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1.
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
2.
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
3.
PLoS Biol ; 17(10): e3000468, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31609975

RESUMO

Recurrent pregnancy loss (RPL) is an important complication in reproductive health. About 50% of RPL cases are unexplained, and understanding the genetic basis is essential for its diagnosis and prognosis. Herein, we report causal KH domain containing 3 like (KHDC3L) mutations in RPL. KHDC3L is expressed in human epiblast cells and ensures their genome stability and viability. Mechanistically, KHDC3L binds to poly(ADP-ribose) polymerase 1 (PARP1) to stimulate its activity. In response to DNA damage, KHDC3L also localizes to DNA damage sites and facilitates homologous recombination (HR)-mediated DNA repair. KHDC3L dysfunction causes PARP1 inhibition and HR repair deficiency, which is synthetically lethal. Notably, we identified two critical residues, Thr145 and Thr156, whose phosphorylation by Ataxia-telangiectasia mutated (ATM) is essential for KHDC3L's functions. Importantly, two deletions of KHDC3L (p.E150_V160del and p.E150_V172del) were detected in female RPL patients, both of which harbor a common loss of Thr156 and are impaired in PARP1 activation and HR repair. In summary, our study reveals both KHDC3L as a new RPL risk gene and its critical function in DNA damage repair pathways.


Assuntos
Aborto Habitual/genética , Instabilidade Genômica , Células-Tronco Embrionárias Humanas/metabolismo , Poli(ADP-Ribose) Polimerase-1/genética , Proteínas/genética , Reparo de DNA por Recombinação , Aborto Habitual/metabolismo , Aborto Habitual/patologia , Animais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Sistemas CRISPR-Cas , Células Cultivadas , Dano ao DNA , Embrião de Mamíferos , Feminino , Edição de Genes , Regulação da Expressão Gênica , Células-Tronco Embrionárias Humanas/patologia , Humanos , Cariótipo , Camundongos , Camundongos SCID , Micronúcleos com Defeito Cromossômico , Poli(ADP-Ribose) Polimerase-1/metabolismo , Gravidez , Proteínas/metabolismo , Transdução de Sinais
4.
Medicine (Baltimore) ; 98(31): e16361, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31374005

RESUMO

RATIONALE: Habitual abortion is caused by complex and diverse factors, such as genetic factors, immune factors, endocrine factors, viruses, bacterial infections, and so on. Allogeneic antibodies, generated due to blood-group incompatibilities between a female and her fetus, are sometimes important for habitual abortion. PATIENT CONCERNS: A 26-year-old woman had undergone abortions 3 times in July 2015 (17 weeks pregnant), March 2017 (15 weeks of gestation) and February 2018 (16 weeks pregnant) before she came to the Reproductive Medicine Center of our hospital for prenatal examinations without pregnancy. DIAGNOSES: Unexplained habitual abortion. INTERVENTIONS: A series of serological tests and nucleotide sequence of 1,4-galactosyltransferase (A4GALT) gene were performed. OUTCOMES: The patient was the rare p phenotype in P1P blood system and the patient's habitual abortion was caused by anti-PP1P antibody which was generated naturally in persons with p phenotype. There was a mutation (903C>G, CCC>CCG) in the 3rd exon of A4GALT gene, which is likely a significant contributor to p phenotype. LESSONS: This is the first case of habitual abortion caused by p phenotype due to independent 903C>G homozygous mutation with no similar record reported before, which indicates that it is a new class of mutation that leads to p phenotype.


