Risk Of Recurrent Miscarriage Research Articles

Association between cytokine polymorphisms and recurrent pregnancy loss: A review of current evidence.

Cytokines are a type of protein that play an important role in the immune response and can also affect many physiological processes in the body. Cytokine polymorphisms refer to genetic variations or mutations that occur within the genes that code for cytokines, which may affect the level of cytokine production and function. Some cytokine polymorphisms have been associated with an increased risk of developing certain diseases, while others may be protective or have no significant effect on health. In recent years, the role of cytokine polymorphisms in the development of recurrent pregnancy loss (RPL) has been studied. RPL or miscarriage is defined as the occurrence of two or more consecutive pregnancy losses before the 20th week of gestation. There are diverse causes leading to RPL, including genetic, anatomical, hormonal, and immunological factors. With regard to cytokine polymorphisms, a few of them have been found to be associated with an increased risk of RPL, for instance, variations in the genes that code for interleukin-6, tumor necrosis factor-alpha, and interleukin-10. The exact mechanisms by which cytokine polymorphisms affect the risk of recurrent miscarriage are still being studied, and further research is essential to fully understand this complex condition. This brief review aims to summarize the recent literature on the association between cytokine polymorphisms and RPL.

HLA-G rs1063320 Polymorphism with the incidence of Recurrent Spontaneous Abortion (RSA) in Iraqi Women

Recurrent spontaneous abortion is a serious complication of pregnancy caused by multiple factors. This study examined whether serum HLA-G concentrations and the HLA-G (rs1063320) SNP were associated with RSA risk. Control 48 healthy females and 48 other with idiopathic RSA were included. By using an ELISA kit for human leukocyte antigen G, the quantity of HLA-G was quantified. HLA-G serum level was 27.26 ± 0.4U/mL and 16.52 ± 0.9 U/mL in women with RSA and apparently healthy women respectively. By employing RT-PCR and the TaqMan genotyping assay, the genotypes were identified. The findings revealed significant distinction in the concentration of HLA-G between apparently healthy as compared with the RSA women. The frequency of allele G was 0.26 and 0.20 in RSA women and control respectively whilst the frequency of allele C was 0.74 and 0.80 in RSA women and control respectively indicating no statistically variations in GG, GC, CC genotype frequency rate distribution and allele frequencies among the studies groups. In conclusion, the genotypes of rs1063320 are not associated with the risk of RSA.

The Effects of PON1 (Q192R, rs662) Gene Polymorphism, Heavy metals and Oxidative Stress on Risk of Recurrent Spontaneous Abortion in Samples of Iraqi Women

Recurrent spontaneous abortion (RSA) is defined as the occurrence of two or more spontaneous pregnancy losses before reaching the midpoint of gestation. Oxidative stress plays a pivotal role in the pathogenesis of RSA, serving as a key factor in its underlying causes. This research aims to investigate the connection between the Q192R polymorphisms identified in the PON1 gene, responsible for encoding an antioxidant enzyme and the vulnerability to RSA. Paraoxonase 1 (PON1) is a critical enzyme in the body's antioxidant defence system, safeguarding cells against damage caused by reactive oxygen species and heavy metal concentrations that affect pregnancy. The most prevalent PON1 polymorphism is Q192R (rs662), known to influence the antioxidant activity and power of the PON1 enzyme. In this research, blood samples were collected from two groups: 50 women with RSA and 50 women who were apparently in good health. Following DNA extraction, high-resolution melting (HRM) analysis was used to identify the studied SNP; Elisa was used to determine DNA damage and MDA concentrations in serum and heavy metals were determined by a Graphite Furnace-Atomic Absorption Spectrophotometer (GFAAS). The results of this study showed significantly higher levels of 8-OHdG, MDA, arsenic and lead in serum in RSA patients than in apparently healthy women. The genotype findings indicated that the prevalence of the QR (AG) genotype in women experiencing recurrent spontaneous abortion was notably greater than that in seemingly healthy women (74% compared to 16%, respectively, with an odds ratio of 27.2). The values of allele frequency for the A allele were 0.76 and 0.51 for apparently healthy women and women with recurrent spontaneous abortion respectively. The G allele frequency was 0.24 and 0.49 for apparently healthy women and women with recurrent spontaneous abortion respectively. The heterozygous QR genotype is related to the risk of RSA and the minor allele (G allele) is increased in women with RSA.

