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1.
Life Sci ; 274: 119332, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33711384

RESUMO

AIMS: Blastocyst implantation is mainly depended on the adhesion between cells and cell matrix. Endometrial adhesion plays an important role in establishing embryo implantation, but the underlying mechanisms are remains unclear. Talin1 is a local adhesion complex protein that is necessary for cell adhesion and movement. However, the role and mechanisms of Talin1 in embryo implantation are still unclear. MAIN METHODS: The expression of Talin1 and Integrin αvß3 was measured in the receptive endometrium from the RIF (Recurrent implantation failure) cohort and NC (normal fertile control group) cohort. A JEG-3 trophoblast and endometrial epithelial cell adhesion model and pregnant mouse model were established. The molecular mechanism of Talin1-mediated cell adhesion was explored by RNA sequencing, RT-qPCR, as well as western blotting assays. KEY FINDINGS: Talin1 enhances endometrial cell adhesion by regulating the Ras signaling pathway, and ultimately facilitates embryo implantation. SIGNIFICANCE: This study revealed the molecular mechanisms of regarding the pathogenesis of RIF caused by endometrial receptivity insufficiency. Further pharmacological research on the Ras signaling pathway would be valuable and might provide new therapeutic targets for RIF patients.


Assuntos
Aborto Habitual/patologia , Adesão Celular , Implantação do Embrião , Endométrio/patologia , Talina/metabolismo , Talina/fisiologia , Proteínas ras/metabolismo , Aborto Habitual/genética , Aborto Habitual/metabolismo , Animais , Apoptose , Proliferação de Células , Células Cultivadas , Endométrio/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Camundongos Knockout , Gravidez , Prognóstico , Talina/genética , Proteínas ras/genética
2.
Medicine (Baltimore) ; 100(7): e24398, 2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33607773

RESUMO

OBJECTIVE: To identify the role of estrogen receptor-beta (ER-ß) gene +1730G/A (rs4986938) polymorphisms in recurrent pregnancy loss (RPL). METHODS: All relevant case-control studies will be systematically searched in multiple databases including PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Internet (CNKI), Wanfang and Cqvip. Both pooled odds rations (ORs) and 95% confidence intervals (CIs) will be used to assess the association between ER-ß gene +1730G/A polymorphisms and RPL risk. The publication bias will be evaluated using Egger test. RESULTS: ER-ß gene +1730G/A variation may be associated with a higher risk of RPL in Caucasian population. CONCLUSIONS: The findings of this meta-analysis will provide high-quality evidence for the association between ER-ß gene +1730G/A polymorphisms and RPL, facilitating clinical practice and further scientific studies. OSF REGISTRATION NUMBER: 10.17605/OSF.IO/EW9FB.


Assuntos
Aborto Habitual/genética , Receptor beta de Estrogênio/genética , Polimorfismo Genético/genética , Feminino , Humanos , Metanálise como Assunto , Gravidez , Receptores Estrogênicos/genética , Revisões Sistemáticas como Assunto
3.
Zhonghua Nan Ke Xue ; 26(9): 811-814, 2020 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-33377705

RESUMO

Objective: To investigate the association of gr/gr, b2/b3 and gr/gr with b1-2/b3-4 deletions (repetitions) in the AZFc region of the Y chromosome with recurrent spontaneous abortion (RSA). METHODS: Using the next-generation sequencing technology, we examined the men with indications of Y chromosome microdeletion at our center from June 2017 to March 2018 and excluded the common causes of RSA through inquiry and other related examinations. Totally, 170 cases of AZFc deletion (80 cases of gr/gr deletion, 75 cases of b2/b3 deletion, and 15 cases of gr/gr with b1-2/b3-4 deletion) were detected and included in the case group, and another 328 normal males enlisted as controls. We analyzed the correlation of Y chromosome microdeletions with the incidence rate of RSA. RESULTS: The incidence rate of RSA was significantly higher in the case group than in the normal controls (28.8% ï¼»49/170ï¼½ vs 13.1% ï¼»43/328ï¼½, P < 0.01), 22.5% (18/80) in the gr/gr deletion cases (P < 0.05), 30.7% (23/75) in the b2/b3 deletion cases (P < 0.01), and 53.3% (8/15) in the gr/gr with b1-2/b3-4 deletion cases (P < 0.01), remarkably lower in the gr/gr than in the gr/gr with b1-2/b3-4 deletion subgroup (P < 0.05), but with no statistically significant difference between the other subgroups. CONCLUSIONS: The gr/gr, b2/b3, and gr/gr with b1-2/b3-4 deletions (repetitions) in the AZFc region of the Y chromosome may cause recurrent spontaneous abortion.