Assuntos
Aborto Habitual/sangue , Galactosiltransferases/análise , Aborto Habitual/genética , Adulto , China , Feminino , Galactosiltransferases/sangue , Humanos , Fenótipo , Gravidez , Estudos Retrospectivos , Mutação Silenciosa/genética
5.
Genet Test Mol Biomarkers ; 23(7): 501-505, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31294627

RESUMO

Aim: To evaluate the associations between idiopathic recurrent early pregnancy loss (REPL) and paraoxonase-1 (PON1) polymorphisms and the activities of its encoded enzymes. Materials and Methods: Ninety-eight women were enrolled in this study, including 21 currently pregnant multiparous women without a history of miscarriage; 18 multiparous women who were not pregnant during the study; 30 women with a history of idiopathic REPL who were pregnant; and 29 who were not. Paraoxonase (PONase) and arylesterase (AREase) activities, two activities of the PON1 enzyme, were measured through commercially available kits (Relassay, Gaziantep, Turkey). PON1 genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) analysis. Data were analyzed using SPSS for Windows version 19.0 (SPSS). Results: There was no association between idiopathic REPL and PON1 polymorphisms or PONase activity. The AREase activity of the PON1 enzyme trended higher in the healthy pregnant group than in the healthy nonpregnant group (p = 0.067), and was higher in the pregnant group with a history of idiopathic REPL than in the nonpregnant group with a history of idiopathic REPL (p = 0.041). Conclusions: Despite there being no detected association between PON1 activities or genotype and idiopathic REPL, we showed that AREase activity increased during early gestation. New studies, including longitudinal changes in serum AREase activity throughout normal pregnancy, should be carried out to further evaluate the association between PON encoded enzymatic activities and early gestational pathophysiology.


Assuntos
Aborto Habitual/genética , Arildialquilfosfatase/genética , Aborto Habitual/enzimologia , Adulto , Arildialquilfosfatase/sangue , Hidrolases de Éster Carboxílico/sangue , Hidrolases de Éster Carboxílico/genética , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Humanos , Polimorfismo de Fragmento de Restrição , Gravidez , Estudos Prospectivos
6.
Int J Mol Sci ; 20(13)2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31284523

RESUMO

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.


Assuntos
Regiões 3' não Traduzidas/genética , Aborto Habitual/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Fator A de Crescimento do Endotélio Vascular/genética , Aborto Habitual/epidemiologia , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene , Haplótipos/genética , Humanos , Incidência , Modelos Lineares , Gravidez
7.
Reprod Biol Endocrinol ; 17(1): 52, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31288842

RESUMO

BACKGROUND: Recurrent pregnancy loss (RPL) refers to two or more spontaneous abortions that occur consecutively with the same spouse. RPL severely affects human reproduction health, and causes extreme physical and mental suffering to patients and their families. METHODS: We used isobaric tags for relative and absolute quantitation (iTRAQ), which was coupled with liquid chromatography mass spectrometry (LC-MS) proteomic analysis, in order to identify differentially expressed proteins. Moreover, we used western blot to analyze differentially expressed proteins. RESULTS: Of the 2350 non-redundant proteins identified, 38 proteins were significantly altered and were identified as potential biomarkers for RPL. The protein-protein interaction network constructed using GeneMANIA revealed that 35.55% displayed similar co-expression, 30.87% were predicted, and 20.95% had physical interaction characteristics. Based on Gene ontology classification and KEGG pathway enrichment analyses, the majority of these differentially expressed proteins were found to be related to biological regulation, metabolic and cellular processes, protein binding and different enzymes activities, as well as disorder of fat and glucose metabolic pathways. It is noteworthy that three metabolism related biomarkers (HK1, ACLY, and FASN) were further confirmed through western blot analysis. CONCLUSIONS: These results suggest that these differentially expressed proteins may be used as biomarkers for RPL, and related signaling pathways may play crucial roles in male induced RPL.


Assuntos
Aborto Habitual/metabolismo , Proteoma/metabolismo , Proteômica/métodos , Espermatozoides/metabolismo , Aborto Habitual/genética , Cromatografia Líquida , Feminino , Perfilação da Expressão Gênica/métodos , Ontologia Genética , Humanos , Masculino , Gravidez , Mapas de Interação de Proteínas/genética , Proteoma/genética , Transdução de Sinais/genética , Espectrometria de Massas em Tandem
8.
J Assist Reprod Genet ; 36(8): 1539-1548, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31273585

