Abstract
Stroke incidence is a multifactorial disease and especially hyperhomocysteinemia is associated with a higher risk of stroke. Previous studies have reported a folate metabolism disorder associated with the MTHFR gene. We investigated four single nucleotide polymorphisms in the MTHFR 3′-UTR [2572 C > A (rs4846049), 4869 C > G (rs1537514), 5488 C > T (rs3737967), and 6685 T > C (rs4846048)] to elucidate associations between ischemic stroke prevalence and prognosis. We examined 511 consecutive patients with ischemic stroke. Additionally, we selected 411 sex-/age-matched control subjects from patients presenting at our hospitals during the same period. The MTHFR 2572 C > A and 6685 T > C were significantly associated with ischemic stroke prevalence in the cardioembolism subgroup (MTHFR 2572CC vs. CA + AA: AOR, 2.145; 95% CI, 1.203–3.827; P = 0.010; MTHFR 6685TT vs. CC: AOR, 10.146; 95% CI, 1.297–79.336; P = 0.027). The gene-environment combined effect was significant, with MTHFR 2572CA + AA and folate levels ≤3.45 ng/mL correlating with ischemic stroke incidence. In addition, the total homocysteine (tHcy) levels in subjects with MTHFR 2572AA were elevated compared to tHcy levels in subjects with MTHFR 2572CC. Therefore, we suggest that MTHFR 2572 C > A and 6685 T > C are associated with ischemic stroke pathogenesis. The combined effects of the MTHFR 3′-UTR polymorphisms and tHcy/folate levels may contribute to stroke prevalence.
Highlights
Stroke is the third most common cause of death in many developed countries, and approximately 80% of stroke cases are ischemic in origin[1,2]
To examine whether the effect of each polymorphism was confined to a specific subtype or related to generalized risks, we further separated the stroke group into three subgroups [large arterial disease (LAD), small-vessel disease (SVD), and, cardioembolism (CE)] according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification[25]
large-artery disease (LAD) was significantly associated with the methylenetetrahydrofolate reductase (MTHFR) 6685 T > C polymorphism [TT vs. TC: adjusted odds ratio (AOR), 0.517; 95% confidence interval (CI), 0.308–0.867; P = 0.012; TT vs. TC + CC: AOR, 0.543; 95% CI, 0.328–0.899; P = 0.018]
Summary
Stroke is the third most common cause of death in many developed countries, and approximately 80% of stroke cases are ischemic in origin[1,2]. Hyperhomocysteinemia is considered an independent, potentially modifiable risk factor for ischemic stroke, and has been previously reported in several studies involving different ethnic groups[9,10,11,12]. It has been reported that elevation of Hcy in the blood is associated with an increased risk for arteriosclerosis, myocardial infarction, venous thrombosis, stroke, and neural tube defects[3,15]. The effect of several polymorphic genes involved in folate metabolism, including MTHFR on ischemic stroke susceptibility and progression, has been reported. We selected four single nucleotide polymorphisms (SNPs) in the MTHFR 3′-UTR region: MTHFR 2572 C > A (rs4846049), 4869 C > G (rs1537514), 5488 C > T (rs3737967), and 6685 T > C (rs4846048) We determined their associations with ischemic stroke prevalence and prognosis. We investigated whether MTHFR 3′-UTR polymorphisms correlate with ischemic stroke susceptibility in Korean subjects
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