Folate metabolism abnormalities in infertile patients with endometriosis.

Background: Homocysteine levels can be impacted by enzymes variations. Aim: To correlate MTHFR, MTR and MTRR variants with homocysteine levels in the blood and follicular fluid and assisted reproduction results. Material & methods:MTHFR (rs2274976, rs1801131, rs1801133), MTR (rs1805087) and MTRR (rs1801394) genotyping was performed by TaqMan assays and compared with homocysteine levels, measured by ELISA, to oocytes retrieved and to the pregnancy status of women with endometriosis and controls. Results: The MTR G allele and GG genotype were more common in patients with endometriosis. They also showed lower levels of homocysteine and more clinical gestations. Epistasis analysis showed a model associated with gestational results, composed of MTHFR+MTR variants (CC+AG). Conclusion: The summation effect of variants in genes participating in folate metabolism was associated with pregnancy status in Brazilian women. MTR variants were more observed in endometriosis patients, as well as lower follicular Hcy levels and increased clinical pregnancy results.

What was the aim of the study? To correlate genetic variants to homocysteine levels in the blood and oocyte surrounding fluid, and the results of assisted reproduction techniques. How was the study done? A total of 152 women with endometriosis and controls with male infertility were evaluated. DNA was extracted from blood for genetic analysis, and homocysteine levels were measured from the blood and oocyte surrounding fluid. Genetic results were correlated to homocysteine levels, oocyte quality and pregnancy status. What were the results? A specific genetic marker occurred more in endometriosis patients. They also showed lower levels of homocysteine and a tendency to more clinical gestations than controls. What do the results of the study mean? Endometriosis patients showed specific genetic markers and different levels of homocysteine compared with controls. These results can be helpful to predict gestational results.

PYGM mRNA expression in McArdle disease: Demographic, clinical, morphological and genetic features.

INTRODUCTION: McArdle disease presents clinical and genetic heterogeneity. There is no obvious association between genotype and phenotype. PYGM (muscle glycogen phosphorylase gene) mRNA expression and its association with clinical, morphological, and genetic aspects of the disease as a set have not been studied previously. METHODS: We investigated genetic variation in PYGM considering the number of PTCs (premature termination codon) per sample and compared mRNA expression in skeletal muscle samples from 15 patients with McArdle disease and 16 controls to PTCs number and different aspects of the disease. RESULTS: The main variant found was c.148C>T (PTC-premature termination codon). Patients with two PTCs showed 42% mRNA expression compared to the control group. Most cases showed an inversely proportional relation among PTCs and mRNA expression. Association between mRNA expression and other aspects of the disease showed no statistically significant difference (p> 0.05). DISCUSSION: mRNA expression is not useful as a predictor factor for the prognosis and severity of the disease. Different mechanisms as post-transcriptional events, epigenetics factors or protein function may be involved.

The role of survivin in the pathogenesis of endometriosis.

INTRODUCTION: Endometriosis is a common, estrogen-dependent condition, defined as the presence of endometrial-like tissue outside of the uterus, associated with often chronic and inflammatory reaction. The association of endometriosis with cancer is unclear, although endometriosis and cancer present some molecular similarities. Survinin, encoded by the BIRC5 gene, is a protein that controls cell division, inhibits apoptosis and promotes angiogenesis. Here we aimed to summarize and to discuss the main findings of studies that addressed the involvement of survivin in the pathogenesis of endometriosis. EVIDENCE ACQUISITION: We conducted a comprehensive retrieval from electronic databases, included the MEDLINE, EMBASE, with no restrictions to time span. We used the search terms endometriosis and survivin or BIRC5 and collected all relevant studies to explore the association between endometriosis and surviving expression. EVIDENCE SYNTHESIS: A total of 21 studies included in the systematic review, comprising sample collected from 1263 women with endometriosis. Results showed the involvement of more than 60 genes and proteins evaluated in eutopic, ectopic, endometrial and ovarian endometriosis, as well as in several gynecological conditions compared to healthy controls. CONCLUSIONS: The studies provided the basis for the involvement of survivin in the pathogenesis of the disease by several and independent pathways.

Influence of STAT4 gene polymorphisms in the pathogenesis of endometriosis.

The STAT4 gene is vital to signaling pathways in the immune response. Immunological alterations are involved in the pathogenesis of endometriosis, and STAT4 polymorphisms may be linked to disease development. This study's aim is to evaluate the possible association between four STAT4 polymorphisms (rs7601754/G > A, rs11889341/C > T, rs7574865/T > G, and rs7582694/C > G) and the pathogenesis of endometriosis in Brazilian women. This case-control study's sample comprised 238 women with endometriosis and 201 healthy, fertile women without endometriosis (which was surgically confirmed). Genotyping was performed using the TaqMan system with a real-time polymerase chain reaction; the genotype, allele, and haplotype frequencies were then compared between groups. A single-polymorphism analysis revealed that the TT genotype of the rs7574865/T > G polymorphism was significantly more frequent in women with minimal or mild endometriosis than in the controls (10% vs. 5%, p = 0.047). The CGAC, GTAT, and GTAC haplotypes were significantly more frequent in the women with endometriosis-related infertility (5.8%, 4.1%, and 2.9%, respectively) than in the controls (2.4%, 1.1%, and 0.8%, respectively; p = 0.020, p = 0.011, and p = 0.032, respectively), but the GGGC and CTAT haplotypes were significantly more prevalent in the control group (34.7% and 13.9%, respectively) than among the infertile group (26.2% and 9.1%, respectively). In addition, the CGAC haplotype was more frequently found in those with minimal or mild endometriosis (6.8%) than in the controls (2.4%, p = 0.009), and the GTAT haplotype was more commonly found in those with moderate or severe disease (3.6%) than in the controls (1.1%, p = 0.028). These findings suggest that STAT4 polymorphisms can influence the pathogenesis of endometriosis.