Assuntos
Aborto Habitual/genética , Deleção Cromossômica , Cromossomos Humanos Y/genética , Aberrações dos Cromossomos Sexuais , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Gravidez
4.
Best Pract Res Clin Endocrinol Metab ; 34(6): 101477, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33353781

RESUMO

Sperm genetic testing has been proposed for clinical diagnosis of possible causes of male infertility. We reviewed the most remarkable publications of sperm DNA integrity and sperm aneuploidy as they relate to clinical outcomes, and the relationship between both genetic defects, and its association to embryo aneuploidy and recurrent pregnancy loss.


Assuntos
Aborto Habitual/genética , Aneuploidia , Infertilidade Masculina/genética , Espermatozoides/metabolismo , Aborto Habitual/diagnóstico , Fragmentação do DNA , Feminino , Doenças Genéticas Inatas/complicações , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/embriologia , Doenças Genéticas Inatas/genética , Testes Genéticos , Humanos , Infertilidade Masculina/diagnóstico , Masculino , Gravidez , Espermatozoides/anormalidades , Espermatozoides/patologia
5.
Medicine (Baltimore) ; 99(40): e21962, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33019388

RESUMO

To evaluate the association between gene polymorphisms of MTHFR (C677T, A1298C) and MTRR (A66G), and the recurrent spontaneous abortion (RSA) risk in Asia.Related case-control studies were collected, selected, and screened. A meta-analysis was conducted by Stata 12.0 software to assess the association between polymorphisms of target genes and RSA.Altogether 30 studies examining the relationship between genetic polymorphism of folate metabolism and RSA risk were included, among which 20 studies were related to MTHFR C677T, 11 to MTHFR A1298C and 6 to MTRR A66G. The studies suggested that MTHFR C677T polymorphism was closely connected with RSA risk under all models (P < .05). Furthermore according to the subgroup analysis of ethnicity, the correlation between C677T polymorphism and RSA was stronger in north of China when compared with south of China and other Asian countries (P > . 05). For MTHFR A1298C, it was closely related to RSA risk in all gene models except for (AC vs AA) (P < .05). However, when it comes to MTRR A66G, there was no significant correlation between gene A66G polymorphism and RSA risk except for the additive gene model (G vs A) (P < .05).The present evidence shows that the correlation between gene polymorphisms and RSA risk can be found in MTHFR C677T, A1298C (except for heterozygote model) and MTRR A66G (only in additive genotypes), and the detection of the correlated gene polymorphisms mentioned above is of certain guiding significance for preventing RSA and screening high-risk groups.


Assuntos
Aborto Habitual/genética , Ferredoxina-NADP Redutase/metabolismo , Ácido Fólico/metabolismo , Metilenotetra-Hidrofolato Redutase (NADPH2)/metabolismo , China , Feminino , Humanos , Estudos Observacionais como Assunto , Polimorfismo de Nucleotídeo Único , Gravidez , Medição de Risco
6.
Cytogenet Genome Res ; 160(5): 245-254, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32485717

RESUMO

Chromosomal microdeletion syndromes present with a wide spectrum of clinical phenotypes that depend on the size and gene content of the affected region. In a healthy carrier, epigenetic mechanisms may compensate for the same microdeletion, which may segregate through several generations without any clinical symptoms until the epigenetic modifications no longer function. We report 2 novel cases of Xq24 microdeletions inherited from mothers with extremely skewed X-chromosome inactivation (sXCI). The first case is a boy presenting with X-linked mental retardation, Nascimento type, due to a 168-kb Xq24 microdeletion involving 5 genes (CXorf56, UBE2A, NKRF, SEPT6, and MIR766) inherited from a healthy mother and grandmother with sXCI. In the second family, the presence of a 239-kb Xq24 microdeletion involving 3 additional genes (SLC25A43, SLC25A5-AS1, and SLC25A5) was detected in a woman with sXCI and a history of recurrent pregnancy loss with a maternal family history without reproductive wastages or products of conception. These cases provide evidence that women with an Xq24 microdeletion and sXCI may be at risk for having a child with intellectual disability or for experiencing a pregnancy loss due to the ontogenetic pleiotropy of a chromosomal microdeletion and its incomplete penetrance modified by sXCI.


