Association between PAI-1 Polymorphisms and Ischemic Stroke in a South Korean Case-Control Cohort.

Stroke is the second leading cause of death in the world. Approximately 80% of strokes are ischemic in origin. Many risk factors have been linked to stroke, including an increased level of plasminogen activator inhibitor-1 (PAI-1). PAI-1 levels increase and remain elevated in blood during the acute phase of ischemic stroke, which can impair fibrinolytic activity, leading to coronary artery disease and arterial thrombotic disorders. Here, we present a case-control study of 574 stroke patients and 425 controls seen for routine health examination or treatment for nonspecific dizziness, nonorganic headache, or anxiety for positive family history of stroke at the Bundang Medical Center in South Korea. Polymorphisms in PAI-1 were identified by polymerase chain reaction/restriction fragment length polymorphism analysis using genomic DNA. Specifically, three variations (-675 4G>5G, 10692T>C, and 12068G>A) were linked to a higher overall prevalence of stroke as well as a higher prevalence of certain stroke subtypes. Haplotype analyses also revealed combinations of these variations (-844G>A, -675 4G>5G, 43G>A, 9785A>G, 10692T>C, 11053T>G, and 12068G>A) that were significantly associated with a higher prevalence of ischemic stroke. To the best of our knowledge, this is the first strong evidence that polymorphic sites in PAI-1 promoter and 3'-UTR regions are associated with higher ischemic stroke risk. Furthermore, the PAI-1 genotypes and haplotypes identified here have potential as clinical biomarkers of ischemic stroke and could improve the prognosis and future management of stroke patients.

Genetic Polymorphisms in miR-604A>G, miR-938G>A, miR-1302-3C>T and the Risk of Idiopathic Recurrent Pregnancy Loss.

The purpose of this study was to investigate whether polymorphisms in five microRNAs (miRNAs), miR-604A>G, miR-608C>G, 631I/D, miR-938G>A, and miR-1302-3C>T, are associated with the risk of idiopathic recurrent pregnancy loss (RPL). Blood samples were collected from 388 patients with idiopathic RPL (at least two consecutive spontaneous abortions) and 227 control participants. We found the miR-604 AG and AG + GG genotypes of miR-604, the miR-938 GA and GA + AA genotypes of miR-938, and the miR-1302-3CT and CT + TT genotypes of miR-1302-3 are less frequent than the wild-type (WT) genotypes, miR-604AA, miR-938GG, and miR-1302-3CC, respectively, in RPL patients. Using allele-combination multifactor dimensionality reduction (MDR) analysis, we found that eight haplotypes conferred by the miR-604/miR-608/miR-631/miR-938/miR-1302-3 allele combination, A-C-I-G-T, A-C-I-A-C, G-C-I-G-C, G-C-I-G-T, G-G-I-G-C, G-G-I-G-T, G-G-I-A-C, G-G-D-G-C, three from the miR-604/miR-631/miR-938/miR-1302-3 allele combination, A-I-G-T, G-I-G-C, G-I-A-T, one from the miR-604/miR-631/miR-1302-3 allele combination, G-I-C, and two from the miR-604/miR-1302-3 allele combination, G-C and G-T, were less frequent in RPL patients, suggesting protective effects (all p < 0.05). We also identified the miR-604A>G and miR-938G>A polymorphisms within the seed sequence of the mature miRNAs and aligned the seed sequences with the 3'UTR of putative target genes, methylenetetrahydrofolate reductase (MTHFR) and gonadotropin-releasing hormone receptor (GnRHR), respectively. We further found that the binding affinities between miR-604/miR-938 and the 3'UTR of their respective target genes (MTHFR, GnRHR) were significantly different for the common (miR-604A, miR-938G) and variant alleles (miR-604G, miR-938A). These results reveal a significant association between the miR-604A>G and miR-938G>A polymorphisms and idiopathic RPL and suggest that miRNAs can affect RPL in Korean women.

Distribution of Intracranial Major Artery Stenosis/Occlusion According to RNF213 Polymorphisms.