Association between Mir-499, Mir-27a, and Mir-146a polymorphisms and their susceptibility to recurrent spontaneous abortion; in silico analysis.

Recurrent spontaneous abortion (RSA) is defined as two or more pregnancy losses before 24 gestational weeks, accounting for 1-3% of fertile couples. A vast majority of single-nucleotide polymorphisms (SNPs) in some microRNA (miRNA) genes can change the miRNA-mRNA interaction and are associated with the risk of RSA. This study was designed to better elucidate the association between miR-27a, miR-499, and miR-146a polymorphisms and RSA risk. SNP genotyping of miR-27a (rs895819), miR-499 (rs3746444), and miR-146a (rs2910164) was performed using polymerase chain reaction (PCR)-restriction fragment length polymorphism and tetra amplification-refractory mutation system PCR in 98 patients with RSA and 105 healthy subjects. Our results showed that the miR-499 rs3746444 and miR-27a rs895819 polymorphisms were significantly associated with RSA risk, whereas no significant differences were observed between the rs2910164 polymorphism and RSA susceptibility. We proposed that the miR-499 rs3746444 and miR-27a rs895819 polymorphisms were correlated with RSA in our population, but the miR-146a rs2910164 variant was not associated with the risk of RSA.

Preimplantation genetic testing in couples with balanced chromosome rearrangement: a four-year period real world retrospective cohort study

BackgroundCouples with balanced chromosome rearrangement (BCR) are at high risk of recurrent miscarriages or birth defects due to chromosomally abnormal embryos. This study aimed to provide real-world evidence of the euploidy rate of blastocysts from couples with BCR using preimplantation genetic testing (PGT) and to guide pretesting genetic counselling.MethodsA continuous four-year PGT data from couples with BCR were retrospectively analyzed. Biopsied trophectoderm cells were amplified using whole genome amplification, and next-generation sequencing was performed to detect the chromosomal numerical and segmental aberrations. Clinical data and molecular genetic testing results were analyzed and compared among the subgroups.ResultsA total of 1571 PGT cycles with 5942 blastocysts were performed chromosomal numerical and segmental aberrations detection during the four years. Of them, 1034 PGT cycles with 4129 blastocysts for BCR couples were included; 68.96% (713/1034) PGT cycles had transferable euploid embryos. The total euploidy rate of blastocysts in couples carrying the BCR was 35.29% (1457/4129). Couples with complex BCR had euploid blastocyst rates similar to those of couples with non-complex BCR (46.15% vs. 35.18%, P > 0.05). Chromosome inversion had the highest chance of obtaining a euploid blastocyst (57.27%), followed by Robertsonian translocation (RobT) (46.06%), and the lowest in reciprocal translocation (RecT) (30.11%) (P < 0.05). Couples with males carrying RobT had higher rates of euploid embryo both in each PGT cycles and total blastocysts than female RobT carriers did, despite the female age in male RobT is significant older than those with female RobT (P < 0.05). The proportions of non-carrier embryos were 52.78% (95/180) and 47.06% (40/85) in euploid blastocysts from couples with RecT and RobT, respectively (P > 0.05). RecT had the highest proportion of blastocysts with translocated chromosome-associated abnormalities (74.23%, 1527/2057), followed by RobT (54.60%, 273/500) and inversion (30.85%, 29/94) (P < 0.05).ConclusionsIn couples carrying BCR, the total euploidy rate of blastocysts was 35.29%, with the highest in inversion, followed by RobT and RecT. Even in couples carrying complex BCR, the probability of having a transferable blastocyst was 46.15%. Among the euploid blastocysts, the non-carrier ratios in RecT and RobT were 52.78% and 47.06%, respectively. RecT had the highest proportion of blastocysts with translocated chromosome-associated abnormalities.