Assuntos
Aborto Habitual/genética , Deleção Cromossômica , Cromossomos Humanos X/genética , Mães , Enzimas de Conjugação de Ubiquitina/deficiência , Enzimas de Conjugação de Ubiquitina/genética , Inativação do Cromossomo X/genética , Adulto , Pré-Escolar , Epigênese Genética , Feminino , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Fenótipo , Síndrome , Adulto Jovem
7.
Arch Gynecol Obstet ; 302(2): 345-354, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32472185

RESUMO

PURPOSE: Heritable thrombophilia is a category of genetic disorders of the coagulation cascade with the increasing risk of thrombus formation and recurrent pregnancy loss (RPL). Factor V Leiden (FVL) (R506Q) mutation is the most common genetic cause of deep venous thrombosis, but its association with RPL has been inconsistent in studies arising from non-Western countries. The present metanalysis was aimed to determine whether an association exists between FVL and RPL in the Middle East. METHODS: We searched PubMed, MEDLINE Web of Science, Scopus, and Embase, evaluating the association between the FVL and RPL. The Middle East countries (Bahrain, Cyprus, Egypt, Iran, Iraq, Israel, Jordan, Kuwait, Lebanon, Oman, Qatar, Saudi Arabia, The State  of Palestine, Syria, Turkey, The United Arab Emirates, and Yemen) were evaluated in succession. Raw data were extracted, and 19 case-control studies were included in our final analysis. RESULTS: Overall, 2513 cases and 1836 controls in the Middle East showed a prevalence of FVL mutation as 12.6% and 4.9% in patients and controls, respectively. To evaluate the relationship between FVL mutation and RPL, we used Forest plot (random effect model) with the overall random OR of 2.37 (CI 95%: 1.50-3.75). FVL mutation was associated with a higher risk of RPL. In Iran, the OR was 1.90 (95% CI 1.04-3.45), and in Turkey, the OR was 3.01 (95% CI 1.10-8.23). CONCLUSION: The results of our study support an association between FVL mutation status and RPL in women of the Middle East countries. It is recommended that specific policies include comprehensive testing for FVL mutation as a standard of care in women of the Middle East region with unexplained RPL.


Assuntos
Aborto Habitual/genética , Perda do Embrião/genética , Fator V/genética , Trombofilia/complicações , Aborto Habitual/epidemiologia , Adulto , Feminino , Predisposição Genética para Doença , Humanos , Mutação , Gravidez , Trombofilia/genética
8.
Fertil Steril ; 113(4): 853-864, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32228881

RESUMO

OBJECTIVE: To determine whether the incidence of chromosomal abnormalities in blastocysts is higher in patients with idiopathic recurrent pregnancy loss (iRPL) who underwent preimplantation genetic testing for aneuploidy (PGT-A) than in those who underwent preimplantation genetic testing for monogenic defects (PGT-M). DESIGN: Retrospective cohort study. SETTING: University-affiliated reproductive center. PATIENT(S): A total of 62 patients with iRPL underwent 101 PGT-A cycles (iRPL group), and 212 patients underwent 311 PGT-M cycles (control group). INTERVENTIONS(S): Blastocyst biopsy and comprehensive chromosome screening technologies, including single-nucleotide polymorphism microarrays and next-generation sequencing. MAIN OUTCOME MEASURE(S): Incidence of chromosomal abnormalities in blastocysts and clinical miscarriage (CM) rate. RESULT(S): Stratification analysis by maternal age showed an increased incidence of chromosomal abnormalities in the iRPL group aged ≤35 years (48.9% vs. 36.9%), whereas no significant increase was found in the iRPL group aged >35 years (66.9% vs. 61.4%). After transfer of euploid embryos, women aged ≤35 years with iRPL exhibited an increased CM rate compared with the control group (26.1% vs. 3.1%). CONCLUSION(S): Young patients with iRPL have a significantly higher rate of chromosomal abnormalities in blastocysts compared with patients with no or sporadic CM. Although euploid embryos were transferred after PGT-A, young patients with iRPL had a higher CM rate, which may indicate that chromosomal abnormalities might not be the only causal factor for iRPL. Therefore, the role of PGT-A in iRPL still needs to be clarified.


