Hyaluronan-binding protein 2 (HABP2) gene variation in women with recurrent miscarriage.
ABSTRACT: BACKGROUND:Idiopathic recurrent miscarriage, defined as three or more consecutive miscarriages, is a distressing early pregnancy complication. Although, the etiology of recurrent miscarriage is still unknown, an aberrant regulation of the endometrial receptivity marker hyaluronan-binding protein 2 (HABP2) has been suggested. The objective of the present study was to investigate the effect of genetic variations of HABP2 in women with idiopathic recurrent miscarriage compared to fertile women. METHODS:This study was designed as a case-control study. In total, 165 women who had three or more consecutive miscarriages and 289 fertile women were included in the study. Polymorphisms in the HABP2 gene were analyzed using TaqMan SNP Genotyping Assays. Three polymorphisms in the HABP2 gene, rs1157916, rs2240879 and rs7080536 (Marburg I) were studied. RESULTS:Polymorphism in HABP2 showed no significant difference in women with recurrent miscarriage compared to fertile women, except for rs1157916 minor A allele that was more prevalent among RM patients (p =?0.058). Significantly higher live birth rate was observed among women with three to four miscarriages compared to those with more miscarriages (p?=?0.001). CONCLUSIONS:Variations in the HABP2 gene did not seem to be involved in the etiology of recurrent miscarriage, while, the number of previous miscarriages had an impact on the live birth rate.
Project description:PURPOSE:To evaluate whether anti-Mullerian hormone, basal follicle-stimulating hormone, luteinizing hormone, estradiol, and female age would predict future outcomes in women with idiopathic recurrent miscarriage. METHODS:One hundred and sixteen women with idiopathic recurrent miscarriage were retrospectively included. Luteal support with or without a combined treatment regimen for idiopathic recurrent miscarriage was applied in a tertiary-care center in Vienna. Occurrence and outcome of further pregnancies were analyzed. RESULTS:Within a median follow-up duration of 42.3 months, 94 women (81.0%) achieved one or more pregnancies. Further miscarriages occurred in 47 patients in whom only a higher number of previous miscarriages was predictive (OR 3.568, 95% CI 1.457-8.738; p?=?0.005). Fifty-seven women had a live birth >?23?+?0 gestational weeks. In a multivariate analysis, age (OR 0.920, 95% CI 0.859-0.986; p?=?0.019) and the number of previous miscarriages (OR 0.403, 95% CI 0.193-0.841; p?=?0.016), but not AMH (OR 1.191, 95% CI 0.972-1.461; p?=?0.091) were significantly predictive. CONCLUSION:AMH seems of either no or only minor relevance for the prediction of further miscarriages and live birth in women with idiopathic recurrent miscarriage.
Project description:CONTEXT:A recent study reported the non-synonymous G534E (rs7080536, allele A) variant in the HABP2 gene as causal in familial non-medullary thyroid cancer (NMTC). OBJECTIVE:The objective of this study was to evaluate the causality of HABP2 G534E in the TCUKIN study, a multi-center population based study of NMTC cases from the British Isles. DESIGN AND SETTING:A case-control analysis of rs7080536 genotypes was performed using 2,105 TCUKIN cases and 5,172 UK controls. PARTICIPANTS:Cases comprised 2,105 NMTC cases. Patients sub-groups with papillary (N=1,056), follicular (N=691) and Hurthle cell (N=86) TC cases were studied separately. Controls comprised 5,172 individuals from the 1958 Birth Cohort (58C) and the National Blood Donor Service (NBS) study. The controls had previously been genotyped using genome-wide SNP arrays by the Wellcome Trust Case Control Consortium study. OUTCOME:Measures: Association between HABP2 G534E (rs7080536A) and NMTC risk was evaluated using logistic regression. RESULTS:The frequency of HABP2 G534E was 4.2% in cases and 4.6% in controls. We did not detect an association between this variant and NMTC risk (OR=0.896, 95% CI: 0.746-1.071, P=0.233). We also failed to detect an association between HABP2 G534E and cases with papillary (1056 cases, G534E frequency= 3.5%, OR=0.74, P=0.017), follicular (691 cases, G534E frequency= 4.7%, OR=1.00, P=1.000) or Hurthle cell (86 cases, G534E frequency= 6.3%, OR=1.40, P=0.279) histology. CONCLUSIONS:We found that HABP2 G534E is a low-to-moderate frequency variant in the British Isles and failed to detect an association with NMTC risk, independent of histological type. Hence, our study does not implicate HABP2 G534E or a correlated polymorphism in familial NMTC and additional data are required before using this variant in NMTC risk assessment.
Project description:siblings of patients with idiopathic recurrent miscarriage have a higher risk of miscarriage. <br>We hypothesized that this in part was conferred by shared genetic factors.<br>We took blood samples from patients with three or more miscarriages and from siblings with two or more miscarriages in order to perform affected sib-pair analysis.