RESUMO

PURPOSE: Non-aneuploid recurrent pregnancy loss (RPL) affects approximately 100,000 pregnancies worldwide annually. Exome sequencing (ES) may help uncover the genetic etiology of RPL and, more generally, pregnancy loss as a whole. Previous studies have attempted to predict the genes that, when disrupted, may cause human embryonic lethality. However, predictions by these early studies rarely point to the same genes. Case reports of pathogenic variants identified in RPL cases offer another clue. We evaluated known genetic etiologies of RPL identified by ES. METHODS: We gathered primary research articles from PubMed and Embase involving case reports of RPL reporting variants identified by ES. Two authors independently reviewed all articles for eligibility and extracted data based on predetermined criteria. Preliminary and amended analysis isolated 380 articles; 15 met all inclusion criteria. RESULTS: These 15 articles described 74 families with 279 reported RPLs with 34 candidate pathogenic variants in 19 genes (NOP14, FOXP3, APAF1, CASP9, CHRNA1, NLRP5, MMP10, FGA, FLT1, EPAS1, IDO2, STIL, DYNC2H1, IFT122, PADI6, CAPS, MUSK, NLRP2, NLRP7) and 26 variants of unknown significance in 25 genes. These genes cluster in four essential pathways: (1) gene expression, (2) embryonic development, (3) mitosis and cell cycle progression, and (4) inflammation and immunity. CONCLUSIONS: For future studies of RPL, we recommend trio-based ES in cases with normal parental karyotypes. In vitro fertilization with preimplantation genetic diagnosis can be pursued if causative variants are found. Utilization of other sequencing technologies in concert with ES should improve understanding of the causes of early embryonic lethality in humans.


Assuntos
Aborto Habitual/diagnóstico , Aborto Habitual/genética , Genes Essenciais , Primeiro Trimestre da Gravidez/genética , Segundo Trimestre da Gravidez/genética , Sequenciamento Completo do Exoma/métodos , Feminino , Humanos , Gravidez
9.
Genes Genet Syst ; 94(3): 109-116, 2019 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-31270294

RESUMO

Interleukins play important roles in pregnancy. Altered expression and splicing of various interleukins have been linked to the pathophysiology of recurrent pregnancy loss. Polymorphisms in interleukin genes can affect the expression and/or splicing of their respective genes and thus influence the risk of recurrent pregnancy loss. In this work, we examined the association between the IL1B rs16944, IL1B rs1143634, IL6 rs1800795, IL6 rs1800796, IL10 rs1800896 and IL18 rs187238 polymorphisms and recurrent pregnancy loss risk in a Chinese population. Study subjects comprised 598 idiopathic recurrent pregnancy loss patients and 603 controls. The genotyping was accomplished by PCR-RFLP. Regression analysis was performed to evaluate the disease association. After adjustment by Bonferroni correction, only the IL1B rs16944 and IL6 rs1800796 polymorphisms were significantly associated with risk of recurrent pregnancy loss. The heterozygous TC genotype of IL1B rs16944 had an adjusted odds ratio (aOR) of 1.4209 (1.1302-1.8929) (P = 0.0019), while the homozygous CC genotype had an aOR of 1.7398 (1.2133-2.3203) (P = 0.0008). A significant association was also observed for the C allele [aOR = 1.3747 (1.1296-1.8972)] (P = 0.0003). For IL6 rs1800796, the heterozygous CG genotype, the homozygous GG genotype and the G allele had aORs of 0.7342 (0.4412-0.8423) (P = 0.0016), 0.5424 (0.1768-0.7865) (P = 0.0014) and 0.7009 (0.4511-0.8034) (P = 0.0007), respectively. In summary, the IL1B rs16944 and IL6 rs1800796 variants were associated with an increased and a decreased recurrent pregnancy loss risk, respectively.