Association of Genetic Polymorphisms in Long Noncoding RNA HOTTIP with Risk of Idiopathic Recurrent Spontaneous Abortion.

The clustered homeobox gene family known as the Hox family plays a fundamental role in the morphogenesis of the vertebrate's embryo. A long noncoding RNA (lncRNA), known as HOTTIP (HOXA transcript at the distal tip), has been functionally characterized and contributed to the pathogenesis of various conditions. The current case-control study was undertaken to examine the gene frequencies and shared alleles of the HOTTIP gene in Iranian participants with or without idiopathic recurrent spontaneous abortion (RSA). Both ARMS-PCR reaction and RFLP-PCR techniques were employed to detect three HOTTIP polymorphisms (rs2023843C/T, rs78248039A/T, and rs1859168C/A) in a DNA sample of 161 women with RSA and 177 healthy women. We found that the TT genotype of the HOTTIP rs2023843 C/T polymorphism was associated with a lower risk for idiopathic RSA. In contrast, the TT genotype of the HOTTIP rs78248039 A/T polymorphism was correlated with an enhanced risk of RSA. The presence of the A-allele for HOTTIP rs1859168 C/A polymorphism was associated with an increased risk for idiopathic RSA. Haplotype analysis showed that the T/T/A, C/T/A, T/T/C, and T/A/A haplotypes of rs2023843/rs78248039/rs1859168 enhanced RSA susceptibility. Computational analysis predicted that this lncRNA might act as a potential sponge for some microRNAs; therefore, affecting the expression of genes being targeted by them. In addition, both rs2023843 and rs1859168 variants could alter the local secondary structure of HOTTIP. Our results showed that HOTTIP rs2023843C/T, rs78248039A/T, and rs1859168C/A polymorphisms may confer genetic susceptibility to idiopathic RSA in an Iranian population.

CD24+ decidual stromal cells: a novel heterogeneous population with impaired regulatory T cell induction and potential association with recurrent miscarriage

To explore the heterogeneity of CD24+ decidual stromal cells (DSCs) in patients with recurrent miscarriages (RMs). We have discerned that the expression of CD24 serves to differentiate two stable and functionally distinct lineages of DSCs. The heterogeneity of CD24+ DSCs has been scrutinized, encompassing variances in stromal markers, transcriptional profiles, metabolic activity, and immune regulation. Department of Reproductive Immunology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University; Shanghai Institute of Immunity and Infection, Chinese Academy of Science. A total of 129 early decidual samples were obtained, comprising 36 from healthy donors and 93 from patients with RMs. Blood samples were collected before the surgical procedure. Paraffin-embedded segments from 20 decidual samples of patients with RMs were obtained. None. The flow cytometry was used to quantify the expression of CD24+ DSCs in both healthy donors and patients with RMs, although it also evaluated the cellular heterogeneity. To ascertain the transcriptomic profiles of CD24+ DSCs by reanalyzing our single-cell transcriptomic data. Additionally, to measure the metabolomic activity of CD24+ DSCs from patients with RMs, ultraperformance liquid chromatography-mass spectrometry was employed. Through the implementation of a coculture system, we unraveled the role of CD24+ DSCs in immune regulation. Patients with RMs exhibit a notable enrichment of CD24+ DSCs, revealing a pronounced heterogeneity characterized by variations in stromal markers and transcriptional profiles. The heightened enrichment of CD24+ DSCs may play a pivotal role in triggering decidual inflammation and dysfunction in decidualization. Furthermore, CD24+ DSCs showed diverse metabolic activities and impeded the induction of naïve CD4+ T cells into regulatory T cells through the abundant secretion of 3-hydroxyisovaleric acid. Finally, our investigations have revealed that intraperitoneal administration of 3-hydroxyisovaleric acid in mouse models can elevate the risk of RM. We have successfully identified a disease-associated subset of CD24+ decidual stromal cells that could potentially contribute to the development of RM through the impairment of decidual immune tolerance. Targeting these specific CD24+ DSCs might hold promising prospects for therapeutic interventions in the clinical management of RM.