Intracranial major artery stenosis/occlusion (ICASO) is the major cause of ischemic stroke. Recent studies have suggested that variants of RNF213, a susceptibility gene for moyamoya disease (MMD), are also related to non-MMD ICASO. Regarding the predominant involvement of steno-occlusion on anterior circulation in MMD, we hypothesized that the ICASO distribution pattern (anterior/posterior) in non-MMD may differ according to RNF213 variants. This study analyzed 1024 consecutive Korean subjects without MMD who underwent computed tomography angiography (CTA) or magnetic resonance angiography (MRA). We evaluated four single nucleotide polymorphisms (SNPs) in the exon region of RNF213: 4448G > A (rs148731719), 4810G > A (rs112735431), 4863G > A (rs760732823), and 4950G > A (rs371441113). Associations between RNF213 variants and anterior/posterior ICASO were examined using multivariate logistic regression analysis. Anterior ICASO was present in 23.0% of study subjects, and posterior ICASO was present in 8.2%. The GA genotype of RNF213 4810G > A (adjusted odds ratio (AOR) [95% confidence interval (CI)], 2.39 [1.14-4.87] compared to GG; p = 0.018) and GA genotype of RNF213 4950G > A (AOR [95% CI], 1.71 [1.11-2.63] compared to GG; p = 0.015) were more frequent in subjects with anterior ICASO. The genotype frequency of RNF213 4863G > A differed significantly according to the presence of posterior ICASO. Further investigations of the functional and biological roles of RNF213 will improve our understanding of the pathomechanisms of ICASO and cerebrovascular disease.

Association between Five Common Plasminogen Activator Inhibitor-1 (PAI-1) Gene Polymorphisms and Colorectal Cancer Susceptibility.

The plasminogen activator inhibitor-1 (PAI-1) is expressed in many cancer cell types and modulates cancer growth, invasion, and angiogenesis. The present study investigated the association between five PAI-1 gene polymorphisms and colorectal cancer (CRC) risk. Five PAI-1 polymorphisms (-844G > A [rs2227631], -675 4G > 5G [rs1799889], +43G > A [rs6092], +9785G > A [rs2227694], and +11053T > G [rs7242]) were genotyped using a polymerase chain reaction-restriction fragment length polymorphism assay in 459 CRC cases and 416 controls. Increased CRC risk was more frequently associated with PAI-1 -675 5G5G polymorphism than with 4G4G (adjusted odds ratio (AOR) = 1.556; 95% confidence interval (CI): 1.012-2.391; p = 0.04). In contrast, for the PAI-1 +11053 polymorphism, we found a lower risk of CRC with the GG genotype (AOR = 0.620; 95% CI: 0.413-0.932; p = 0.02) than with the TT genotype, as well as for recessive carriers (TT + TG vs. GG, AOR = 0.662; 95% CI: 0.469-0.933; p = 0.02). The +43AA genotype was associated with lower overall survival (OS) than the +43GG genotype. Our results suggest that the PAI-1 genotype plays a role in CRC risk. This is the first study to identify an association between five PAI-1 polymorphisms and CRC incidence worldwide.

The microRNApolymorphisms inmiR-150 and miR-1179 are associated with risk of idiopathic recurrent pregnancy loss.

RESEARCH QUESTION: Are single nucleotide polymorphisms of microRNAs (miRNAs) and risk of idiopathic recurrent pregnancy loss (RPL) associated? DESIGN: A total 375 patients with idiopathic RPL (age, mean ± standard deviation [SD] 33.02 ± 4.24 years; body mass index [BMI], mean ± SD, 21.57 ± 3.70 kg/m2) and 276 control participants (age, mean ± SD, 33.01 ± 5.27 years; BMI, mean ± SD, 21.58 ± 3.20) were recruited. Pregnancy loss was diagnosed using human chorionic gonadotrophin concentrations, ultrasonography and/or physical examination prior to 20 weeks of gestation. The genotype of the participants was determined by polymerase chain reaction restriction fragment length polymorphism analysis. Statistical analysis was performed to investigate the differences in frequencies between the control and RPL genotypes RESULTS: The miR-150G>A heterozygous genotype was significantly associated with increased risk of RPL (adjusted odds ratio 2.502, 95% confidence interval 1.555-4.025; P = 0.0002). The miR-1179A>T heterozygous genotype was significantly associated with decreased risk of RPL (adjusted odds ratio 0.633, 95% confidence interval 0.454-0.884; P = 0.007). Some allele combinations that included miR-150A or miRNA-1179T resulted in an increase or decrease in risk of RPL, respectively. CONCLUSIONS: The miR-150G>A and miR-1179A>T polymorphisms were more frequently associated with RPL compared with controls.

