HyungChul Rah

Association of the miR-146aC>G, miR-149T>C, miR-196a2T>C, and miR-499A>G polymorphisms with gastric cancer risk and survival in the korean population

We investigated whether four common microRNA polymorphisms (miR‐146aC>G [rs2910164], miR‐149T>C [rs2292832], miR‐196a2T>C [rs11614913], and miR‐499A>G [rs3746444]) are associated with the susceptibility and prognosis of gastric cancer in the Korean population. The four microRNA single‐nucleotide polymorphisms (SNPs) were identified in a case–control study (461 patients; 447 controls) by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) analysis in the Korean population. When patients were stratified into diffuse and intestinal‐type gastric cancer groups, subjects with the miR‐499AG and AG + GG genotypes had reduced adjusted odds ratios (AORs) for diffuse‐type gastric cancer (AOR = 0.54 with 95% confidence interval [CI] = 0.31–0.97; AOR = 0.57 with 95% CI = 0.33–0.97). In the stratified analyses for gastric cancer risk, the miR‐146aGG and CG + GG genotypes were associated with increased risk of gastric cancers among the non‐smokers, whereas the miR‐149TC and TC + CC genotypes showed lower risk of gastric cancer in males. The miR‐196a2CC genotype was associated with elevated gastric cancer risk among females. For gastric cancer prognosis, intestinal‐type gastric cancer patients with miR‐146aCG + GG genotypes had significantly higher survival rates (log‐rank P = 0.030) than patients with the CC genotype, and patients with the miR‐499AA genotype had significantly increased survival rates compared to patients with the AG + GG genotypes (log‐rank P = 0.013). When miR‐146aCG + GG and miR‐499AA genotypes were combined, the survival rate of intestinal‐type gastric cancer patients was elevated (log‐rank P < 0.001). No association was found between gastric or diffuse‐type cancer prognosis and other miRNAs. Our data demonstrate that specific miRNA SNPs are associated with gastric cancer susceptibility (miR‐499A>G) and prognosis (miR‐146aC>G and miR‐499A>G) in the Korean population depending on gastric cancer type.

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], 1.042–2.417) and miR-499AG+GG genotypes (AOR, 1.587; 95% CI, 1.096–2.298) [corrected] compared with the control group. The combination of miR-196a2CC and miR-499AG+GG showed synergistic effects (AOR, 3.541; 95% CI, 1.645–7.624). CONCLUSION miR-196a2CC, miR-499AG+GG, and the miR-196a2CC/miR-499AG+GG combination are significantly associated with idiopathic RSA in Korean women.

Association of miR-146aC>G, miR-196a2T>C, and miR-499A>G polymorphisms with risk of premature ovarian failure in Korean women.

We investigated whether microRNA (miRNA) polymorphisms (miR-146aC>G, miR-196a2T>C, and miR-499A>G) confer risk of premature ovarian failure (POF) in Korean women. DNA samples from 136 patients with POF and 234 controls were genotyped for the 3 miRNA single-nucleotide polymorphisms by polymerase chain reaction–restriction fragment length polymorphism. The miR-146aCG/miR-196a2TC combined genotype was less frequent in patients than in controls (P < .05), conferring less susceptibility. Using haplotype-based multifactor dimensionality reduction analysis, the C-C-A and G-T-A inferred haplotypes (miR-146a/miR-196a2/miR-499) were less frequent in patients, suggesting protective effects (P < .05 for each), whereas the C-T-A and G-C-A haplotypes were more frequent in patients (P < .05 for each). The C-T and G-C haplotypes (miR-146a/miR-196a2) were more frequent in patients, whereas the C-C and G-T haplotypes were less frequent in patients (P < .05 for each). However, none of the 3 miRNA polymorphisms alone was associated with POF risk. Our findings suggest that putative gene–gene interaction between miR-146 and miR-196a2 may be involved in POF development.

Association of polymorphisms in microRNA machinery genes (DROSHA, DICER1, RAN, and XPO5) with risk of idiopathic primary ovarian insufficiency in Korean women.