Assuntos
Aborto Habitual/genética , Predisposição Genética para Doença , Interleucina-1beta/genética , Interleucina-6/genética , Aborto Habitual/fisiopatologia , Adulto , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Interleucina-10/genética , Interleucina-18/genética , Polimorfismo de Nucleotídeo Único/genética , Gravidez
10.
J Assist Reprod Genet ; 36(7): 1315-1328, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31254142

RESUMO

PURPOSE: The aim is to summarize and evaluate current systematic reviews and meta-analyses on MTHFR polymorphisms in recurrent pregnancy loss (RPL). METHODS: We searched Pubmed and Embase databases and selected in form of PICOS (participants, interventions, comparisons, outcomes, and study design). Our methodology was registered on PROSPERO (CRD42017042762). Systematic reviews and meta-analyses containing primary studies were extracted for meta-analyses, along with their OR and 95%CI. We assessed the quality of the included studies using AMSTAR and OQAQ criteria. RESULTS: Eleven systematic reviews and meta-analyses were identified. C677T was significantly related to RPL overall in Allele (OR, 95%CI 1.43, 1.29-1.60), Recessive (OR, 95%CI 1.66, 1.42-1.95), and Homozygous (OR, 95%CI 2.08, 1.66-2.61). There was no correlation observed between A1298C and RPL, except for in Heterozygous (OR, 95%CI 1.62, 1.17-2.25). CONCLUSIONS: We identified a difference in the association between MTHFR C677T polymorphism and RPL, especially in Asian population. No significant correlation was found between A1298C and RPL.


Assuntos
Aborto Habitual/genética , Predisposição Genética para Doença , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Aborto Habitual/patologia , Alelos , Feminino , Genótipo , Homozigoto , Humanos , Polimorfismo de Nucleotídeo Único/genética , Gravidez , Fatores de Risco
11.
J Assist Reprod Genet ; 36(7): 1355-1359, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31190166

RESUMO

PURPOSE: To investigate the effect of the anticoagulation factor annexin A5 on male fertility and to provide perspective on the influence of members of the coagulation cascade on fertility. METHODS: Patients with normozoospermia and with unexplained severe oligozoospermia were retrospectively selected and their genomic DNA sequenced for the promoter region of ANXA5. The genotypes proportions and the odds ratio for carriership of the haplotype M2 were compared between the groups and population control. The clinical data used were gathered from parameters determined during routine clinical assessment and were compared between carriers and non-carriers within the patient groups. RESULTS: The carrier rates for the haplotype M2/ANXA5 were of 25.73%, 20.81%, and 15.3% in the severe oligozoospermic, the normozoospermic, and the general population control groups, respectively. The OR between patients groups was of 1.31 (95% CI 0.88 to 1.96 p = 0.176). Oligozoospermic and normozoospermic patients compared with the control group had an OR of 1.9 (95% CI 1.33 to 2.73 p < 0.001) and 1.45 (95% CI 0.99 to 2.10 p = 0.054) respectively. The clinical parameters that differed between the carriers and non-carriers of the haplotype M2/ANXA5 were prolactin, α-glucosidase, and fructose. The differences were only statistically significant in the normozoospermic group. CONCLUSIONS: Athough the infertile patient groups had a higher prevalence of promoter variants, we could not demonstrate any biologically relevant effect of lower levels of annexin A5 on most male fertility parameters. A deficiency in an anticoagulation factor does not seem to impact male fertility.


Assuntos
Aborto Habitual/genética , Anexina A5/genética , Predisposição Genética para Doença , Infertilidade Masculina/genética , Aborto Habitual/epidemiologia , Aborto Habitual/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Frutose/genética , Genótipo , Haplótipos/genética , Humanos , Infertilidade Masculina/epidemiologia , Infertilidade Masculina/patologia , Masculino , Pessoa de Meia-Idade , Gravidez , Prolactina/genética , Regiões Promotoras Genéticas , Estudos Retrospectivos , Fatores de Risco , Contagem de Espermatozoides , Adulto Jovem , alfa-Glucosidases/genética
12.
J Obstet Gynaecol Res ; 45(8): 1442-1447, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31172624

RESUMO

AIM: The aim of this study is to determine the association between C677T polymorphism in MTHFR gene and plasma homocysteine concentration in recurrent fetal miscarriages. METHODS: Overall, 100 women were included in the research, the case group comprised of 50 women who had a history of spontaneously recurrent miscarriage with unspecified cause, and 50 of whom had experienced at least two successful pregnancy, as controls. Methods used in the study included PCR-RFLP with limited effective HinfI enzyme in order to investigate MTHFR polymorphism and enzyme-linked immunosorbent assay analysis to investigate plasma homocysteine concentration. RESULTS: There was a significant increase in the prevalence of mutant TT genotype among women with miscarriage history. Also, the mean homocysteine level in the case group was significantly higher than that in the control group (P = 0.002) and higher level of homocysteine was found in the carriers of T allele. CONCLUSION: Our data suggest that C677TT genotype may be a risk factor for miscarriage and CC wild type genotype supposed to have protective effect on hyperhomocysteinemia.