Assuntos
Aborto Habitual/genética , Aneuploidia , Blastocisto/fisiologia , Aberrações Cromossômicas/embriologia , Diagnóstico Pré-Implantação/métodos , Aborto Habitual/diagnóstico , Adulto , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Estudos de Coortes , Feminino , Testes Genéticos/métodos , Humanos , Gravidez , Estudos Retrospectivos
9.
Hum Genet ; 139(5): 605-613, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32172300

RESUMO

Infertility affects 10% of reproductive-age women and is extremely heterogeneous in etiology. The genetic contribution to female infertility is incompletely understood, and involves chromosomal and single-gene defects. Our aim in this study is to decipher single-gene causes in infertile women in whom endocrinological, anatomical, and chromosomal causes have been excluded. Our cohort comprises women with recurrent pregnancy loss and no offspring from spontaneous pregnancies (RPL, n = 61) and those who never achieved clinical pregnancy and were referred for in vitro fertilization [primary infertility (PI), n = 14]. Whole-exome sequencing revealed candidate variants in 14, which represents 43% of those with PI and 13% of those with RPL. These include variants in previously established female infertility-related genes (TLE6, NLRP7, FSHR, and ZP1) as well as genes with only tentative links in the literature (NLRP5). Candidate variants in genes linked to primary ciliary dyskinesia (DNAH11 and CCNO) were identified in individuals with and without systemic features of the disease. We also identified variants in genes not previously linked to female infertility. These include one homozygous variant each in CCDC68, CBX3, CENPH, PABPC1L, PIF1, PLK1, and REXO4, which we propose as candidate genes for infertility based on their established biology or compatible animal models. Our study expands the contribution of single genes to the etiology of PI and RPL, improves the precision of disease classification at the molecular level, and offers the potential for future treatment and development of human genetics-inspired fertility regulators.


Assuntos
Aborto Habitual/genética , Marcadores Genéticos , Genômica/métodos , Infertilidade Feminina/genética , Mutação , Aborto Habitual/patologia , Adulto , Feminino , Humanos , Infertilidade Feminina/patologia , Gravidez , Recidiva , Sequenciamento Completo do Exoma
10.
Reprod Sci ; 27(1): 29-38, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32046408

RESUMO

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.


Assuntos
Aborto Habitual/genética , Implantação do Embrião/genética , Predisposição Genética para Doença , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único , Feminino , Genótipo , Humanos
11.
Gene ; 736: 144406, 2020 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-32007580

RESUMO

Estrogen receptor (ER) signaling is key regulator for maintaining successful pregnancy. Several research suggested that genetic variation in ER genes (ESR)1 and ESR2 is associated with the susceptibility to unexplained recurrent pregnancy loss (RPL), often with inconclusive results. In this study, we investigate the relationship between ESR1 and ESR2 polymorphisms and idiopathic RPL. A total of 444 patients with RPL, defined as three or more consecutive pregnancy losses of unknown etiology, and 446 control women were recruited to the study and their genotypes for ESR1-rs2234693, ESR1-rs3020314, and ESR2-rs928554 variants were determined using allelic exclusion method on real-time polymerase chain reaction. Minor allele frequencies (MAF) of tagging SNPs ESR1 rs2234693 and rs3020314, and ESR2 rs928554 were not significantly different between RPL cases and control women. Considerable higher frequencies of homozygous (2/2) ESR1 rs2234693 genotype carriers were seen between patients vs. control women, which maintained after controlling for age, body mass index (BMI), and menarche. ESR1 haplotype analysis demonstrated two common haplotype (rs2234693-rs3020314) with no linkage disequilibrium between both polymorphisms, and no 2-locus haplotype linked with RPL risk was revealed. The present study confirmed a significant association of specific ESR1 variant (rs2234693) with an increased risk of RPL, further supporting a role for ESR1 as an important candidate locus inducing RPL.


Assuntos
Aborto Habitual/genética , Aborto Espontâneo/genética , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Estudos de Casos e Controles , Estrogênios/genética , Feminino , Frequência do Gene/genética , Genótipo , Humanos , Desequilíbrio de Ligação/genética , Gravidez , Estudos Retrospectivos , Tunísia
12.
Genet Test Mol Biomarkers ; 24(2): 78-84, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31999488

RESUMO

Aims: This study was designed to determine whether genetic polymorphisms of the killer immunoglobulin-like receptor (KIR) and human leukocyte antigen class I (HLA-C) genes are associated with recurrent spontaneous abortion (RSA) in Saudi women. Materials and Methods: Sixty-five healthy women with a history of RSA (three or more spontaneous abortions) and 65 healthy controls (with two or more healthy-born children) living in Riyadh were typed for 17 KIR genes and the HLA-C1 and HLA-C2 allotypes using polymerase chain reaction-sequence-specific primer methodology. Results: The frequencies of KIR2DS2 and KIR2DL5A were significantly lower among RSA women compared to healthy controls (odds ratio [OR] = 0.17; p < 0.001; OR = 0.16; p < 0.001, respectively). No association with maternal HLA-C genotypes was observed. Analysis of KIR-HLA-C combinations indicated a protective effect of KIR2DS2 with its cognate HLA-C1 ligand in both homozygote or heterozygote combinations. Conclusion: Our results demonstrate that the KIR genes of the B haplotype may play an important role in ensuring the success of pregnancy.