Objective The aim of our study was to investigate whether polymorphisms in microRNA machinery genes are associated with the risk of primary ovarian insufficiency (POI). Methods We genotyped 136 POI patients and 236 controls among Korean women for nine single nucleotide polymorphisms (SNPs; DROSHA rs6877842 and rs10719; DICER1 rs13078 and rs3742330; RAN rs14035; and XPO5 rs34324334, rs2257082, rs11544382, and rs11077) by polymerase chain reaction–restriction fragment length polymorphism analysis. Differences in genotype frequencies between patients and controls were compared, and odds ratios (ORs) and 95% CIs were determined as measures of the strength of the association between genotype and POI. Results Of the nine SNPs, XPO5 rs34324334 and rs11544382 were monomorphic and were not analyzed further. The XPO5 rs2257082 CT and CT + TT variant genotypes were more frequent in patients (OR, 2.097; 95% CI, 1.207-3.645) than in controls (OR, 2.030; 95% CI, 1.196-3.445). The combined frequencies of XPO5 rs2257082 CT + TT and rs11077 AC + CC genotypes were higher in patients than in controls (OR, 2.526; 95% CI, 1.088-5.865). An association of POI risk with other polymorphisms was not found. A haplotype-based analysis of seven polymorphisms of the microRNA machinery genes for gene-gene interactions suggests that ***ACTA, ***GCCA, ***G*C*, *T*ATTA, and ***ACT* haplotypes (asterisk indicates SNP locus not included; DROSHA rs6877842 and rs10719, DICER1 rs13078 and rs3742330, RAN rs14035, and XPO5 rs2257082 and rs11077 polymorphisms) are associated with higher POI prevalence, and that ***GCTA, ***ACCA, *C*ATTA, and *C*ATT* haplotypes are associated with lower POI prevalence. Conclusions Our data demonstrate that the XPO5 rs2257082 T variant allele occurs more frequently in POI patients than in controls, suggesting that this allele may be associated with increased POI risk.

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

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.

Solute Carrier Family 19, Member 1 (SLC19A1) Polymorphisms (−43T>C, 80G>A, and 696C>T), and Haplotypes in Idiopathic Recurrent Spontaneous Abortion in a Korean Population

The objective was to investigate the association between idiopathic recurrent spontaneous abortion (RSA) and 3 SLC19A1 polymorphisms (−43T>C, 80G>A, and 696C>T). DNA from 269 patients with RSA and 125 controls were genotyped for the 3 SLC19A1 single nucleotide polymorphisms (SNPs) by polymerase chain reaction–restriction fragment length polymorphism. Homocysteine and folate levels of 100 patients with RSA were available for analysis. The combination genotypes of SLC19A1 −43TC/80GG, −43TC/80AA, and −43CC/80GA; 80GA/696TT, 80AA/696CC; and −43TC/696CC were less frequent in patients with RSA compared to controls (P < .05 for each). The −43C/80A/696 T and −43T/80G/696C haplotypes were more frequent in patients than controls, whereas −43T/80A/696C, −43C/80A/696C, −43C/80G/696C, −43C/80G/696T, and −43T/80G/696T haplotypes were less frequent in patients (P < .05 for each). The −43T/80G and 80A/696T haplotypes were more frequent in patients, while −43T/80A, −43C/80G, 80A/696C, 80G/696T, and −43C/696C haplotypes occurred less frequently in patients (P < .05 for each). The associations between idiopathic RSA occurrence and SLC19A1 −43T>C/80G>A/696C>T polymorphisms were identified and can be developed as biomarkers for RSA risk.

Association of methylenetetrahydrofolate reductase (MTHFR 677C>T) and thymidylate synthase (TSER and TS 1494del6) polymorphisms with premature ovarian failure in Korean women.