Association study of miR-146a, miR-149, miR-196a2, and miR-499 polymorphisms with venous thromboembolism in a Korean population.

Despite much progress in microRNA (miRNA) research, information regarding the association between miRNAs and venous thromboembolism (VTE), especially in Asian patients, remains limited. This case-control study sought to determine the correlation between the presence of polymorphisms in the genes encoding the miRNAs miR-146a, miR-149, miR-196a2, miR-499, and VTE in Korean patients. We observed no statistically significant differences in the genotype frequency of miRNA polymorphisms between 300 control individuals and 203 VTE patients. However, we observed a significant association between three allelic combinations of miRNA polymorphisms and VTE risk. Overall, our findings suggest that specific miRNA polymorphisms are associated with the risk of VTE in a Korean population.

Genetic polymorphisms of the cobalamin transport system are associated with idiopathic recurrent implantation failure.

PURPOSE: Vitamin B12 (cobalamin, Cbl) plays a role in the recycling of folate, which is important in pregnancy. Transcobalamin II (TCN2) and transcobalamin receptor (TCblR) proteins are involved in the cellular uptake of Cbl. TCN2 binds Cbl in the plasma, and TCblR binds TCN2-Cbl at the cell surface. Therefore, we investigated the potential association between polymorphisms in Cbl transport proteins, TCN2 and TCblR, and recurrent implantation failure (RIF) susceptibility. METHODS: The genotypes of TCN2 67A>G, TCN2 776C>G, and TCblR 1104C>T were determined for RIF patients and healthy controls using a polymerase chain reaction restriction fragment length polymorphism assay. Additionally, statistical analysis was performed to compare the genotype frequencies between RIF patients and controls. RESULTS: The TCN2 67 polymorphism AG type was associated with RIF risk. Some allele combinations that contained the TCN2 67 polymorphism G allele were associated with increased RIF risk, whereas other allele combinations that contained the TCblR 1104 polymorphism T alleles were associated with decreased RIF risk. In genotype combination analysis, two combinations containing the TCN2 67 polymorphism AG type were associated with RIF risk. CONCLUSION: Our study showed that the polymorphisms of TCN2 and TCblR are associated with RIF and are potential genetic predisposing factors for RIF among Korean women. Additionally, our findings support a potential role for TCN2 and TCblR in RIF among Korean women. However, further studies are required to investigate the role of the polymorphisms in those proteins and RIF because the roles of the TCN2 and TCblR polymorphisms in RIF are not clear.

3'-UTR Polymorphisms in the Vascular Endothelial Growth Factor Gene (VEGF) Contribute to Susceptibility to Recurrent Pregnancy Loss (RPL).

Numerous studies have examined the genetic association of vascular endothelial growth factor (VEGF) single nucleotide polymorphisms (SNPs) with recurrent pregnancy loss (RPL). However, of the four known SNPs in the 3'-untranslated region (3'-UTR) of VEGF, three SNPs-namely rs3025040 (1451C>T), rs10434 (1612G>A), and rs3025053 (1725G>A)-remain poorly characterized with regard to RPL. Herein, we evaluated the association between these three SNPs in the VEGF 3'-UTR and RPL susceptibility. We analyzed VEGF 3'-UTR gene variants in with and without RPL using TaqMan allelic discrimination. There were significant differences in the genotype frequencies of 1612G>A (GA: adjusted odds ratio (AOR), 0.652; 95% confidence interval (CI), 0.447-0.951; p = 0.026) and 1725G>A (GA: AOR, 0.503; 95% CI, 0.229-0.848; p = 0.010) in RPL patients vs. controls. Our results indicate that the 1612G>A and 1725G>A polymorphisms in the 3'-UTR of VEGF are associated with RPL susceptibility in Korean women. These data suggest that VEGF 3'-UTR polymorphisms may be utilized as biomarkers for the detection of RPL risk and prevention.

Association of genetic polymorphisms in VEGF -460, -7 and -583 and hematocrit level with the development of idiopathic recurrent pregnancy loss and a meta-analysis.