Assuntos
Aborto Habitual , Antígenos HLA-C , Receptores KIR , Aborto Habitual/genética , Aborto Habitual/imunologia , Adolescente , Adulto , Feminino , Antígenos HLA-C/genética , Antígenos HLA-C/imunologia , Humanos , Pessoa de Meia-Idade , Gravidez , Receptores KIR/genética , Receptores KIR/imunologia , Arábia Saudita
13.
Eur J Obstet Gynecol Reprod Biol ; 245: 121-126, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31891895

RESUMO

OBJECTIVE: Recurrent miscarriage (RM) is a multifactorial condition that involves frequent uterine anatomical abnormalities, parental karyotype abnormalities, and clotting disorders. We investigate the potential roles of endometrium FoxP3+ Tregs and CD56+ cells (uNK cells) and endometrial expression of PGRMC1 in the development of recurrent miscarriage. STUDY DESIGN: This prospective study included 102 out of 286 cases of SA patients. The cases were divided into groups with RM (+RM) and without RM (-RM). Immunohistochemistry staining was made using primary antibodies to FoxP3, CD56, and PGRMC1 in both groups. Morphometry analyses were carried out in 10 non-overlapping high power fields. Mann-Whitney U test, Fisher two-tail test, correlation analysis and relative risk (RR) were evaluated. A p < 0.05 was considered statistically significant. RESULTS: An increased presence of CD56-positive (p < 0.001) and FoxP3+ Treg (p = 0.0005) cells was found in the endometrium, with a reduction in PGRMC1 expression compared with -RM group (p = 0.004). A positive correlation was shown between the number of CD56-positive cells and FoxP3+ cells (r = 0.55), and an inverse correlation with PGRMC1 (r =  -0.35) in the + RM group. A similar observation was found in the -RM group, with a positive correlation of uNK cell number with the number of pregnancies (p < 0.001; r = 0.34). Endometrial infiltration of CD56-positive (p < 0.0001) and FoxP3+ (p < 0.0001) cells revealed an increased relative risk of RM. This increased risk was also revealed in SA with a loss of PGRMC1 expression (p < 0.0001). CONCLUSION: Our prospective study suggests, for the first time, that increased endometrial infiltration of uNK, FoxP3+ Treg cells and a decreased PGRMC1 expression may play potential roles in the development of RM.


Assuntos
Aborto Habitual/genética , Antígeno CD56/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Células Matadoras Naturais/metabolismo , Proteínas de Membrana/metabolismo , Receptores de Progesterona/metabolismo , Adulto , Endométrio/metabolismo , Feminino , Predisposição Genética para Doença/genética , Humanos , Paridade/genética , Gravidez , Estudos Prospectivos , República de Belarus , Linfócitos T Reguladores/metabolismo , Útero/citologia
14.
Am J Obstet Gynecol ; 222(2): 168.e1-168.e8, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31437424

RESUMO

BACKGROUND: Miscarriage can be a devastating outcome for couples, and most miscarriages are unexplained. Many adverse obstetric outcomes (such as preeclampsia, preterm birth, and growth restriction) are thought to be inherited. It is possible that these conditions could share similar pathophysiologic mechanisms (such as endothelial dysfunction) with miscarriage. Therefore, it was hypothesized that there could be a susceptibility to miscarriage transmitted from mother to daughter. OBJECTIVE: This study aimed to investigate the association between a maternal history of miscarriage and the risk of miscarriage in daughters. STUDY DESIGN: A case-control study nested within an intergenerational cohort was conducted. Mother-daughter pairs were identified from the intergenerational cohort within the Aberdeen Maternity and Neonatal Databank, United Kingdom. A mother's history of miscarriage was the exposure. The primary outcome was miscarriage in daughters. There were 31,565 mother-daughter pairs who were eligible for inclusion. A population average model that used generalized estimating equations with robust standard errors was used to estimate the odds of a mother's history of miscarriage in daughters with a miscarriage compared with daughters with only livebirths. This method accounted for clustering of daughters within mothers, and multiadjusted analyses were performed to include confounders at the daughter's pregnancy level. RESULTS: Daughters who miscarried had 11% greater odds of being born to mothers with a history of miscarriage (adjusted odds ratio, 1.11; 95% confidence interval, 1.01-1.22). Daughters with recurrent miscarriage (≥2) were also more likely to be born to a mother with a history of miscarriage (adjusted odds ratio, 1.25; 95% confidence interval, 1.04-1.49). CONCLUSION: There may be an inherited predisposition to miscarriage transmitted from mother to daughter. Future research should investigate genetic or familial environmental factors that may predispose women to miscarriage.


