Association of the miR-146a, miR-149, miR-196a2, and miR-499 polymorphisms with ischemic stroke and silent brain infarction risk.

OBJECTIVE: MicroRNAs play a role in atherosclerosis-related diseases, such as cerebrovascular or cardiovascular disease. However, the effect of miR-146a, miR-149, miR-196a2, and miR-499 polymorphisms on stroke and silent brain infarction (SBI) susceptibility has not been reported. METHODS AND RESULTS: Using polymerase chain reaction-amplified DNA, microRNA polymorphisms were analyzed in 678 patients with ischemic stroke, 373 patients with SBI, and 553 control subjects. The miR-146aC>G polymorphism and miR-146aG/-149T/-196a2C/-499G allele combination was significantly associated with ischemic stroke prevalence. For SBI prevalence, there were no statistically significant genetic markers. However, some allele combinations were associated with increased SBI incidence (C-T-C-G and G-T-T-A of miR-146a/-149/-196a2/-499). In subgroup analyses, miR-146aC>G increased stroke risk in female, normotensive, and nondiabetic groups. There were significant combined effects between microRNA polymorphisms and homocysteine/folate levels on ischemic stroke and SBI prevalence. CONCLUSIONS: The miR-146aG allele and miR-146aG/-149T/-196a2C/-499G allele combination were associated with ischemic stroke pathogenesis. The combined effects between microRNA polymorphisms and homocysteine/folate levels may contribute to stroke and SBI prevalence.

The 677C>T mutation of the MTHFR gene increases the risk of venous thromboembolism in Koreans and a meta-analysis from Asian population.

The frequency of methylenetetrahydrofolate reductase (MTHFR) mutations varies between racial and ethnic groups, and there are also conflicting data regarding MTHFR gene mutations in Asian patients with venous thromboembolism (VTE). The aim of this study was to examine the association between common MTHFR gene mutations (677C>T and 1298A>C) and risk of VTE in Koreans. This study was a retrospective case-control study. We enrolled 203 patients with VTE and 403 controls. For the 677C>T polymorphism, there was no difference in the frequency of the CT genotype and TT genotype between the patients with VTE and the controls. However, in the recessive analysis (CC + CT vs TT), the frequency of the TT genotype was significantly higher in VTE than in controls (odds ratio = 1.700; 95% confidence interval = 1.108-2.607, P = .015). In conclusion, the TT genotype of MTHFR 677C>T increases the risk of VTE in Koreans. This finding was supported by meta-analysis of previous Asian studies.

Association of the miR-146aC>G, miR-149T>C, miR-196a2T>C, and miR-499A>G polymorphisms with risk of spontaneously aborted fetuses.

PROBLEM: The miR-196a2T>C and miR-499A>G polymorphisms have been reported to be genetic risk factors for recurrent spontaneous abortion; however, that previous study focused on the genetic analyses of pregnant women rather than aborted fetuses. Because annexin A1 is a target of miR-196a2 and is related to anti-inflammation, miR-196a2 may be immunologically important. Moreover, miR-146a, miR-149, miR-196a2, and miR-499 have shown associations with immune responses. METHOD OF STUDY: One hundred and eighty-two spontaneously aborted fetuses (SAFs) were <20 weeks of gestational age. The control subjects were 101 healthy children and 302 adults collected from a convenience sample. Polymerase chain reaction and restriction fragment length polymorphism analysis was performed to identify the miR-146aC>G, miR-149T>C, miR-196a2T>C, and miR-499A>G genotypes. RESULTS: Chromosomally normal SAFs had significantly different frequencies of the miR-196a2CC, miR-146aCC/miR-196a2CC, and miR-149TT/miR-196a2CC genotypes compared with control subjects. CONCLUSIONS: miR-196a2CC, miR-146aCC/miR-196a2CC, and miR-149TT/miR-196a2CC in fetuses are possible risk factors for spontaneous abortion.

Association study of microRNA polymorphisms with risk of idiopathic recurrent spontaneous abortion in Korean women.

AIM: The aim of this study was to investigate the association of microRNA polymorphisms (miR-146aC>G, miR-149T>C, miR-196a2T>C, and miR-499A>G) in Korean patients with recurrent spontaneous abortion (RSA). METHODS: We conducted a case-control study of 564 Korean women: 330 patients with at least two unexplained consecutive pregnancy losses and 234 healthy controls with at least one live birth and no history of pregnancy loss. RESULTS: RSA patients exhibited significantly different frequencies of the miR-196a2CC (TT+TC vs. CC; adjusted odds ratio [AOR], 1.587; 95% confidence interval [CI], 1.042­2.417) and miR-499AG+GG genotypes (AOR, 1.587; 95% CI, 1.096­2.298) [corrected] compared with the control group. The combination of miR-196a2CC and miR-499AG+GG showed synergistic effects (AOR, 3.541; 95% CI, 1.645­7.624). CONCLUSION: miR-196a2CC, miR-499AG+GG, and the miR-196a2CC/miR-499AG+GG combination are significantly associated with idiopathic RSA in Korean women.

Vascular endothelial growth factor gene polymorphisms in spontaneously aborted fetuses.

PROBLEMS: The VEGF-1154G>A polymorphism has been reported to be a genetic risk factor for recurrent spontaneous abortion in various studies; however, these studies have focused on genetic analyses of pregnant women rather than aborted fetuses. To evaluate and confirm the association between the VEGF-1154G>A polymorphism and spontaneous abortion, we focused on the relationship between four polymorphisms in the VEGF gene (-2578C>A, -1154G>A, -634G>C, and 936C>T) and spontaneously aborted fetuses (SAFs). METHOD OF STUDY: The subjects included 118 SAFs at <20 weeks gestation and 380 normal controls consisting of children and adults. The polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: Spontaneously aborted fetuses exhibited significantly different frequencies of the -2578CA+AA/-634CC and -1154GA+AA/-634CC combined genotypes compared with control subjects. The frequency of the -2578A/-1154A/-634C/936C haplotype was significantly higher in SAFs. CONCLUSIONS: VEGF genes -2578CA+AA/-634CC and -1154GA+AA/-634CC in the fetus are possible risk factors for spontaneous abortion.