BACKGROUND: The present study was performed to investigate whether genetic variants of VEGF are associated with recurrent pregnancy loss (RPL) in Korean women and to provide insight into the role of VEGF in the pathogenesis of RPL development. METHODS: A cohort of 384 women with idiopathic RPL with a history of two or more uxexplained consecutive early pregnancy losses and 236 control women were recruited from an infertility center of university-teaching hospital in Korea between March 1999 and February 2010. We examined three VEGF polymorphisms (rs833061, rs3025020 and rs25648). Genotyping was assessed by polymerase chain reaction (PCR)-restriction fragment length polymorphism analyses (rs3025020) or real-time PCR (rs833061, rs25648). RESULTS: There was no statistically significant difference in frequency of each three VEGF polymorphic loci between the control and RPL groups. Allele combinations of VEGF rs3025020/rs833061 TT/TC and TT/TC + CC genotypes were associated with an increased frequency of RPL development [odds ratio (OR) = 3.525, 95% confidence interval (CI) = 1.154-10.767, p = 0.027 and OR = 3.815, 95% CI = 1.256-11.588, p = 0.018, respectively]. Haplotype analysis revealed that two allele combinations (rs833061/rs3025020 C-T and rs25648/rs3025020 T-T) were associated with an increased prevalence of RPL (OR = 2.548, 95% CI = 1.502-4.320, p = 0.0004 and OR = 16.50, 95% CI = 0.976-278.8, p = 0.003, respectively). Allele combinations and haplotypes of rs3025020/rs833061 were associated with maternal blood hematocrit (HCT) levels in the RPL group (p = 0.048 and 0.006, respectively). CONCLUSIONS: The VEGF rs833061/rs3025020 genotype allele was related to the development of RPL and was also associated with maternal blood HCT levels in RPL patients. However, further studies are needed to clarify the exact mechanism of how VEGF and HCT are involved in RPL development.

Association of miR-938G>A Polymorphisms with Primary Ovarian Insufficiency (POI)-Related Gene Expression.

MicroRNAs (miRNAs) post-transcriptionally regulate gene expression in animals and plants. The aim of this study was to investigate whether polymorphisms in miR-938 are associated with the risk of primary ovarian insufficiency (POI) and POI-related target gene regulation. We identified the miR-938G>A polymorphisms within the seed sequence of mature miRNA and aligned the seed sequence with the 3' untranslated region (UTR) of the gonadotropin-releasing hormone receptor (GnRHR) mRNA, a miR-938 target gene. We found that the binding of miR-938 to the 3'-UTR of GnRHR mRNA was significantly different between normal and variant alleles. Our data suggests that the dysregulation of miR-938G>A influences the binding to GnRHR and that miR-938G>A polymorphisms might contribute to regulation of POI-related target genes.

The Role of RNF213 4810G>A and 4950G>A Variants in Patients with Moyamoya Disease in Korea.

Although a founder variant of RNF213 4810G>A is a major genetic risk factor for moyamoya disease (MMD) in East Asians, the frequency and disease susceptibility of RNF213 variants remain largely unknown. This study investigated the mutation analysis of RNF213 (4448, 4810, 4863, and 4950) between Korean MMD and healthy controls. We performed a polymerase chain reaction-restriction fragment length polymorphism analysis. To identify the association between RNF213 gene polymorphisms and MMD disease, we performed statistical analyses such as multivariable logistic regression and Fisher's exact test. Genetic data from 117 MMD patients were analyzed and compared with 253 healthy controls. We assessed and compared single nucleotide polymorphisms of RNF213 (4448, 4810, 4863, and 4950) between MMD and control groups. We performed genome-wide association studies to investigate the genetic pathophysiology of MMD. Among the RNF213 variants (4448G>A, 4810G>A, 4863G>A, and 4950G>A), RNF213 4810G>A and 4950G>A variants were more frequent in MMD patients. In a subgroup analysis, the RNF213 4810G>A was more frequent in moyamoya disease, and the comparison with GG+AA genotype was also significantly different in moyamoya patients. These results confirm that RNF213 4810G>A and RNF213 4950G>A were more frequent in MMD patients. We have confirmed that RNF213 4810G>A and 4950G>A are strongly associated with Korean MMD in children and adults as well as for the ischemic and hemorrhagic types.

miR-665-Mediated Regulation of AHCYL2 and BVES Genes in Recurrent Implantation Failure.