Assuntos
Aborto Espontâneo/genética , Mães , Núcleo Familiar , Aborto Habitual/epidemiologia , Aborto Habitual/genética , Aborto Espontâneo/epidemiologia , Adulto , Estudos de Casos e Controles , Suscetibilidade a Doenças , Feminino , Predisposição Genética para Doença , Humanos , Nascimento Vivo/epidemiologia , Nascimento Vivo/genética , Gravidez , Reino Unido/epidemiologia , Adulto Jovem
15.
Eur J Med Genet ; 63(2): 103644, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30991114

RESUMO

Next generation sequencing (NGS) has revolutionized the diagnosis of postnatal genetic diseases, but so far has been used less frequently to study reproductive disorders. Here we provide an overview of approaches and outcomes of genome sequencing for identifying causes of recurrent pregnancy loss (RPL). This includes exome sequencing to look for pathogenic sequence changes in the whole exome or in a preselected list of genes considered important for early embryonic development and pregnancy maintenance, as well as low coverage whole genome sequencing useful for identifying cryptic balanced chromosome rearrangements and copy number variants (CNVs) in couples with RPL and miscarriages. For the purpose of this review only studies with at least 2 pregnancy losses were included with NGS performed on complete families, or only on miscarriages, couples or females with RPL. Overall, mutations in candidate genes responsible for recurrent embryonic/fetal loss were found in up to 60% of cases, opening the door for possible identification of affected future pregnancies at the preimplantation stage. Recurrence of specific mutations or affected genes in different studies was rare (e.g.DYNC2H1, KIF14, RYR1 and GLE1) however genes involved in cell division, cilia function or fetal movement were frequently identified as candidates, the later possibly reflecting the fact that a large number of studied cases had features of fetal akinesia deformation sequence (FADS). Genome sequencing of the couple and miscarriages is most informative, as it allows analysis of the individual mutations as well as their collective burden on the genome and biological processes. However genome sequencing of the couple with RPL with follow up of candidate parental mutations in miscarriages appears to be a promising avenue when miscarriage DNA amounts or quality are suboptimal for whole genome studies. In the future, increasing the number of studied families, establishment of a database cataloguing CNVs and mutations found in early pregnancy loss as well as their functional assessment in miscarriage cells and parental reproductive tissues is needed for improved understanding of their role in adverse pregnancy outcome.


Assuntos
Aborto Habitual/genética , Sequenciamento de Nucleotídeos em Larga Escala , Sequenciamento Completo do Exoma , Sequenciamento Completo do Genoma , Variações do Número de Cópias de DNA , Características da Família , Feminino , Humanos , Masculino , Mutação , Gravidez
16.
J Matern Fetal Neonatal Med ; 33(3): 442-448, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29950129

RESUMO

Objective: To evaluate the difference between chromosomal abnormalities between the gender of couples affected by Recurrent miscarriage (RM) and if there is an association between previous obstetric history and chromosomal abnormalities of the parents.Methods: Multicenter, retrospective, observational study from seven different RM clinics between 2006 and 2016. We enrolled 707 couples (1014 participants) with a history of RM. We compared the frequency of chromosomal abnormalities between groups of couples with primary and secondary RM and separated between women and their partners. Furthermore, we compared the prevalence of chromosomal abnormalities between groups based on the number of previous spontaneous abortions.Results: The overall prevalence of all cytogenetic abnormalities was 5.59% (n = 1414, women and their partners). Excluding cases of polymorphism and inversion of chromosome 9, which are considered variants of normality, the prevalence in all individuals was 2.26% (n = 32/1414). The comparative analysis of cases of chromosomal abnormalities among couples with primary and secondary RM based on the number of previous miscarriages (PM) revealed a similar frequency between groups. The statistical analysis of the total cases (primary PM + secondary PM) in these three groups were as follows: (a) couple, 2 pm versus 3 pm vs. ≥4 PM, p = .514; (b) women, 2 pm versus 3 pm vs. ≥4 PM, p = .347; and (3) partner, 2 pm versus 3 pm vs. ≥4 PM, p = .959. Chromosomal abnormalities were significantly more prevalent among women than among their partners (6.9 versus 4.2%; p = .027). Moreover, the distribution of leading chromosomal abnormalities among women was different compared with their partners. Among women, we observed these abnormalities in the following frequency order: mosaicism (38.8%), polymorphism (32.6%), translocation (16.3%), and inversion (12.3%). Among their partners, these abnormalities were polymorphism (73.3%), inversion (13.3%), mosaicism (6.7%), and translocation (6.7%).Conclusion: The number of PM and the history of full-term pregnancy does not correlate with an increase or decrease in the prevalence of cytogenetic abnormalities in couples with RM.