Project description:The main nonmedullary form of thyroid cancer is papillary thyroid carcinoma (PTC) that accounts for 80-90% of all thyroid malignancies. Only 3-10% of PTC patients have a positive family history of PTC yet the familiality is one of the highest of all cancers as measured by case control studies. A handful of genes have been implicated accounting for a small fraction of this genetic predisposition. It was therefore of considerable interest that a mutation in the HABP2 gene was recently implicated in familial PTC. The present work was undertaken to examine the extent of HABP2 variant involvement in PTC. The HABP2 G534E variant (rs7080536) was genotyped in blood DNA from 179 PTC families (one affected individual per family), 1160 sporadic PTC cases and 1395 controls. RNA expression of HABP2 was tested by qPCR in RNA extracted from tumor and normal thyroid tissue from individuals that are homozygous wild-type or heterozygous for the variant. The variant was found to be present in 6.1% familial cases, 8.0% sporadic cases (2 individuals were homozygous for the variant) and 8.7% controls. The variant did not segregate with PTC in one large and 6 smaller families in which it occurred. In keeping with data from the literature and databases the expression of HABP2 was highest in the liver, much lower in 3 other tested tissues (breast, kidney, brain) but not found in thyroid. Given these results showing lack of any involvement we suggest that the putative role of variant HABP2 in PTC should be carefully scrutinized.
Project description:CONTEXT:Recurrent miscarriages, the loss of three or more consecutive intrauterine pregnancies before 20 weeks of gestation with the same partner, affect 1%-1.5% of the pregnant population. The inadequate secretion of progesterone in early pregnancy has been proposed as a cause of recurrent miscarriages. AIMS:The aim was to investigate the efficacy of progesterone supplementation in patients with unexplained recurrent miscarriages. SETTINGS AND DESIGN:This was a 9-year cohort study of women with otherwise unexplained recurrent miscarriages who attended a recurrent miscarriage clinic in a tertiary care university hospital. SUBJECTS AND METHODS:Women with at least three unexplained recurrent miscarriages were included in the study. They were divided into three groups according to their initial and 48-h repeat progesterone levels. For women with inadequate endogenous progesterone secretion, natural progesterone vaginal pessaries 400 mg 12-hourly were offered until 12 weeks gestation. STATISTICAL ANALYSIS:Proportions and 95% confidence intervals calculated for categorical variables and the chi-square test were used to show statistical significance. Medians and ranges were calculated for noncontinuous variables. RESULTS:Pregnancy cycles (n = 203) were analyzed to examine the miscarriage rate following progesterone supplementation. Overall live birth and miscarriage rates were 63% and 36%, respectively. When analyzed by the number of previous miscarriages there was a reduction in the miscarriage rate following progesterone supplementation in women with 4 previous miscarriages when compared with historical data. CONCLUSIONS:Progesterone supplementation may have beneficial effects in women with otherwise unexplained recurrent miscarriages.
Project description:Next-generation sequencing using exome capture is a common approach used for analysis of familial cancer syndromes. Despite the development of robust computational algorithms, the accrued experience of analyzing exome data sets and published guidelines, the analytical process remains an ad hoc series of important decisions and interpretations that require significant oversight. Processes and tools used for sequence data generation have matured and are standardized to a significant degree. For the remainder of the analytical pipeline, however, the results can be highly dependent on the choices made and careful review of results. We used primary exome sequence data, generously provided by the corresponding author, from a family with highly penetrant familial non-medullary thyroid cancer reported to be caused by HABP2 rs7080536 to review the importance of several key steps in the application of exome sequencing for discovery of new familial cancer genes. Differences in allele frequencies across populations, probabilities of familial segregation, functional impact predictions, corroborating biological support, and inconsistent replication studies can play major roles in influencing interpretation of results. In the case of HABP2 rs7080536 and familial non-medullary thyroid cancer, these factors led to the conclusion of an association that most data and our re-analysis fail to support, although larger studies from diverse populations will be needed to definitively determine its role.
Project description:BACKGROUND: Idiopathic recurrent miscarriage is defined as 3 consecutive pregnancy losses with no contributing features found on investigations. At present there are no treatments of proven efficacy for idiopathic recurrent miscarriage. Uterine natural killer (uNK) cells, the most predominant leucocyte in the endometrium are adjacent to foetal trophoblast cells and thought to be involved in implantation. The exact mechanisms of how uNK cells affect implantation are not clear but are probably through the regulation of angiogenesis. Multiple studies have shown an association between high density of uterine natural killer cells and recurrent miscarriage. We have shown that prednisolone reduces the number of uNK cells in the endometrium. The question remains as to whether reducing the number of uNK cells improves pregnancy outcome. METHODS: We propose a randomised, double-blind, placebo controlled trial of prednisolone with a pilot phase to assess feasibility of recruitment, integrity of trial procedures, and to generate data to base future power calculations. The primary aim is to investigate whether prednisolone therapy during the first trimester of pregnancy is able to improve live birth rates in patients with idiopathic recurrent miscarriage and raised uNK cells in the endometrium. Secondary outcomes include conception rate, karyotype of miscarriage, miscarriages (first and second trimester), stillbirths, pregnancy complications, gestational age at delivery, congenital abnormality and side effects of steroids. The trial has 2 stages: i) screening of non-pregnant women and ii) randomisation of the pregnant cohort. All patients who fit the inclusion criteria (<40 years old, > or =3 consecutive miscarriages with no cause found and no contraindications to prednisolone therapy) will be asked to consent to an endometrial biopsy in the mid-luteal phase to assess their levels of uNK cells. Women with high levels of uNK cells (> or =5%), will be randomised to either prednisolone or placebo when a pregnancy is confirmed. Follow-up includes 2 weekly ultrasound scans in the first trimester, an anomaly scan at 20 weeks gestation, growth scans at 28 and 34 weeks gestation and a postnatal follow-up at 6 weeks. TRIAL REGISTRATION: Current Controlled Trials ISRCTN28090716.