The primary goal of this investigation was to identify mRNA targets affected by dysregulated miRNAs in RIF. This was accomplished by comprehensively analyzing mRNA and miRNA expression profiles in two groups: female subjects with normal reproductive function (control, n = 5) and female subjects experiencing recurrent implantation failure (RIF, n = 5). We conducted transcriptome sequencing and small RNA sequencing on endometrial tissue samples from these cohorts. Subsequently, we validated a selection of intriguing findings using real-time PCR with samples from the same cohort. In total, our analysis revealed that 929 mRNAs exhibited differential expression patterns between the control and RIF patient groups. Notably, our investigation confirmed the significant involvement of dysregulated genes in the context of RIF. Furthermore, we uncovered promising correlation patterns within these mRNA/miRNA pairs. Functional categorization of these miRNA/mRNA pairs highlighted that the differentially expressed genes were predominantly associated with processes such as angiogenesis and cell adhesion. We identified new target genes that are regulated by miR-665, including Blood Vessel Epicardial Substance (BVES) and Adenosylhomocysteinase like 2 (AHCYL2). Our findings suggest that abnormal regulation of genes involved in angiogenesis and cell adhesion, including BVES and AHCYL2, contributes to the endometrial dysfunction observed in women with recurrent implantation failure (RIF) compared to healthy women.

Genetic Variations miR-10aA>T, miR-30cA>G, miR-181aT>C, and miR-499bA>G and the Risk of Recurrent Pregnancy Loss in Korean Women

This study investigated the genetic association between recurrent pregnancy loss (RPL) and microRNA (miRNA) polymorphisms in miR-10aA>T, miR-30cA>G, miR-181aT>C, and miR-499bA>G in Korean women. Blood samples were collected from 381 RPL patients and 281 control participants, and genotyping of miR-10aA>T, miR-30cA>G, miR-181aT>C, and miR-499bA>G was carried out by TaqMan miRNA RT-Real Time polymerase chain reaction (PCR). Four polymorphisms were identified, including miR-10aA>T, miR-30cA>G, miR-181aT>C, and miR-499bA>G. MiR-10a dominant model (AA vs. AT + TT) and miR-499bGG genotypes were associated with increased RPL risk (adjusted odds ratio [AOR] = 1.520, 95% confidence interval [CI] = 1.038−2.227, p = 0.032; AOR = 2.956, 95% CI = 1.168−7.482, p = 0.022, respectively). Additionally, both miR-499 dominant (AA vs. AG + GG) and recessive (AA + AG vs. GG) models were significantly associated with increased RPL risk (AOR = 1.465, 95% CI = 1.062−2.020, p = 0.020; AOR = 2.677, 95% CI = 1.066−6.725, p = 0.036, respectively). We further propose that miR-10aA>T, miR-30cA>G, and miR-499bA>G polymorphisms effects could contribute to RPL and should be considered during RPL patient evaluation.

Association of methionine synthase (rs1805087), methionine synthase reductase (rs1801394), and methylenetetrahydrofolate dehydrogenase 1 (rs2236225) genetic polymorphisms with recurrent implantation failure.

One-carbon metabolism, in which folate plays an essential role, is important for maintaining pregnancy and foetal development. Here, polymorphisms in three genes involved in the methylation of homocysteine were examined: methionine synthase (MTR), methionine synthase reductase (MTRR), and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), each of which is involved in methionine metabolism, a component of the one-carbon metabolism process. This involved a case-control study of 343 Korean women: 118 patients with RIF and 225 controls with at least one live birth and no history of pregnancy loss. The MTHFD1 1958GA genotype was observed less frequently than the MTHFD1 1958GG genotype (IF ≥ 4, p = 0.015) in women with RIF. In addition, the MTRR 66A > G polymorphism was associated with increased plasma homocysteine levels (p = 0.019). Based on these results, we propose that the MTRR 66A > G and MTHFD1 1958G > A polymorphisms are predisposing factors for RIF development. This study is the first to examine a potential association between the MTHFD1 and MTRR polymorphisms and RIF susceptibility in Korean patients.

3'-UTR Polymorphisms in Thymidylate Synthase with Colorectal Cancer Prevalence and Prognosis.