Assuntos
Aborto Habitual/sangue , Aborto Habitual/genética , Homocisteína/sangue , Hiper-Homocisteinemia/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Adulto , Feminino , Humanos , Polimorfismo Genético , Gravidez
13.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 35(4): 351-356, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31167695

RESUMO

Objective To explore the genome-wide DNA methylation level and the expression of DNA methylation-related enzymes in the villi tissue of patients with unexplained recurrent spontaneous abortion (URSA). Methods The villi samples were obtained from thirty-one URSA patients (URSA group) and thirty pregnancy women who underwent induced abortion (control group). Total DNA methylation was determined by ELISA. Real-time quantitative PCR was used to detect mRNA levels of DNMT1, DNMT3a, DNMT3b, TET1, TET2 and TET3, and Western blot analysis was used to detect protein levels of DNMT1, DNMT2, DNMT3, TET1, TET2 and TET3. Immunohistochemistry was performed to detect the expression and distribution of DNMT1, DNMT3a, DNMT3b, TET1, TET2 and TET3 in villi tissues. Results Methylation level of total DNA in the URSA group was significantly lower than that of the control group. Compared with the control group, mRNA and protein expression levels of DNMT1 and DNMT3b significantly decreased, while TET1 and TET2 significantly increased in the villi of the URSA group. Conclusion The methylation level is reduced in the villi of URSA women, which may be correlated with up-regulated expression of DNMT1 and DNMT3b and down-regulated expression of TET1 and TET2.


Assuntos
Aborto Habitual/genética , DNA (Citosina-5-)-Metiltransferase 1/genética , DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA , Proteínas de Ligação a DNA/genética , Oxigenases de Função Mista/genética , Proteínas Proto-Oncogênicas/genética , Feminino , Humanos , Imuno-Histoquímica , Gravidez , RNA Mensageiro
14.
J Clin Lab Anal ; 33(6): e22919, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31124188

RESUMO

Studies have shown that many genes that regulate cell migration are associated with susceptibility to recurrent miscarriage. Terminal differentiation-induced non-coding RNA (TINCR) regulates the migration and invasion of a variety of tumor cells and is associated with susceptibility to various diseases. However, whether the lncRNA TINCR polymorphism is associated with susceptibility to recurrent miscarriage is unclear. Therefore, we investigated the relationship between the rs2288947 A > G polymorphism of the lncRNA TINCR and susceptibility to recurrent abortion. We recruited 248 recurrent spontaneous abortion patients and 392 healthy control subjects from the Southern Chinese population and used the TaqMan method for genotyping. There was no evidence that this polymorphism is associated with recurrent miscarriage (AG vs AA: adjusted OR = 0.904, 95% CI = 0.647-1.264, P = 0.5552; GG and AA: adjusted OR = 0.871, 95% CI = 0.475-1.597, P = 0.6542; dominant model: AG/GG vs AA: adjusted OR = 0.898, 95% CI = 0.653-1.236, P = 0.5101; and recessive model: GG vs AA/AG: adjusted OR = 0.910, 95% CI = 0.505-1.639, P = 0.7527). The stratified analysis also showed no significant associations. This study suggests that the rs2288947 A > G polymorphism of the lncRNA TINCR may not be associated with recurrent miscarriage in a Southern Chinese population. A larger multicenter study is needed to confirm our conclusions.