Project description:We correlated Anti-Mullerian hormone (AMH) levels and other parameters for ovarian reserve to the gestational age at the time of pregnancy loss in women with idiopathic recurrent miscarriage. In a retrospective study, 79 patients had suffered a total of 266 miscarriages. When comparing women with an "unembryonic" to those with an "embryonic" most recent miscarriage, there was no difference in median age (36.3 years, IQR 31.6-40.1 versus 34.2 years, IQR 29.9-38.0; p = 0.303) but in median AMH levels (0.7, IQR 0.2-18, versus median 1.8, IQR 1.3-3.3, respectively, p = 0.044) and in the rate of patients with an AMH ≤ 1 ng/mL (23/37, 62.2%, versus 8/42, 19%; p < 0.001). Thus, AMH might add to the diagnostic process in recurrent miscarriage in the future.
Project description:Idiopathic secondary recurrent miscarriage may be associated with an abnormal maternal immune response to subsequent pregnancies. Intravenous immunoglobulin (IVIG) has been studied in randomized controlled trials (RCTs) with conflicting results. Therefore, a definitive trial was proposed.We conducted an investigator-initiated, multicentered, randomized, double-blinded, placebo-controlled trial comparing IVIG with saline in women with idiopathic secondary recurrent miscarriage, defined as a history of at least one prior ongoing pregnancy followed by three or more consecutive unexplained miscarriages. Subjects received either IVIG 500 mg/kg or the equivalent volume of normal saline. Preconception infusions were administered 14-21 days from the projected next menstrual period. With documentation of pregnancy, the subject received the same infusion every 4 weeks until 18-20 weeks of gestation. The primary outcome was an ongoing pregnancy of at least 20 weeks of gestation.A total of 82 patients enrolled, of whom 47 had an index pregnancy. All ongoing pregnancies resulted in live births. Therefore, the live birth rates were 70% (16/23) in the IVIG group and 63% (15/24) in the control group (P = 0.760); odds ratio (OR) 1.37 [95% confidence interval (CI) 0.41-4.61]. Including only clinical pregnancies (embryo with cardiac activity at 6 weeks of gestation), the live birth rates were equivalent, 94% (16/17) and (15/16), respectively (P > 0.999); OR 1.07 (95% CI 0.06-18.62). Meta-analysis of randomized controlled trials (RCTs) evaluating IVIG for idiopathic secondary recurrent miscarriage revealed live birth rates of 70% (31/44) in the IVIG group and 62% (28/45) in the control group (P = 0.503); common OR 1.44 (95% CI 0.59-3.48).This is the largest RCT to date in which IVIG was evaluated in women with idiopathic secondary recurrent miscarriage; no treatment benefit was found. The meta-analysis, which combined our study results with two prior RCTs, also showed no significant effect of treatment with IVIG.
Project description:OBJECTIVE:To evaluate anti-Mullerian hormone, basal follicle stimulating hormone, luteinizing hormone, estradiol, and female age in women with recurrent miscarriage and to compare women with explained and idiopathic recurrent miscarriage. DESIGN:Retrospective cohort study. SETTING:University hospital, tertiary care center. PATIENTS:Women with recurrent miscarriage (78 explained, 66 idiopathic). INTERVENTION(S):None. MAIN OUTCOME MEASURES(S):Anti-Mullerian hormone, basal follicle stimulating hormone, luteinizing hormone, estradiol, and age. RESULTS:Anti-Mullerian hormone and estradiol were significantly lower in women with idiopathic recurrent miscarriage (median 1.2 ng/ml, IQR 0.6-2.1, and median 36.5 pg/ml, IQR 25.8-47.3, respectively) than in women with explained recurrent miscarriage (median 2.0 ng/ml, IQR 1.1-2.7, and median 42.5 pg/ml, IQR 32.8-59.8, respectively; p<0.05). Optimized cut-off values for the prediction of idiopathic recurrent miscarriage were <39.5 pg/ml for estradiol (sensitivity: 63.3%, 95% CI: 50.9-75.1; specificity: 56.4%, 95% CI: 44.7-67.6) and <1.90 ng/ml for anti-Mullerian hormone (sensitivity: 72.7%, 95% CI: 60.4-83.0; specificity: 52.6%, 95% CI: 40.9-64.0). CONCLUSION:Idiopathic recurrent miscarriage was associated with lower basal estradiol and anti-Mullerian hormone levels compared to explained recurrent miscarriage.