Platelet Glycoprotein Receptor Ia-C807T and IIIa-PlA1/PlA2 Genetic Polymorphisms Are Associated With Enhanced Platelet Function in Women With Recurrent Miscarriages.

Thrombophilic genetic polymorphisms of the platelet glycoproteins Ia (GpIa) and IIIa (GpIIIa) have been associated with an increased risk of recurrent miscarriages. The aim of this study was to investigate the association of genetic polymorphisms GpIa-C807T and GpIIIa-T1565C-PlA1/PlA2 with platelet function in women with unexplained spontaneous recurrent miscarriages. This cross-sectional study comprised 196 unrelated nulliparous Greek women with a history of unexplained recurrent miscarriages. Patients were genotyped for the presence of the GpIa-C807T (rs1126643) and GpIIIa-T1565C-PlA1/PlA2 (rs5918) genetic polymorphisms by pyrosequencing, and the collagen/epinephrine closure time (COL/EPI CT) of the subjects was assessed using the platelet function analyzer (PFA)-100. In the total population of women with recurrent miscarriages, the COL/EPI CT ranged from 70 to 160 seconds (median: 122 seconds, interquartile range (IQR): 102.3-138 seconds). In comparison with the double homozygotes CC/PlA1PlA1 that had the most prolonged CT (mean: 131.9 ± 17.5 seconds), the COL/EPI CT was statistically significantly shorter for the GpIa-807T single carriers (mean: 120.3 ± 20.9 seconds) (p=0.011) (absolute difference: 11.6 seconds, 95% confidence interval (CI): 21.2 to -2.0 seconds;relative difference: -9%, 95% CI: -16% to -2%), and the GpIIIa-PlA2 single carriers also displayed a trend for shorter COL/EPI CT (mean:121.3 ± 23.7 seconds) (p=0.141) (absolute difference: -10.6 seconds, relative difference: -8%), whereas the combined carriers of the GpIa-807T and the GpIIIa-PlA2 alleles exhibited the shortest COL/EPI CT (mean: 104.1 ± 19.7 seconds) (absolute difference: -27.7 seconds, 95% CI: -39.1 to -16.3 seconds; relative difference: -21%, 95% CI: -30% to -12%) (p<0.001). In comparing genotype frequencies in the lower half with those in the upper half of the COL/EPI CT range, the GpIa-807T and the GpIIIa-PlA2 single carriers were associated with higher odds of COL/EPI CT < 122 seconds (odds ratio (OR)=3.4, 95% CI: 1.5 to 7.5, p=0.002, and OR=2.6, 95% CI: 1.0 to 7.2, p=0.053, respectively). The association was strongest for the combined carriers with OR of 15.0 (95% CI: 5.2 to 43.2, p<0.001) for COL/EPI CT below the medianand OR of 35.5 (95% CI: 4.4 to 284.5, p<0.001) for COL/EPI CT < 100 seconds. The GpIa-C807T and GpIIIa-PlA1/PlA2 polymorphisms and more pronouncedly the combined carriers of the risk variants are associated with enhanced platelet reactivity expressed via shorter COL/EPI CT. These findings provide further evidence for the role of platelet-associated genetic thrombophilia in the pathogenesis of recurrent miscarriages and promotethe analysis of platelet function as a diagnostic tool in the evaluation of this disorder.

Analysis of copy number variations and possible candidate genes in spontaneous abortion by copy number variation sequencing.