Assuntos
Aborto Habitual/genética , Aberrações Cromossômicas/estatística & dados numéricos , Adulto , Feminino , Humanos , Masculino , Estudos Retrospectivos , Fatores Sexuais
17.
BMC Res Notes ; 12(1): 790, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31801604

RESUMO

OBJECTIVE: Recurrent spontaneous abortion (RSA) is a condition which is defined as three consecutive pregnancy losses prior to 20 weeks from the last menstrual period. Progesterone is a steroid hormone that has an essential role in the implantation and maintenance of pregnancy. The progesterone signaling is performed by nuclear progesterone receptors (NPRs) and membrane progesterone receptors (mPR). The aim of this study was to analyze gene expression of mPR-α, mPR-ß and NPR in the endometrium of patients with a history of RSA compared to normal fertile women. RESULTS: In this study, endometrial samples were obtained from 10 women with a history of RSA and 10 fertile women during days 10-14 of menstrual cycle. Relative expression of mPR-α, mPR-ß and NPR genes were studied by a quantitative real time polymerase chain reaction (qRT-PCR) and compared between the two groups. The mean relative expression of mPR-ß gene was significantly lower in the case group compared to the fertile women (p < 0.05). However, the gene expression of mPR-α and NPR showed no significant difference between two groups. The findings suggest a reduction of endometrial gene expression of mPR-ß in RSA patients may play an important role in pathogenesis of RSA.


Assuntos
Aborto Habitual/genética , Endométrio/metabolismo , Receptores de Superfície Celular/metabolismo , Receptores de Progesterona/metabolismo , Aborto Habitual/metabolismo , Adulto , Estudos de Casos e Controles , Feminino , Expressão Gênica , Humanos , Gravidez , Progesterona/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Superfície Celular/genética , Receptores de Progesterona/genética
18.
Dis Markers ; 2019: 7090767, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31885742

RESUMO

Unexplained recurrent spontaneous abortion (URSA) is defined as the loss of two or more consecutive pregnancies before the 20th week of gestation with normal findings on routine screening tests. Our understanding of the cellular and molecular pathogenesis of URSA is still far from complete. Noncoding RNAs (ncRNAs) play a pivotal role in transcription and expression. The functions of ncRNAs may also improve understanding of URSA pathogenesis. Because of their stability in the circulatory system and at the maternal-fetal interface, it may be possible to use ncRNAs as biomarkers for certain disease states. Here, we provide a narrative review of the current state of knowledge about ncRNAs associated with URSA. The possibility of developing a diagnostic tool using ncRNAs is discussed. The underlying mechanisms of how ncRNAs may lead to the onset of URSA are explored in this review.


Assuntos
Aborto Habitual/genética , Segundo Trimestre da Gravidez/genética , RNA não Traduzido/genética , Aborto Habitual/diagnóstico , Estudos de Casos e Controles , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Gravidez
19.
Medicine (Baltimore) ; 98(46): e17919, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31725642