Colorectal cancer (CRC) is the third most common type of cancer and the second leading cause of cancer-related mortality in Western countries. Polymorphisms in one-carbon metabolism and angiogenesis-related genes have been shown to play important roles in tumor development, progression, and metastasis for many cancers, including CRC. Moreover, recent studies have reported that polymorphisms in specific microRNA (miRNA)-binding regions, which are located in the 3'-untranslated region (UTR) of miRNA-regulated genes, are present in a variety of cancers. Here, we investigated the association between two thymidylate synthase (TYMS or TS) 3'-UTR polymorphisms, 1100T>C [rs699517] and 1170A>G [rs2790], and CRC susceptibility and progression in Korean patients. A total of 450 CRC patients and 400 healthy controls were enrolled in this study, and genotyping at the TS locus was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or TaqMan allelic discrimination assays. We found that TS 1170A>G genotypes, as well as the TS 1100T-1170G and 1100C-1170A haplotypes, are strongly associated with CRC. The TS 1100TC+CC type was associated with a poor survival (OS and RFS) rate. In addition, levels of the TS 1100C and TS 1170G allele were found to be significantly increased in CRC tissue. Our study provides the first evidence for 3'-UTR variants in TS genes as potential biomarkers of CRC prognosis and prevention.

Associations between HOTAIR polymorphisms rs4759314, rs920778, rs1899663, and rs7958904 and risk of primary ovarian insufficiency in Korean women.

BACKGROUND: We investigated the association between the Hox transcript antisense RNA (HOTAIR) polymorphisms rs4759314, rs920778, rs1899663, and rs7958904 and primary ovarian insufficiency (POI) in Korean women. METHODS: We conducted a case-control study of 134 Korean women with POI and 383 control individuals with at least one live birth and no history of pregnancy loss. RESULTS: The GT genotype of rs1899663 was associated with a decreased risk of POI compared with other genotypes at that locus. In addition, compared with the wild-type homozygous genotypes, the combination of the AA genotype of rs4759314 and the GC genotype of rs7958904 was associated with a decreased risk of POI (P < 0.05), whereas the combination of the GG genotype of rs1899663 and the GC genotype of rs7958904 was associated with an increased risk of POI (P = 0.003). Haplotype analysis revealed that certain haplotypes involving some or all of the polymorphisms were associated with a decreased risk of POI, whereas other haplotypes were associated with an increased risk of POI. Serum levels of luteinizing hormone, follicle-stimulating hormone, and estradiol differed between patients with POI and control individuals (P < 0.05). CONCLUSIONS: Our results suggest that the HOTAIR polymorphisms rs4759314, rs920778, rs1899663, and rs7958904 are involved in POI.

MiR-10a, 27a, 34b/c, and 300 Polymorphisms are Associated with Ischemic Stroke Susceptibility and Post-Stroke Mortality.

A recent study of the ischemic stroke described the roles played by miRNAs in the downregulation of specific cell-cycle gene expression and it is thought to require the development of biomarkers for the prognostic of ischemic stroke. Here, we hypothesized that four miRNA polymorphisms (miR-10a, miR-27a, miR-34b/c, and miR-300) may affect stroke susceptibility and mortality. Blood samples were collected from 530 patients and 403 controls. Genetic polymorphisms were detected by polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis and real-time PCR. We found that the miR-300 rs12894467 TC genotype and the dominant model (AOR: 2.069, p-value: 0.017; AOR: 1.931, p-value: 0.027) were significantly associated with an increased risk for the ischemic stroke subtype. In Cox proportional hazard regression models, the miR-10a rs3809783 A>T and miR-34b/c rs4938723 T>C polymorphisms were associated with the mortality rates among ischemic stroke patients. We found that a miR-300 polymorphism was associated with increased ischemic stroke susceptibility among the Korean population. Additionally, polymorphisms in miR-10a and miR-34b/c were associated with the increased or decreased mortality of ischemic stroke patients. This study marks the first report of an association between ischemic stroke and miRNA polymorphisms (miR-10aA>T, miR-27aT>C, miR-34b/cT>C, and miR-300T>C) in the Korean population.

Correction to: Association of miR-27aA > G, miR-423C > a, miR-449bA > G, and miR-604A > G Polymorphisms with Risk of Recurrent Implantation Failure.

The article should have been classified as an "Original Article," not a "Review Article."

