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


CONCLUSIONS
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.
Wei
W
He
Minzhi
M
Lu
Guoqing
G
Li
Zhigang
Z
Sun
Dinghua
D
Liu
Lujun
L
Gu
D000368:Aged; D000483:Alleles; D001665:Binding Sites; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D057809:HEK293 Cells; D006710:Homocysteine / Q000097:blood; D006801:Humans; D006973:Hypertension / Q000150:complications; D015810:Linkage Disequilibrium; D008075:Lipoproteins, HDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012306:Risk; D012907:Smoking; D020521:Stroke / Q000150:complications / Q000175:diagnosis / Q000235:genetics*
D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D035683:MicroRNAs; D006710:Homocysteine; D042965:Methylenetetrahydrofolate Reductase (NADPH2)
Homocysteine; Methylene tetrahydrofolate reductase (MTHFR); Outcome; SNPs; Stroke; miR-1203