Embryonic chromosomal abnormalities represent a major causative factor in early pregnancy loss, highlighting the importance of understanding their role in spontaneous abortion. This study investigates the potential correlation between chromosomal abnormalities and spontaneous abortion using copy number variation sequencing (CNV-seq), a Next-Generation Sequencing (NGS) technology. We analyzed Copy Number Variations (CNVs) in 395 aborted fetal specimens from spontaneous abortion patients by CNV-seq. And collected correlated data, including maternal age, gestational week, and Body Mass Index (BMI), and analyzed their relationship with the CNVs. Out of the 395 cases, 67.09% of the fetuses had chromosomal abnormalities, including numerical abnormalities, structural abnormalities, and mosaicisms. Maternal age was found to be an important risk factor for fetal chromosomal abnormalities, with the proportion of autosomal trisomy in abnormal karyotypes increasing with maternal age, while polyploidy decreased. The proportion of abnormal karyotypes with mosaic decreased as gestational age increased, while the frequency of polyploidy and sex chromosome monosomy increased. Gene enrichment analysis identified potential miscarriage candidate genes and functions, as well as pathogenic genes and pathways associated with unexplained miscarriage among women aged below or over 35 years old. Based on our study, it can be inferred that there is an association between BMI values and the risk of recurrent miscarriage caused by chromosomal abnormalities. Overall, these findings provide important insights into the understanding of spontaneous abortion and have implications for the development of personalized interventions for patients with abnormal karyotypes.

Investigating the Association of MTHFR C677T Gene Polymorphism with Recurrent Spontaneous Abortion Among Azerbaijani Women from Northwest Iran.

Background: Recurrent spontaneous abortion (RSA), defined as two or more succeeding abortions during 20 weeks of gestation, affects 3-5% of pregnancies. Several studies have found that most women with RSA had at least one (and sometimes two copies) of the methylenetetrahydrofolate reductase (MTHFR) C677T variant. Materials and Methods: The study involved 118 women who had two or more spontaneous abortions (SAs) as the case group and 118 women who had at least one live birth but no SA as the control group. Clinical features such as age, body mass index (BMI), medication received, family history of abortion, and thrombophilia were investigated. Real-time PCR was used for genotyping subjects for MTHFR C677T gene polymorphism. Results: Significant differences in age, BMI, and medication received characters have been shown between those in the patients' group. For the MTHFR C677T gene, the genotypes for the patients' group were 36%, 60%, and 4%, whereas the genotypes for the control group were 30%, 58%, and 12%. In addition, the C and T allelic frequencies were 59% and 41% in the healthy control group and 67% and 33% in the patients' group, respectively. A significant association was found between the TT genotype and RSA. A 3.84-fold increased risk of RSA was associated with the TT genotype (odds ratio = 3.84, confidence interval: 1.28-10.93, p-value = 0.02). Conclusions: In this study, homozygosity for the T allele was significantly lower in the RSA-affected than in healthy women, whereas heterozygosity did not vary substantially between the two groups, which was in line with other studies.

The Association of NKp46-Positive uNK Cells With a Higher Risk of Recurrent Miscarriage and IVF Failure

Background: Uterine natural killer (uNK) cells have a significant impact on pregnancy and related complications. Given the importance of receptors in the activity of uNK cells, the present study aimed to determine the number of uNK cells and NKp46 (one of the most important NK cell-activating receptors) expression in the endometrium of women with recurrent miscarriage (RM) or a history of in vitro fertilization (IVF) failure. Materials and Methods: This case-control study was performed on 48 participants, including 16 healthy controls, 27 cases with RM, and 5 cases with repeated implantation failure (RIF) during the mid-luteal phase according to a standardized diagnostic protocol. All participants were assessed using transvaginal ultrasound to determine embryo survival rate and confirm gestational age. Endometrial specimens were collected and subjected to immunohistochemistry (IHC) staining using an anti-human NKp46 antibody expressed by uNK cells. Results: A significantly higher number of cells positive for NKp46 was obtained among two groups of cases versus healthy subjects (patients: 1.46±0.78, controls: 0.82±62, P=0.006), and the number of CD56+cells was significantly higher in patients than in controls (patients: 18.14±7.14, controls: 11.71±6.17, P=0.003). Additionally, there was not a significant difference in the frequency ratio of NKp46+NK cell subset to CD56+uNK cells between the patients (P=0.59) and control healthy group. Conclusion: The increase in the number of uterine NK cells and their cytotoxic activity during implantation and early pregnancy, possibly resulting from an excessive expression of inflammatory cytokines, confirms a significant association between uNK cell activity and a higher risk of RM and RIF. Therefore, immunomodulatory treatments may benefit these patients.

