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Background: Primary ovarian insufficiency (POI) is one of the leading female infertility diseases in which ovarian function stops before the age of 40. Reports that POI is associated with transforming growth factor (TGF)-β/bone morphogenetic protein (BMP) signaling pathway–associated genes (e.g., TGF-β, and BMP15) have been continuous since publication that the TGF-β superfamily acts as important regulators for ovary and placenta function in humans. Mechanistically, the secretion of follicle-stimulating hormone, progesterone, and estrogen is affected by the TGF-β superfamily in granulosa cells, which are involved in the development of theca cells, oocytes, and granulosa cells. Objective: This study aimed to identify the association between genes related to the TGF-β/BMP signaling pathway and the risk of POI pathogenesis. Methods: Possible associations between six gene polymorphisms and POI susceptibility were examined in 139 patients with POI and 345 control subjects. Results: Allele combination of TGFBR1 rs334348 G > A and TGFBR3 rs1805110G > A exhibited association with decreased POI risk (adjusted odds ratio [AOR] = 0.165; 95% confidence interval [CI] 0.032–0.847; P = 0.031). Also, TGFBR1 rs1590 G > T and rs334348 G > A and TGFBR3 rs1805110 G > A allele combination exhibited association with decreased POI risk (OR = 0.553; 95% CI 0.374–0.816; P = 0.003). Conclusion: This study suggests that polymorphisms in the TGF-β signaling pathway genes can be useful biomarkers for POI diagnosis and treatment. [ABSTRACT FROM AUTHOR]

ApoE4 enhances Tau neurotoxicity and promotes the early onset of AD. Pretangle Tau in the noradrenergic locus coeruleus (LC) is the earliest detectable AD-like pathology in the human brain. However, a direct relationship between ApoE4 and Tau in the LC has not been identified. Here we show that ApoE4 selectively binds to the vesicular monoamine transporter 2 (VMAT2) and inhibits neurotransmitter uptake. The exclusion of norepinephrine (NE) from synaptic vesicles leads to its oxidation into the toxic metabolite 3,4-dihydroxyphenyl glycolaldehyde (DOPEGAL), which subsequently activates cleavage of Tau at N368 by asparagine endopeptidase (AEP) and triggers LC neurodegeneration. Our data reveal that ApoE4 boosts Tau neurotoxicity via VMAT2 inhibition, reduces hippocampal volume, and induces cognitive dysfunction in an AEP- and Tau N368-dependent manner, while conversely ApoE3 binds Tau and protects it from cleavage. Thus, ApoE4 exacerbates Tau neurotoxicity by increasing VMAT2 vesicle leakage and facilitating AEP-mediated Tau proteolytic cleavage in the LC via DOPEGAL. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Recurrent implantation failure (RIF) is diagnosed when pregnancy failure occurs after 2 consecutive in vitro fertilization–embryo transfers (IVF-ET) to the endometrium using at least 4 high-quality embryos. MicroRNAs (miRNAs) are a class of small noncoding RNA and reported to play an important role in cell proliferation as well as implantation process. Recently, it has been reported that miRNA can regulate RIF occurrence. So, we were to examine the association between the specific miRNA polymorphisms and RIF in Korean women. Genotyping was performed by polymerase chain reaction—restriction fragment length polymorphism (PCR-RFLP) assay to determine the frequency of the following polymorphisms: miR-605A>G, miR-608G>C, miR-631I>D, miR-938C>T, and miR-1302-3C>T. Our results demonstrate a decreased incidence of RIF in patients with the miR-1302-3C>T polymorphism (adjusted odds ratio [AOR], 0.234; 95% confidence interval [CI], 0.089-0.618; P = .003). Based on our allele combination analysis, the C-T (miR-938/miR-1302-3: OR = 0.259; 95% CI, 0.100-0.674; P = .003) allele was also associated with decreased RIF risk. From our interaction analysis with miR-1302-3, the miR-1302-3CC genotype (AOR = 43.332; 95% CI, 5.576-336.745) showed an association with RIF prevalence in participants with an activated partial thromboplastin time (aPTT) ≤22.6. We found that the miR-1302-3C>T polymorphism is significantly associated with RIF development in Korean women. Specifically, our study suggests that the T allele of miR-1302-3 may decrease the risk of RIF in Korean women. [ABSTRACT FROM AUTHOR]

This study was purposed to investigate whether genetic polymorphisms in the function of stop-gain are associated with a fetal or placental development play roles and a development of idiopathic recurrent pregnancy loss (RPL) in Korean females. Three stop-gain polymorphisms were selected using next-generation sequencing screening, which allows for the rigorous examination and discovery of previously uncharacterized stop-gain genes and stop-gain expression profiles. Accordingly, we investigated the association of stop-gain polymorphisms in Korean women with RPL. Three functional polymorphisms in the TAS2R46G>A (rs2708381), OR4C16G>A (rs1459101), and OR4X1A>T (rs10838851) genes were genotyped using polymerase chain reaction (PCR)—restriction fragment length polymorphism assays and real-time PCR analysis. We determined that the OR4C16G>A polymorphism was associated with idiopathic RPL in Korean women (Adjusted odds ratio [AOR] 1.782; 95% confidence interval [CI] 1.004-3.163; P = 0.048, and AOR 1.766; 95% CI 1.020-3.059; P = 0.042). In addition, the prevalence of RPL was increased in women with the OR4C16GA + AA genotype and blood coagulation measures of prothrombin time (PT) > 10.4 s (AOR 8.292; 95% CI 2.744-25.054). We suggest that the OR4C16G>A polymorphism might serve as a clinically useful biomarker for the development, prevention, and prognosis of RPL. [ABSTRACT FROM AUTHOR]

The article should have been classified as an "Original Article," not a "Review Article." [ABSTRACT FROM AUTHOR]

An Argonaute (AGO) protein within the RNA-induced silencing complex binds a microRNA, permitting the target mRNA to be silenced. We hypothesized that variations in AGO genes had the possibility including affected the miRNA function and associated with recurrent pregnancy loss (RPL) susceptibility. Especially, we were chosen the AGO1 (rs595961, rs636832) and AGO2 (rs2292779, rs4961280) polymorphisms because of those polymorphisms have already reported in other diseases excluding the RPL. Here, we conducted a case-control study (385 RPL patients and 246 controls) to evaluate the association of four polymorphisms with RPL. We found that the AGO1 rs595961 AA genotype, recessive model (P = 0.039; P = 0.043, respectively), the AGO1 rs636832 GG genotype, and recessive model (P = 0.037; P = 0.016, respectively) were associated with RPL in women who had had four or more consecutive pregnancy losses. The patients with the AGO1 rs636832 GG genotypes had greater platelet counts (P = 0.023), while the patients with the AGO2 rs4961280 CA genotypes had less homocysteine (P = 0.027). Based on these results, we propose that genetic variations with respect to the AGO1 and AGO2 genotypes are associated with risk for RPL, and might serve as useful biomarkers for the prognosis of RPL. [ABSTRACT FROM AUTHOR]