Tagging SNPs in the MTHFR Gene and Risk of Ischemic Stroke in a Chinese Population

Bao-Sheng Zhou,Yi-Pin Zhou,Bin-Ge Chang,Guo-Yun Bu,Mu Li

doi:10.3390/ijms15058931

Abstract

Stroke is currently the leading cause of functional impairments worldwide. Folate supplementation is inversely associated with risk of ischemic stroke. Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate metabolism. The aim of this study is to examine whether genetic variants in MTHFR gene are associated with the risk of ischemic stroke and fasting total serum homocysteine (tHcy) level. We genotyped nine tag SNPs in the MTHFR gene in a case-control study, including 543 ischemic stroke cases and 655 healthy controls in China. We found that subjects with the rs1801133 TT genotype and rs1801131 CC genotype had significant increased risks of ischemic stroke (adjusted odds ratio (OR) = 1.82, 95% confidence interval (CI): 1.27–2.61, p = 0.004; adjusted OR = 1.99, 95% CI: 1.12–3.56, p = 0.01) compared with subjects with the major alleles. Haplotype analysis also found that carriers of the MTHFR CTTCGA haplotype (rs12121543-rs13306553-rs9651118-rs1801133-rs2274976-rs1801131) had a significant reduced risk of ischemic stroke (adjusted OR = 0.53, 95% CI: 0.35–0.82) compared with those with the CTTTGA haplotype. Besides, the MTHFR rs1801133 and rs9651118 were significantly associated with serum levels of tHcy in healthy controls (p < 0.0001 and p = 0.02). These findings suggest that variants in the MTHFR gene may influence the risk of ischemic stroke and serum tHcy.

Highlights

Stroke is a devastating neurological disease that mainly caused by abnormal perfusion of brain tissue, which ranked the second leading cause of death in people older than 60 years worldwide [1]
To help clarify whether the Methylenetetrahydrofolate reductase (MTHFR) variants are associated with susceptibility of ischemic stroke and total serum homocysteine level, we examined nine tag SNPs in the MTHFR gene in a case-control study in the Chinese population
We demonstrated that two genetic mutations in MTHFR gene were significantly associated with risk of ischemic stroke, and rs1801133 and rs9651118 were significantly associated with serum total serum homocysteine (tHcy) levels in our study population

Summary

Introduction

Stroke is a devastating neurological disease that mainly caused by abnormal perfusion of brain tissue, which ranked the second leading cause of death in people older than 60 years worldwide [1]. The annual stroke mortality rate in China is approximately 157 per 100,000, which has become the leading cause of death and adult disability [3]. Data have shown that certain nutrients and vascular endothelial regulation factors, such as folic acid and Kruppel-like factor 2, are protective factor for ischemic stroke [6]. Folic acid intake appears to reduce the risk of stroke through the regulation of plasma homocysteine concentration, which was a strong and independent risk factor for stroke [7]. It was reported that a 25% lower usual homocysteine level was associated with a 19% lower risk of stroke [8]. Several polymorphisms in homocysteine regulatory genes, such as MTRR, SHMT1 and TCN2, have been found to have impacts on plasma homocysteine level and ischemic stroke risk [9]. MTHFR (methylenetetrahydrofolate reductase), a folate-dependent enzyme, plays an important role in the conversion of the amino acid homocysteine to another amino acid, methionine, by converting 5,10-methylenetetrahydrofolate to

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