Role of tumor necrosis factor-alpha -238 G>A promoter region polymorphism on recurrent miscarriage: An association study and meta-analysis.

Recurrent miscarriage (RM) is defined as the loss of two or more consecutive pregnancies. A functional SNP, -238G>A in the promoter region of TNF-α, affects the gene transcription activity with implications on human pregnancy. Previous limited studies, linking the TNF-α -238 G>A to the risk of recurrent miscarriage have been inconclusive. The PCR-RLFP technique was used to evaluate this polymorphism in 199 RM cases and 215 control women from Amritsar, Punjab. For a meta-analysis, a total of 13 eligible studies (including the present study) comprising 2947 cases and 2933 controls were included. To evaluate the association among different genetic models, odds ratio with a 95% confidence interval (CI) and chi-square were used. Genotype and allelic frequency did not differ significantly between both groups (p=.07 and p=.24, respectively). In the present meta-analysis, a significant association was found with the recessive model (OR-1.78 CI:1.24-2.55, p=.002). Although, TNF-α -238 G>A polymorphism did not provide any risk in the case-control study but provided risk towards the development of RM with the recessive genetic model in the pooled analysis.

Endometrial fate decisions at implantation and the risk of recurrent miscarriage

Endometrial fate decisions at implantation and the risk of recurrent miscarriage

Role of the HLA-G regulatory region polymorphisms in idiopathic recurrent spontaneous abortions (RSA).

HLA-G polymorphisms have a functional impact on its expression and may cause a breakdown of maternal tolerance towards the semi-allogenic fetus, resulting in recurrent spontaneous abortions (RSA). This study reports on the association of HLA-G regulatory region polymorphisms with idiopathic RSA. Seventy-five couples with ≥2 spontaneous abortions were recruited in comparison to 75 healthy couples who had normal pregnancies. About 5mL of blood samples were collected from all the participants, and DNA was extracted. Screening of HLA-G 5'-upstream regulatory region (5'-URR) was done by direct sequencing in 50 each of RSA and healthy couples, respectively. The 14bp deletion/insertion polymorphism in the 3'-untranslated region (3'-UTR) was genotyped in 75 each of RSA and healthy couples, respectively, by PCR amplification of HLA-G exon 8. MedCalc, GraphPad Prism, Haploview, PLINK, and multifactor dimensionality reduction were used to analyze the data. HLA-G screening revealed the presence of -762C/T, -725C/G, -716T/G, -689A/G, -486C/A, and -477C/G single nucleotide polymorphisms (SNPs) in the 5'-URR. At positions -762 and -477, the frequency of CC homozygotes was significantly higher in controls compared to the patients. The 14bp deletion/insertion polymorphism in the 3'-UTR showed an association with RSA with the heterozygous genotype being significantly higher in RSA compared to controls. The study indicates a protective role of the CC genotypes of the two HLA-G 5'-URR polymorphisms, -762C/T and -477C/G, against RSA. It also suggests that women with the 14bp deletion/insertion genotype have a significantly higher risk of RSA.