Assuntos
Aborto Habitual/genética , Polimorfismo de Nucleotídeo Único , RNA Longo não Codificante/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos
15.
Genes (Basel) ; 10(5)2019 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-31067818

RESUMO

Recurrent pregnancy loss (RPL) refers to two or more consecutive pregnancy losses. It is estimated that fewer than 5% of women experience RPL. Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that play important roles in providing a safe and conducive environment for the stable development of the fetus. In this case-control study, we evaluated the associations between RPL and single nucleotide polymorphisms (SNPs) in MMP-8 and MMP-27. We recruited 375 Korean women with a history of RPL and 240 ethnically-matched healthy parous controls, and we performed genotyping for the MMP-8 rs2509013 C>T, MMP-8 rs11225395 G>A, and MMP-27 rs3809017 T>C polymorphisms. All SNPs were genotyped via the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. In the genotype frequency analyses, the TT genotype of the MMP-8 rs2509013 C>T (age-adjusted odds ratio, 0.415; 95% confidence interval, 0.257-0.671; P = 0.0003) and TC genotype of MMP-27 rs3809017 T>C (age-adjusted odds ratio, 0.681; 95% confidence interval, 0.483-0.961; P = 0.029) were associated with decreased RPL susceptibility. Moreover, these trends were maintained in the haplotype and genotype combination analyses. Interestingly, amongst the RPL patients, higher levels of homocysteine (P = 0.042) and uric acid (P = 0.046) were associated with MMP-27 rs3809017 T>C. In conclusion, the two polymorphisms of MMP-8 and MMP-27 were significantly associated with RPL risk, both individually and in combination. Therefore, these two polymorphisms are potential biomarkers for RPL susceptibility.


Assuntos
Aborto Habitual/genética , Metaloproteinase 8 da Matriz/genética , Metaloproteinases da Matriz Secretadas/genética , Adulto , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Genótipo , Humanos , Polimorfismo de Nucleotídeo Único , Gravidez
16.
Biomed Res Int ; 2019: 9797104, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31061830

RESUMO

Translocations are the most common type of structural chromosomal abnormalities. Unbalanced translocations are usually found in children who present with congenital abnormalities, developmental delay, or intellectual disability. Balanced translocations are usually found in adults who frequently present with reproductive failure; either subfertility, or recurrent pregnancy loss. Herein, we report the spectrum and frequency of translocations in a Sri Lankan cohort. A database of patients undergoing cytogenetic testing was maintained prospectively from January 2007 to December 2016 and analyzed, retrospectively. A total of 15,864 individuals were tested. Among them, 277 (1.7%) had translocations. There were 142 (51.3%) unbalanced translocations and 135 (48.7%) balanced translocations. Majority (160; 57.8%) were Robertsonian translocations. There were 145 (52.3%) children and adolescents aged less than 18 years with translocations, and 142 (97.9%) were unbalanced translocations. Majority [138 (95.2%)] were referred due to congenital abnormalities, developmental delay, or intellectual disability, and 91 were children with translocation Down syndrome. All adults aged 18 years or above (132) had balanced translocations. Subfertility and recurrent pregnancy loss [84 (63.6%)] and offspring(s) with congenital abnormalities [48 (36.4%)] were the most common indications in this group. Majority (68.2%) in this group were females with reciprocal translocations (55.3%). Chromosomes 21, 14, and 13 were the most commonly involved with rob(14q21q) [72 (26%)], rob(21q21q) [30 (13.7%)], and rob(13q14q) [34 (12.3%)] accounting for 52% of the translocations. Chromosomes 1, 8, 11, and 18 were most commonly involved in reciprocal translocations. The observed high frequency of chromosomal translocations in our cohort highlights the importance of undertaking cytogenetic evaluation and providing appropriate genetic counseling for individuals with the phenotypes associated with these translocations.


