44.
Kanani PM, Sinkey CA, Browning RL, et al. Role of oxidant stress in endothelial dysfunction produced by experimental hyperhomo-cyst(e)inemia in humans. Circulation 1999; 100(11): 1161-8.
Li P, Qin C. Methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and susceptibility to ischemic stroke: A metaanalysis. Gene 2014; 535(2): 359-64. Epub Oct 16.
[ 09.066.]
Casas JP, Bautista LE, Smeeth L, et al. Homocysteine and stroke: evidence on a causal link from mendelian randomisation. Lancet 2005; 365(9455): 224-32.
Dichgans M. Genetics of ischaemic stroke. Lancet Neurol 2007; 6(2): 149-61.
Tong N, Fang Y, Li J, et al. Methylenetetrahydrofolate reductase polymorphisms, serum methylenetetrahydrofolate reductase levels, and risk of childhood acute lymphoblastic leukemia in a Chinese population. Cancer Sci 2010; 101(3): 782-6. Epub 2009 Nov 11.

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