The hormone-sensitive lipase C-60G polymorphism is correlated with recurrent spontaneous abortion in women with polycystic ovary syndrome

Objective(s)Disrupted lipid metabolism has been associated with the development of polycystic ovary syndrome (PCOS) in women of reproductive age. Hormone-sensitive lipase (HSL) is an intracellular lipase that has a crucial role in normal lipid metabolism. This study aimed to assess the frequency of C-60G polymorphism of HSL in healthy women and PCOS women, and its correlation with infertility and recurrent spontaneous abortion (RSA) in PCOS patients. Study designA total of 324 PCOS patients (including 199 infertile patients and 125 patients with a history of RSA and 144 healthy controls) were enrolled in this study. Biochemical parameters were measured, and the genotypes of C-60G polymorphism of the HSL gene were determined using PCR-restriction fragment length polymorphism (RFLP) techniques. ResultsThere was no significant difference in the genotype and allele frequencies of C-60G polymorphism between PCOS, PCOS-infertile woman, and non-PCOS subjects. However, a higher percentage of combined variants (CG + GG) and CG genotypes, as well as G allele was found in the PCOS-RSA group in comparison with non-PCOS women. The presence of the G allele conferred a 2.4-fold risk for RSA in women with PCOS (OR: 2.4, 95 % CI [1.22–4.70], P = 0.011). Furthermore, a significant correlation between CG or GG genotype of HSL and the level of free testosterone was observed. ConclusionAccording to the obtained results, the C-60G polymorphism in the HSL promoter was associated with PCOS-related RSA, possibly through increasing the level of free testosterone. Therefore, the rs34845087 polymorphism may be a promising prognostic biomarker for RSA in women with PCOS.

Association of microRNA gene polymorphisms with recurrent spontaneous abortion: An updated meta‑analysis.

Numerous studies have reported single nucleotide polymorphisms (SNPs) in microRNAs (miRNAs) associated with unexplained recurrent spontaneous abortion (URSA). The present study aimed to conduct an updated meta-analysis to confirm a pooled effect size of the association between miRNA SNPs and URSA. The relevant literature was searched on PubMed, EMBASE, Web of Science and Cochrane Library before July 2022 to identify case-control studies. The pooled odds ratio and confidence intervals at 95% of the eligible studies were extracted and evaluated under five genetic models. A total of 18 studies involving 3,850 cases and 4,312 controls were included. miR499a rs3746444 A>G, miR-149 rs2292832 T>C, miR-125a rs41275794 G>A and miR-10a rs3809783 A>T may enhance the risk of recurrent spontaneous abortion (RSA) under various genetic models. Although no separate association was found between the miR-125a rs12976445 C>T and miR-27a rs895819 A>G polymorphisms and RSA, statistical significance was found in certain ethnic groups only. The current analysis suggests a high significance of an up-to-date meta-analysis for screening out and preventing URSA among high-risk women by testing miRNA SNPs and RSA susceptibility.

Correlation between methylenetetrahydrofolate reductase gene-specific methylation and recurrent spontaneous abortion

ABSTRACT Objective: To investigate the correlation between methylenetetrahydrofolate reductase (MTHFR) gene-specific methylation and recurrent spontaneous abortion (RSA). Methods: A total of 50 RSA patients who visited our hospital were recruited in the study group; 50 multiparous women who underwent physical examinations during the same period were enrolled in the control group. The levels of homocysteine, folic acid, and vitamin B12 and their MTHFR gene polymorphism and specific methylation were measured in both groups. The Logistic regression equation was used to analyze the correlation between MTHFR gene-specific methylation and RSA. Results: The methylated allele MM was not found in the control group, and the frequency in the study group was 1.19%. The frequency of the MU genotype in the study group 32.93% was higher than that in the control group 12.45%. The frequency of methylated alleles of CC and CT genotypes carrying MTHFR C677T polymorphism in the study group was higher than that in the control group (P < 0.05). There was no significant difference in the TT genotype between the two groups (P > 0.05). Multivariate Logistic regression analysis exhibited that patients with methylated alleles of CC genotype had a risk of RSA increased by 1.167 times, and the risk increased by 2.500 times in patients with methylated alleles of CT genotype (P < 0.05). 83.33% of RSA patients carrying methylated alleles affected hyperhomocysteinemia. In patients with elevated homocysteine levels, the risk of RSA caused by methylated allele was significantly increased by 7.321 times. Conclusion: MTHFR gene-specific methylation can significantly increase the risk of RSA.