Assuntos
Aborto Habitual/genética , Cromossomos Humanos/genética , Síndrome de Down/genética , Translocação Genética , Aborto Habitual/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Síndrome de Down/epidemiologia , Feminino , Aconselhamento Genético , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Sri Lanka/epidemiologia
17.
J Gynecol Obstet Hum Reprod ; 48(7): 521-525, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31085277

RESUMO

OBJECTIVE: Chromosomal abnormalities are more common in the first trimester abortions. We aimed to investigate the types and prevalence of chromosomal abnormalities in couples with recurrent first trimester miscarriages in Sivas, Turkey. MATERIALS AND MEDHODS: Three hundred couples (600 individuals) who had a story of recurrent abortion were included in the study. Chromosome analysis was performed after the preparation of lymphocyte culture with the standard method. Karyotype analyses were supported by FISH and aCGH studies. RESULTS: Total 26 chromosome abnormalities (8.7%) were found in the couples (19 females and 7 males). Fifteen cases (57.7%) were structural anomalies and eleven cases (42.3%) were numerical chromosomal aberrations. We detected 5 balanced translocations (33.3%), 4 Robertsonian translocations (26.7%), 3 inversions (20%), 2 duplications (13.3%) and one deletion (6.7%) among the structural anomalies. Mosaic monosomy X in five cases (45.4%), the combination of mosaic monosomy-trisomy X in three cases (27.3%), the combination of mosaic monosomy-trisomy and tetrasomy X in two cases (18.2%) and mosaic pentasomy X in only one individual (9.1%) were encountered as numerical chromosome aberrations. 19 cases had heterochromatic changes or other chromosomal variations (satellite increments and inv9). CONCLUSION: Chromosome analysis in couples with recurrent miscarriage is necessary for possible preimplantation genetic diagnosis. As well as numerical and structural chromosome abnormalities, some chromosomal variations (heterochromatin and satellite increments etc.) may also contribute to recurrent miscarriages. Numerical chromosomal abnormalities are often associated with sex chromosomes and usually seen in females.


Assuntos
Aborto Habitual/epidemiologia , Aborto Habitual/genética , Transtornos Cromossômicos/epidemiologia , Primeiro Trimestre da Gravidez , Aborto Habitual/diagnóstico , Adolescente , Adulto , Transtornos Cromossômicos/diagnóstico , Características da Família , Feminino , Humanos , Cariotipagem , Masculino , Gravidez , Prevalência , Estudos Retrospectivos , Turquia/epidemiologia , Adulto Jovem
18.
J Assist Reprod Genet ; 36(5): 995-1002, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30937706

RESUMO

PURPOSE: Idiopathic recurrent pregnancy loss (RPL) is a multifactorial reproductive disorder where an impaired control of apoptosis is likely involved. Triggering the cell death mechanism occurs in a spatiotemporal manner and is strongly related to a healthy pregnancy. Single nucleotide polymorphisms (SNPs) at the regulatory regions of genes are known to influence the expression patterns of apoptosis-related molecules. METHODS: A total of 296 unrelated female Brazilian patients were evaluated for clinical-demographic variables and genetic factors: 140 women who had experienced an unexplained RPL (with at least two consecutive abortions) and 156 healthy multiparous women. In all patients, six SNPs were evaluated in genes of apoptosis-related pathways: FAS (rs2234767, rs1800682), FAS-L (rs763110, rs5030772), BAX (rs4645878), and BCL-2 (rs2279115) by PCR followed by a restriction fragment length polymorphism (RFLP)-based analysis. RESULTS: The BAX-248GA genotype is independently associated with idiopathic RPL [adjusted OR = 0.30, 95% CI 0.13-0.70, P = 0.005] susceptibility. In the same multivariate model, the variables ethnicity, smoking, and alcohol consumption were statistically associated with RPL susceptibility (P < 0.05). No association with RPL susceptibility was reported for the remaining SNPs. CONCLUSION: Our study is the first to evaluate the role of the main SNPs from both the extrinsic and intrinsic apoptosis pathways in RPL susceptibility. The association of BAX-248G/A with RPL susceptibility suggests that maternal predisposition for RPL has an essential contribution from genes involved in the delicate balance of endometrium cell turnover (cell death/proliferation). Therefore, apoptotic genes may represent promising targets for future studies on healthy pregnancies and the spectrum of pregnancy disorders.


