Methylene Tetrahydrofolate Reductase (MTHFR) rs868014 Polymorphism Regulated by miR-1203 Associates with Risk and Short Term Outcome of Ischemic Stroke

Abstract

Background/Aims: Genetic polymorphisms of methylene tetrahydrofolate reductase (MTHFR) were associated with ischemic stroke risk. This study analyzed MTHFR polymorphisms at the 3'-untranslated region for association with risk and outcome of ischemic stroke in a Chinese Han population. Methods: 500 patients and 600 healthy volunteers were enrolled for MTHFR rs868014 genotyping identified bioinformatically. The binding of miR-1203 to MTHFR rs868014 was determined by luciferase assay, MTHFR expression was assessed using qRT-PCR, and plasma homocysteine levels were assayed by ELISA. Results: Cigarette smoking, alcohol consumption, diabetes, hypertension (all P <0.001), low levels of serum high-density lipoprotein-C (P = 0.01), and high levels of serum low-density lipoprotein-C (P = 0.005) were associated with an increased risk of developing ischemic stroke. BMI and total serum cholesterol concentration was not associated with ischemic stroke. MTHFR rs868014 TC and CC genotypes were significantly associated with increased risk of ischemic stroke compared with the TT genotype (OR: 1.52; 95% CI: 1.01-3.39 for TC genotype, while OR: 1.99; 95% CI: 1.29-3.88 for CC genotype). Furthermore, the MTHFR rs868014 SNP was associated with a poor short-term ischemic stroke outcome. qRT-PCR confirmed that MTHFR rs868014 TC or CC genotypes could facilitate miR-1203 binding leading to low MTHFR levels in cells. In addition, patients carrying the MTHFR rs868014 TC or CC genotypes were associated with accumulation of serum tHcy and a poor ischemic stroke outcome. Linkage disequilibrium analysis indicated that the newly identified SNP rs868014 was strongly linked with the MTHFR A1298C polymorphism. Conclusion: This study demonstrates that the MTHFR rs868014 SNP is associated with increased risk in developing ischemic stroke, miR-1203 binding, low MTHFR levels in cells, and poor shot term outcome of patients.

Tagging Functional Polymorphism in 3’ Untranslated Region of Methylene Tetrahydrofolate Reductase and Risk of Ischemic Stroke

“…The 677TT allele was also associated with elevated tHcy levels, predominantly in individuals with low plasma folate levels. Higher tHcy concentrations have in turn been shown to have a negative effect on stroke [16, 19]. …”

“…For example, the rs1801133 polymorphism was associated with reductions in MTHFR activity of approximately 70% and 35% in TT and CT genotype carriers, respectively, leading to increased levels of tHcy, which predicted a poor prognosis among IS patients [14-16]. The A1298C variant resulted in substitution of glutamate (Glu) by alanine (Ala) at codon 429 in the S-adenosylmethionine regulatory domain of the MTHFR protein [17-19]. …”

A Genetic Variant of miR-34a Contributes to Susceptibility of Ischemic Stroke Among Chinese Population

“…MTHFR is a key enzyme which plays an important role in the metabolism of homocysteine. A lower expression level of MTHFR causes accumulation of homocysteine, and then results in a higher level of homocysteine (Moll and Varga, 2015; He W. et al, 2017; Liu et al, 2018). According to research conducted by Zhang et al (2015), as a member of the miR-34 family, miR-34b may influence the serum level of homocysteine by binding the 3′-UTR of MTHFR mRNA.…”

Genetic susceptibility to cerebrovascular disease: A systematic review

“…18,19 In their Asian and Caucasian study population, Wei et al 16 were also able to associate ischemic stroke with the 1298A > C variant (rs1801131) of the same gene, which reduces MTHFR activity by an estimated 40%. In a Chinese cohort, He et al 20 discovered a relationship between ischemic stroke and a third MTHFR variant (rs868014), which causes a quantitative decrease in MTHFR.…”