Diverse cardiovascular risk of recurrent spontaneous abortion: A prospective cohort study using UK Biobank

Previous studies have reported that history of recurrent spontaneous abortion (RSA) can increase the risk for cardiovascular disease. However, previous studies mainly focused on atherosclerotic cardiovascular disease (ASCVD), such as coronary artery disease or stroke, hence the effect of RSA on non-atherosclerotic cardiovascular diseases (non-ASCVD) remains unknown. In the current study, we examined if women with a history of RSA have an increased risk for long-term cardiovascular outcomes including both ASCVD and non-ASCVD. The UK Biobank is a prospective cohort study that recruited participants 40 to 69 years old with ongoing follow-up. Among women enrolled in UK Biobank, those with at least one pregnancy history and without pre-existing cardiovascular disease were included. The new occurrence of ASCVD and non-ASCVD after enrollment were compared between the women with RSA history and without RSA history. To evaluate the incidence of cardiovascular outcomes, a Cox proportional hazard model was used with adjustment for covariates including age, race, BMI, nulliparity, use of hormones, smoking, early menopause, hysterectomy, prevalent diseases, and medication by Cox proportional hazards regression analysis. In the presence of a history of RSA, the risk of new occurrence of overall cardiovascular disease, was higher (adjusted hazard ratio (aHR), 1.24 (95% CI 1.15-1.35), Figure 1). Specifically, the incidence of coronary artery disease, myocardial infarction, peripheral artery disease, heart failure, mitral regurgitation, atrial fibrillation/flutter were all increased in cases with a history of RSA (Figure 2). The women with history of RSA had an increased long-term risk of not only ASCVD, but also non-ASCVD.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

MiR604A>G gene polymorphism is associated with recurrent pregnancy loss in Turkish women.

Recurrent pregnancy loss is considerably a reproductive health problem for couples. Genetic, epigenetic, and environmental factors play an important role in the development of recurrent pregnancy loss. While there are many causes, genetic and epigenetic factors are common. Inthis study, we aimed to examine the association between miR604 (rs2368393) A>G gene polymorphism and the risk of recurrent miscarriage in the Turkish population. The study included 250 participants (i.e., 150 patients and 100 controls). DNA samples were isolated from peripheral blood, and polymerase chain reactions and restriction fragment length polymorphism methodologies were applied. The genotype distribution and allele frequencies of miR604A>G gene showed statistically significant differences between patients and control groups (p=0.002 and p<0.002, respectively). As a result of the study, we found that the AA genotype and A allele of the miR604A>G gene were statistically significant for the risk of recurrent pregnancy loss in Turkish women.

Elevated histone demethylase KDM5C increases recurrent miscarriage risk by preventing trophoblast proliferation and invasion

KDM5C is a histone H3K4-specific demethylase, which has been shown to play a key role in biological disease and development. However, the role of KDM5C in trophoblasts at early pregnancy is currently unknown. Here, we showed that KDM5C was upregulated in placental trophoblasts from recurrent miscarriage (RM) patients compared with healthy controls (HCs). Trophoblast proliferation and invasion was inhibited by KDM5C overexpression and was promoted by KDM5C knockdown. Transcriptome sequencing revealed that elevated KDM5C exerted anti-proliferation and anti-invasion effects by repressing the expression of essential regulatory genes. The combination analysis of RNA-seq, ChIP-seq and CUT&Tag assay showed that KDM5C overexpression leads to the reduction of H3K4me3 on the promoters and the corresponding downregulation of expression of several regulatory genes in trophoblasts. Among these genes, TGFβ2 and RAGE are essential for the proliferation and invasion of trophoblasts. Importantly, overexpression of KDM5C by a systemically delivered KDM5C adenovirus vector (Ad-KDM5C) promoted embryo resorption rate in mouse. Our results support that KDM5C is an important regulator of the trophoblast function during early pregnancy, and suggesting that KDM5C activity could be responsible for epigenetic alterations seen RM disease.