Assuntos
Aborto Habitual/genética , Proteína Ligante Fas/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteína X Associada a bcl-2/genética , Receptor fas/genética , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Genótipo , Humanos , Gravidez , Prognóstico , Adulto Jovem
19.
Gene ; 704: 68-73, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30986448

RESUMO

AIM: The purpose of the present study is to evaluate and understand the association of global and MTHFR gene specific methylation in preeclampsia and recurrent miscarriages in light of MTHFR C677T polymorphism. METHODS: The subjects comprised of recurrent miscarriage cases, their gestation matched controls, preeclampsia cases and matched controls. A set of women at full term were also recruited. Fasting blood sample (~5 ml) was drawn from all the participants followed by DNA extraction, global DNA methylation and MTHFR gene specific methylation. MTHFR C677T polymorphism was analysed by PCR followed by RFLP. RESULTS HIGHER: Global DNA methylation at maternal front (p = 0.04) and hypomethylation of MTHFR gene at fetal front (p = 0.001) might be a characteristic of preeclampsia. Recurrent miscarriage cases were having significantly (p = 0.002) hyper MTHFR gene specific methylation as compared to controls. Women carrying CT genotype were found to be having significantly (p = 0.001) higher global DNA methylation in PE cases and MTHFR gene specific methylation (p = 0.005) in RM cases. Intergenerational analysis revealed similar patterns of global DNA methylation and MTHFR gene specific methylation among both PE and RM cases at maternal and fetal fronts. CONCLUSION: The study highlights the importance of global DNA methylation in Preeclampsia and MTHFR gene specific methylation in recurrent miscarriages. MTHFR C677T gene polymorphism in association with global and gene specific methylation seem to play a pivotal role in PE and RM respectively.


Assuntos
Aborto Habitual/genética , Metilação de DNA , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pré-Eclâmpsia/genética , Adulto , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Homocistinúria/complicações , Homocistinúria/genética , Humanos , Índia , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Espasticidade Muscular/complicações , Espasticidade Muscular/genética , Polimorfismo de Fragmento de Restrição , Polimorfismo de Nucleotídeo Único , Pré-Eclâmpsia/diagnóstico , Gravidez , Segundo Trimestre da Gravidez/genética , Terceiro Trimestre da Gravidez/genética , Transtornos Psicóticos/complicações , Transtornos Psicóticos/genética
20.
J Obstet Gynaecol Res ; 45(6): 1106-1113, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30968528

RESUMO

AIM: As angiogenesis is an essential step for chorionic villi formation. Vascular endothelial growth factor (VEGF) is essential for endothelial cell proliferation. Endothelial nitric oxide synthase (eNOS) is a powerful playmaker in hypoxia-induced angiogenesis. Thrombin-activatable fibrinolysis inhibitor (TAFI) regulates both fibrinolysis and inflammation. Genetic alterations of these factors may lead to recurrent spontaneous abortion (RSA). We aimed to investigate the combined genetic variants of VEGF G-1154A and two eNOS genetic variants: T-786C promoter region and intron 4 variable number of tandom repeats in addition to TAFI C-1040T among RSA patients. METHODS: The study included 50 patients with RSA and 50 healthy controls. Polymerase chain reaction and restriction fragment length polymorphism were used for genotyping. RESULTS: Both genetic alterations of eNOS confirmed at least a sixfold increase of RSA risk. Interestingly, they were associated with TAFI C-1040Tgenetic variant in 21 patients, eight of them had both studied eNOS genetic alterations and TAFI C-1040Tgenetic variant, while each eNOS genetic variant associated with TAFI C-1040Tconfirmed an almost one and half fold increase risk of RSA. CONCLUSION: These findings highlighted the role of eNOS and nitric oxide metabolism in RSA and opened the gate to investigate the interaction of vasoconstrictive and fibrinolytic inhibitor systems.


Assuntos
Aborto Habitual/genética , Carboxipeptidase B2/genética , Óxido Nítrico Sintase Tipo III/genética , Fator A de Crescimento do Endotélio Vascular/genética , Adolescente , Adulto , Estudos de Casos e Controles , Egito , Feminino , Humanos , Gravidez , Adulto Jovem
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