RESUMO

To evaluate the associations between Tumor necrosis factor-α (TNF-α)(-238G>A) and Interleukin-6 (IL-6)(-174G>C) polymorphism and risk of unexplained recurrent spontaneous abortion (URSA).Correlated case-control studies were collected by computer retrieval. A meta-analysis was conducted by Stata 12.0 software to analysis the strength of association between polymorphism of TNF-α -238G>A and IL-6 -174G>C and URSA.Twenty-one articles with twenty-two studies were included, of which 12 and 10 studies were respectively related to mutation of TNF-α -238G>A, IL-6 -174G>C and URSA. The integrated results showed that the TNF-α-238G>A gene mutation was significantly correlated with the risk of URSA under homozygote model (AA vs GG;OR 1.533,95% CI 1.022-2.301) and recessive model (AA vs GG+AG;OR 1.571,95%CI 1.050-2.350)(P < .05). There was no association between URSA and TNF-α -238G>A under heterozygote model (AG vs GG;OR 0.963,95% CI 0.816-1.137), dominant model (AA+AG vs GG; OR 1.031,95%CI 0.880-1.209) and additive model (A vs G;OR 1.046,95%CI 0.909-1.203)(P > .05). The results of subgroup analysis based on ethnicity showed that -238G>A was significantly correlated with the risk of URSA in Asians under all gene models except for heterozygote model (AG vs GG; OR 1.129,95% CI 0.857-1.487) (P < .05). In Caucasians, it was dominant model (AA+AG vs GG; OR 1.430,95%CI 1.040-1.965) (P < .05) rather than others that showed relationship with URSA. From the integrated results, association was manifested between -174G>C and URSA under all gene models (P < .05) except for recessive model (CC vs GG+CG, OR 1.166, 95%CI 0.938-1.449) (P > .05), which is identical to subgroup analysis based on ethnicity.It is of great guiding significance for screening out and preventing URSA among high-risk women to test on TNF-α -238G>A and IL-6 -174G>C under gene models mentioned above which are highly associated with the risk of URSA, which can act as biological markers for URSA.


Assuntos
Aborto Habitual/genética , Interleucina-6/genética , Fator de Necrose Tumoral alfa/genética , Aborto Habitual/etnologia , Estudos de Casos e Controles , Grupos de Populações Continentais , Feminino , Predisposição Genética para Doença , Humanos , Polimorfismo de Nucleotídeo Único , Gravidez , Fatores de Risco
20.
EBioMedicine ; 50: 343-354, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31707150

RESUMO

BACKGROUND: Recurrent implantation failure (RIF) remains a critical and challenging problem in assisted reproductive technology mainly due to impaired decidualization. The endocytic and transcytotic activity in the endometrium are crucial for decidualization. The most representative endocytic gene is the C-terminal Eps15 homology domain-containing 1 (EHD1), but whether EHD1-mediated endocytic function is responsible for embryo implantation during decidualization remains unclear. METHODS: A transcriptomic analysis was performed to evaluate the differentially expressed genes between the fertile control and RIF group. The expression and location of EHD1 in endometrial tissues were further examined by IHC, qRT-PCR and Western blotting. The transduction of an EHD1 recombinant adenovirus into human endometrial stromal cells was performed to investigate relevant decidualization marker genes. Additionally, a microarray analysis following the adenovirus-mediated overexpression of EHD1 was conducted to identify EHD1-related changes in HESCs, and the potential molecular mechanisms were further confirmed through immunofluorescence and coimmunoprecipitation analyses. FINDINGS: An RNA-seq analysis demonstrated that EHD1 expression was significantly higher in the mid-secretory endometrium of the RIF group than in that of the fertile control group. The analysis of the menstrual cycle showed that expression of EHD1 increased in the mid-proliferative phase and showed a gradual decrease in the mid-secretory and decidual phases. Furthermore, EHD1 overexpression impaired decidualization by suppressing the expression of prolactin and insulin-like growth factor binding protein-1 and the formation of the cytoskeleton. The mechanistic analysis revealed the EHD1 regulated LRP5/6 protein function through the endocytic pathway, and subsequently suppressed the Wnt4/ß-catenin pathway during decidualization. In addition, a Wnt4 agonist improved an impaired decidualization process. INTERPRETATION: Regulation of the EHD1-Wnt4 pathway might serve as a promising therapeutic strategy for improving endometrial receptivity in RIF women.


Assuntos
Aborto Habitual/genética , Aborto Habitual/metabolismo , Decídua/metabolismo , Transdução de Sinais , Proteínas de Transporte Vesicular/genética , Proteína Wnt4/metabolismo , beta Catenina/metabolismo , 8-Bromo Monofosfato de Adenosina Cíclica/farmacologia , Aborto Habitual/diagnóstico , Adulto , Biomarcadores , Decídua/efeitos dos fármacos , Decídua/patologia , Células-Tronco Embrionárias/citologia , Células-Tronco Embrionárias/efeitos dos fármacos , Células-Tronco Embrionárias/metabolismo , Feminino , Imunofluorescência , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Adulto Jovem
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