Association of miR-27aA>G, miR-423C>a, miR-449bA>G, and miR-604A>G Polymorphisms with Risk of Recurrent Implantation Failure.

Recurrent implantation failure (RIF) is defined when pregnancy failure occurs after two consecutive in vitro fertilization-embryo transfers to the endometrium using at least four high-quality embryos in women. MicroRNAs are well-known function modulators and are involved in many diseases. Recently, studies on microRNA and recurrent pregnancy loss (RPL) have been actively carried out; however, single nucleotide polymorphisms of miRNA in RPL are not well known. Therefore, we set the aim of this study to identify whether polymorphisms in miRNAs that miR-27aA>G, miR-423C>A, miR-449bA>G, and miR-604A>G are risk factors for idiopathic recurrent implantation failure (RIF) in Korean women. Genotyping was assessed with a polymerase chain reaction-restriction fragment length polymorphism assay. We examined polymorphisms in four miRNA genes: miR-27aA>G, miR-423C>A, miR-449bA>G, and miR-604A>G. We found that the miR-27aA>G, miR-449bA>G, and miR-604A>G polymorphisms were significantly associated with a risk of RIF. In addition, the miR-27aA>G and miR-449bA>G polymorphisms were associated with the frequency of implantation failures. Specifically, the miR-449bAG+GG genotype was associated with RIF prevalence (total RIF: adjusted odd ratio [AOR] = 1.584, 95% CI = 1.008-2.490, P = 0.046; IF ≥ 3 group: AOR = 1.747, 95% CI = 1.088-2.803, P = 0.021; IF ≥ 4: AOR = 1.932, 95% CI = 1.122-3.327, P = 0.018). Based on these results, the miR-449b A>G may be a predisposing factor to RIF susceptibility. However, the mechanism underlying the function of miR-449b A>G in RIF remains to be determined and further studies are needed to improve understanding of the roles of miR-449b A>G, using a larger and more heterogeneous cohort.

3'-UTR Polymorphisms of Vitamin B-Related Genes Are Associated with Osteoporosis and Osteoporotic Vertebral Compression Fractures (OVCFs) in Postmenopausal Women.

As life expectancy increases, the prevalence of osteoporosis is increasing. In addition to vitamin D which is well established to have an association with osteoporosis, B vitamins, such as thiamine, folate (vitamin B9), and cobalamin (vitamin B12), could affect bone metabolism, bone quality, and fracture risk in humans by influencing homocysteine/folate metabolism. Despite the crucial role of B vitamins in bone metabolism, there are few studies regarding associations between B vitamin-related genes and osteoporosis. In this study, we investigated the genetic association of four single nucleotide polymorphisms (SNPs) within the 3'-untranslated regions of vitamin B-related genes, including TCN2 (encodes transcobalamin II), CD320 (encodes transcobalamin II receptor), SLC19A1 (encodes reduced folate carrier protein 1), and SLC19A2 (encodes thiamine carrier 1), with osteoporosis and osteoporotic vertebral compression fracture (OVCF). We recruited 301 postmenopausal women and performed genotyping of CD320 rs9426C>T,TCN2 rs10418C>T, SLC19A1 rs1051296G>T, and SLC19A2 rs16862199C>T using a polymerization chain reaction-restriction fragment length polymorphism assay. There was a significantly higher incidence of both osteoporosis (AOR 5.019; 95% CI, 1.533-16.430, p < 0.05) and OVCF (AOR, 5.760; 95% CI, 1.480-22.417, p < 0.05) in individuals with genotype CD320 CT+TT and high homocysteine concentrations. Allele combination analysis revealed that two combinations, namely CD320 C-TCN2 T-SLC19A1 T-SLC19A2 C (OR, 3.244; 95% CI, 1.478-7.120, p < 0.05) and CD320 T-TCN2 C-SLC19A1 G-SLC19A2 C (OR, 2.287; 95% CI, 1.094-4.782, p < 0.05), were significantly more frequent among the osteoporosis group. Our findings suggest that SNPs within the CD320 gene in 3´-UTR may contribute to osteoporosis and OVCF occurrences in some individuals. Furthermore, specific allele combinations of CD320, TCN2, SLC19A1, and SLC19A2 may contribute to increased susceptibility to osteoporosis and OVCF.