ObjectiveThe aim of our study was to investigate whether methylenetetrahydrofolate reductase (MTHFR) gene variant (MTHFR 677C>T) and thymidylate synthase (TS) gene variants (TS enhancer region [TSER] and TS 1494del6) confer a risk for premature ovarian failure (POF). MethodsWe genotyped 136 POF patients and 236 controls among Korean women for the three single nucleotide polymorphism sites using polymerase chain reaction restriction fragment length polymorphism analysis. Differences in the MTHFR 677C>T, TSER, and TS 1494del6 genotype frequencies between POF patients and controls were compared, and odds ratios (ORs) and 95% CIs were determined as a measure of the strength of the association between genotypes and POF. ResultsThe MTHFR 677CT and CT + TT variant genotypes were more frequent in POF patients than in controls (OR, 2.249; 95% CI, 1.317-3.843; and OR, 2.132; 95% CI, 1.268-3.585, respectively). The combined genotype frequencies of MTHFR 677CT + TT/TSER 3R3R and 677CT + TT/TS 1494del6 del6/del6 were higher in patients than in controls (OR, 2.300; 95% CI, 1.219-4.337; and OR, 3.314; 95% CI, 1.623-6.767, respectively). The T-3R-del6 and T-2R-del6 (MTHFR 677C>T/TSER/TS 1494del6) haplotypes were more frequent in patients (OR, 1.450; 95% CI, 1.050-2.002; and OR, 2.911; 95% CI, 1.191-7.117, respectively), whereas the C-2R-del6 haplotype was less frequent in patients (OR, 0.372; 95% CI, 0.152-0.912). The T-del6 (MTHFR 677/TS 1494del6) haplotype frequency was higher among patients (OR, 1.653; 95% CI, 1.206-2.266), whereas the C-del6 haplotype frequency was lower among patients (OR, 0.700; 95% CI, 0.516-0.950). We did not find an association between TSER or TS 1494del6 polymorphisms and POF. ConclusionsOur data suggest that the MTHFR 677T allele may increase the risk for POF, which could lead to the development of novel genetic markers for predicting the risk of POF in patients.

The reduced folate carrier-1 ( RFC1 696T>C) polymorphism is associated with spontaneously aborted embryos in Koreans

The major cause of early spontaneous abortion is believed to be chromosomal abnormality. However, the genetic etiologies of spontaneous abortion are still unknown. A central feature of fetal development is widespread rapid cell division. Due to its role in DNA synthesis, the need for folate increases during periods of rapid fetal growth. Folate transport across cell membranes is mediated by reduced folate carrier-1 (RFC1). Variants within SLC19A1 may influence folate and homocysteine concentrations. The aim of this study was to investigate the association of RFC1 mutations with spontaneous abortion in aborted embryos. We studied 115 spontaneously aborted embryos at <20 weeks of gestational age, 102 child controls, and 353 adult controls. The genotype frequencies of RFC1 polymorphisms, 80A>G and 696T>C, in spontaneously aborted embryos were measured. The RFC1 696T>C mutation was significantly increased in spontaneously aborted embryos compared to child controls. Further studies will be required to examine the functional significance of the RFC1 696T>C polymorphism.

Vascular Endothelial Growth Factor Gene Polymorphisms in Spontaneously Aborted Fetuses

Citation Jeon YJ, Kim JH, Rah HC, Kim SY, Yoon TK, Choi DH, Cha SH, Shim SH, Kim NK. Vascular endothelial growth factor gene polymorphisms in spontaneously aborted fetuses. Am J Reprod Immunol 2011; 66: 544–553

Transcobalamin II (TCN2 67A>G and TCN2 776C>G) and Transcobalamin II Receptor (TCblR 1104C>T) Polymorphisms in Korean Patients with Idiopathic Recurrent Spontaneous Abortion

The transcobalamin II (TCN2) 776C>G polymorphism has been reported to be a genetic risk factor for idiopathic recurrent spontaneous abortion (RSA). However, the sample size in previous studies was small, and other TCN2 polymorphisms have not been studied. Moreover, the TCN2 67A>G and 776C>G polymorphisms, and the transcobalamin II receptor (TCblR/CD320) 1104C>T polymorphism, have demonstrated associations with immune responses.