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INTRODUCTION: Thrombophilic genetic polymorphisms of the platelet glycoproteins Ia (GpIa) and IIIa (GpIIIa) have been associated with an increased risk of recurrent miscarriages. The aim of this study was to investigate the association of genetic polymorphisms GpIa-C807T and GpIIIa-T1565C-PlA1/PlA2 with platelet function in women with unexplained spontaneous recurrent miscarriages. METHODS: This cross-sectional study comprised 196 unrelated nulliparous Greek women with a history of unexplained recurrent miscarriages. Patients were genotyped for the presence of the GpIa-C807T (rs1126643) and GpIIIa-T1565C-PlA1/PlA2 (rs5918) genetic polymorphisms by pyrosequencing, and the collagen/epinephrine closure time (COL/EPI CT) of the subjects was assessed using the platelet function analyzer (PFA)-100. RESULTS: In the total population of women with recurrent miscarriages, the COL/EPI CT ranged from 70 to 160 seconds (median: 122 seconds, interquartile range (IQR): 102.3-138 seconds). In comparison with the double homozygotes CC/PlA1PlA1 that had the most prolonged CT (mean: 131.9 ± 17.5 seconds), the COL/EPI CT was statistically significantly shorter for the GpIa-807T single carriers (mean: 120.3 ± 20.9 seconds) (p=0.011) (absolute difference: 11.6 seconds, 95% confidence interval (CI): 21.2 to -2.0 seconds; relative difference: -9%, 95% CI: -16% to -2%), and the GpIIIa-PlA2 single carriers also displayed a trend for shorter COL/EPI CT (mean: 121.3 ± 23.7 seconds) (p=0.141) (absolute difference: -10.6 seconds, relative difference: -8%), whereas the combined carriers of the GpIa-807T and the GpIIIa-PlA2 alleles exhibited the shortest COL/EPI CT (mean: 104.1 ± 19.7 seconds) (absolute difference: -27.7 seconds, 95% CI: -39.1 to -16.3 seconds; relative difference: -21%, 95% CI: -30% to -12%) (p<0.001). In comparing genotype frequencies in the lower half with those in the upper half of the COL/EPI CT range, the GpIa-807T and the GpIIIa-PlA2 single carriers were associated with higher odds of COL/EPI CT < 122 seconds (odds ratio (OR)=3.4, 95% CI: 1.5 to 7.5, p=0.002, and OR=2.6, 95% CI: 1.0 to 7.2, p=0.053, respectively). The association was strongest for the combined carriers with OR of 15.0 (95% CI: 5.2 to 43.2, p<0.001) for COL/EPI CT below the median and OR of 35.5 (95% CI: 4.4 to 284.5, p<0.001) for COL/EPI CT < 100 seconds. CONCLUSION: The GpIa-C807T and GpIIIa-PlA1/PlA2 polymorphisms and more pronouncedly the combined carriers of the risk variants are associated with enhanced platelet reactivity expressed via shorter COL/EPI CT. These findings provide further evidence for the role of platelet-associated genetic thrombophilia in the pathogenesis of recurrent miscarriages and promote the analysis of platelet function as a diagnostic tool in the evaluation of this disorder.
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INTRODUCTION: The maternal immune system has a major role in the successful embryo implantation and maintenance of the pregnancy. This study aimed to investigate the maternal immunophenotyping profile (percentage of Natural Killer [NK] cells and the CD4/CD8 [cluster designation] ratio in peripheral blood lymphocytes) and the HLA (Human Leukocyte Antigen)-DQA1 alleles sharing in infertile couples. METHODS: This cross-sectional study included 78 women who had experienced at least two spontaneous miscarriages and 110 women with a history of recurrent implantation failures after in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) and embryo transfer (ET) (IVF-ET failures). The NK cell percentage and the CD4/CD8 ratio were determined by flow cytometry. Genotyping of the HLA-DQA1 alleles was carried out for all women and their partners, and couple HLA-DQA1 compatibility was expressed as the percentage of common HLA-DQA1 alleles (totaling 35 alleles) shared between spouses to the sum of the unique alleles observed. RESULTS: In women with recurrent miscarriages, high values (%) of the NK population with a median (interquartile range [IQR]) of 10.3% (7.7% to 12.5%) and CD4/CD8 ratio (1.7) (1.5 to 2.1) were found. In women with IVF-ET failures, the (%) NK population (10.5%) (8.6% to 12.5%) and CD4/CD8 ratio (1.8) (1.5 to 2.1) were similarly increased (p=0.390, and p=0.490, respectively). The proportion of women with >10% NK cells was 53.8% and 58.2% in women with miscarriages and IVF-ET failures, respectively (p=0.554). The prevalence of HLA-DQA1*5 allele carriage was elevated in women with miscarriages as well as those with IVF-ET failures (52.6% and 61.8%, respectively; p=0.206). The proportion of couples with high (>50%) HLA-DQA1 sharing was 65.4% in the group with miscarriages and 73.6% in the group with IVF-ET failures, respectively (p=0.222). The CD4/CD8 ratio was statistically significantly positively correlated with the (%) NK population in women with IVF-ET failures (rho = 0.297, p=0.002) and with the (%) HLA-DQA1 sharing in the group with miscarriages (rho = 0.266, p=0.019). The couples in which both spouses were carriers of the HLA-DQA1*5 allele had an increased probability of high (>50%) HLA-DQA1 compatibility compared with the couples in which neither of the spouses carried the allele in the miscarriage group (OR = 24.3, 95% CI: 3.0 to 198.9, p<0.001), and the IVF-ET failure group (OR = 10.5, 95% CI: 2.2 to 49.8, p<0.001). CONCLUSION: The peripheral NK (%) population and CD4/CD8 ratio, as well as the prevalence of the HLA-DQA1*5 allele, were elevated in women with recurrent miscarriages and IVF-ET failures. Furthermore, these couples with negative reproductive outcomes had a high percentage of HLA-DQA1 allele similarity. The presence of the HLA-DQA1*5 allele in spouses was strongly associated with overall couple HLA-DQA1 compatibility, implying that it could be used as a surrogate marker for assessing overall immunological compatibility in infertile couples.
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INTRODUCTION: The aim of this study was to investigate the possible effect of the PECAM-1-C373G (Leu125Val) and P-Selectin-A37674C (Thr715Pro) polymorphisms in unexplained spontaneous abortions. METHODS: In a case-control design, Greek nulligravida women with recurrent idiopathic miscarriages <20 weeks of gestation and fertile controls were genotyped by pyrosequencing. RESULTS: There was no significant association of the PECAM-1-C373G (Leu125Val) polymorphism with recurrent abortions. Although the P-Selectin-A37674C (Thr715Pro) polymorphism was not associated with miscarriages overall, the association was statistically significant for younger women (carriers of the P-Selectin-37674C allele: <35 years: odds ratio (OR) = 3, 95% confidence interval (CI): 1.13-7.97, p = 0.023; <30 years: OR = 6.75, 95%CI: 2.02-22.58, p = 0.002). In comparison with CC/AA genotype, the combined carriers of the PECAM-1-373G and P-Selectin-37674C alleles had OR =8.81 (95%CI: 1.07-72.50, p = 0.024). The association of the coexistence of the two polymorphisms was stronger in younger women (<35 years: OR = 12.07, 95%CI: 1.38-105.68, p = 0.014; <30 years: OR = 65, 95%CI: 3.38-1251.28, p = 0.001), and late (OR = 10.64, 95%CI: 1.16-97.60, p = 0.024) and second-trimester miscarriages (OR = 26, 95%CI: 1.84-367.71, p = 0.014). The association between carriage of the P-Selectin-37674C allele and recurrent miscarriages was significant for younger women. CONCLUSION: The coexistence of the PECAM-1-373G and P-Selectin-37674C alleles increased the miscarriage risk for the total population studied, suggesting an interaction between the two polymorphisms, more pronouncedly in younger women and the association was stronger for late fetal loss.
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PURPOSE: Both vitamin D and estrogens play an important role in breast cell growth and differentiation. Therefore, we hypothesized that FokI polymorphism in the Vitamin D Receptor (VDR) gene, as well as PvuII polymorphism in the Estrogen Receptor (ESR) gene might be associated with progression of breast cancer. The aim of this study was to prospectively examine the association of these polymorphisms with histopathological features and prognosis among women with histologically proven breast cancer. METHODS: Patient characteristics, tumor histopathology, and genotyping of one VDR polymorphism variant (FokI) and one ER polymorphism variant (PvuII) were recorded. Patients were also routinely followed up. RESULTS: There was a significant difference regarding nodal stage (p<0.001) between the different genotypes of FokI polymorphisms (FF, Ff, ff), even though a trend was also detected in the frequency between ductal and lobular type, as well as tumor size (p=0.077). When further analysis was performed regarding patients whose polymorphism included the f allele, we found statistically significant differences in tumor size (p<0.001), nodal stage (p=0.03), tumor grade (p=0.04) and lymphovascular invasion (p<0.001), while no differences in nodal status, distant metastases and tumor stage were noticed. No significant associations were found between any of the PvuII polymorphism variants and tumor histopathology and stage. No statistical significance was proven between FokI polymorphism's variants or f allele and overall or progression-free survival. Statistically significant associations between overall and progression- free survival and PvuII polymorphism's variants was demonstrated (p<0.001). CONCLUSION: The f allele was associated with the presence of lymphovascular invasion and poorly differentiated tumors, whereas the PP genotype was associated with increased overall and progression-free survival, suggesting that this variant is related to a more favorable prognosis.