Pharmacogenetic algorithm for individualized controlled ovarian stimulation in assisted reproductive technology cycles.

Controlled ovarian stimulation (COS) is crucial for optimizing in-vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) success. Multiple factors influence the ovarian response to COS, making predictions about oocyte yields not so straightforward. As a result, the ovarian response may be poor or suboptimal, or even excessive, all of which have negative consequences for the affected patient. There is a group of patients that present with a suboptimal response to COS despite normal biomarkers of ovarian reserve, such as AFC and AMH. These patients have a lower number of retrieved oocytes than what was expected based on their ovarian reserve, thus showing the inadequacy of using only the traditional ovarian reserve biomarkers to predict the ovarian response. Suboptimal response to COS might be related to ovarian sensitivity to exogenous gonadotropins modulated by genetic factors. The understanding of the gene polymorphisms related to reproductive function can help to improve the clinical management of this patient population and to explain some of the individual patient variability in response to COS. The development of a pharmacogenetic approach concerning COS in the context of assisted reproduction seems attractive as it might help to understand the relationship between genetic variants and ovarian response to exogenous gonadotropins. The patient's genetic profile could be used to select the most appropriate gonadotropin type, predict the optimal dosage for each drug, develop a cost-effective treatment plan, maximize the success rates, and lastly, decrease the time-to-pregnancy.

Kisspeptin/GPR54 System: What Do We Know About Its Role in Human Reproduction?

Kisspeptin is involved in the control of human reproduction bridging the gap between the sex steroid levels and feedback mechanisms that control the gonadotropin releasing hormone (GnRH) secretion; however, studies considering this peptide and infertility are limited. We conducted a review and critical assessment of available evidence considering kisspeptin structure, physiology, function in puberty and reproduction, its role in assisted reproduction treatments, kisspeptin dosage and the impact on KISS1 and GPR54 genes. Literature searches were conducted in PubMed using keywords related to: (i) kisspeptin or receptors, kisspeptin-1 (ii) reproduction or infertility or fertility (iii) gene and (iv) dosage or measurement or quantification or serum level, in human. Kisspeptin is a product of KISS1 gene that binds to a G-protein-coupled receptor (GPR54/KISS1R) stimulating the release of GnRH by hypothalamic neurons, leading to secretion of pituitary gonadotropins (LH and FSH) and sexual steroids, which in turn will act in the gonads to produce the gametes. Kisspeptin is being recognized as a crucial regulator of the onset of puberty, the regulation of sex hormone mediated secretion of gonadotropins, and the control of fertility. Inactivating and activating mutations in both KISS1 or GPR54 genes were associated with hypogonadotropic hypogonadism and precocious puberty. Despite this, studies considering kisspeptin and infertility are scarce. The understanding of the role of kisspeptin may lead to its use as a biomarker in infertility treatments and use in controlled ovarian hyperstimulation.

AMH and AMHR2 polymorphisms and AMH serum level can predict assisted reproduction outcomes: a cross-sectional study.

BACKGROUND: In human assisted reproduction, the ovarian response to exogenous recombinant Follicle-stimulating Hormone (FSH) therapy is variable and difficult to predict. The standard protocol of ovarian hyperstimulation can result in satisfactory response; however, an unsatisfactory response necessitates FSH dose adjustment or results in ovarian hyperstimulation syndrome (OHSS). Polymorphisms in AMH and AMHR2 genes appear to affect hormone biological activities, thus affecting follicle recruitment and development, leading to infertility. We aimed to evaluate AMH and AMHR2 polymorphisms in infertile women, and correlate those findings with AMH, FSH and estradiol serum level response to controlled ovarian hyperstimulation (COH), as well as assisted reproduction outcomes. METHODS: A cross-sectional study comprising 186 infertile women that underwent one cycle of high complexity assisted reproductive treatment. Blood samples were collected and a TaqMan assay was used for AMH G146T/rs10407022 and AMHR2 A-482G/rs2002555, A10G/rs11170555, C1749G/rs2071558 and G4952A/rs3741664 genotyping, and FSH, estradiol and AMH levels were measured. The findings were correlated to human reproduction outcomes. RESULTS: AMH rs10407022 and AMHR2 rs2002555 polymorphisms were not associated with hormonal measurements, whereas AMHR2 rs11170555 and rs3741664 were positively associated with AMH, estradiol and FSH levels. The genotype distribution of AMH and AMHR2 genes according to Controlled Ovarian Hyperstimulation did not show a positive association. However, an association with AFC, degree of oocyte maturation (allele G of AMHR2 rs2071558) the number of embryos produced (alleles T and G of AMH rs10407022 and AMHR2 rs2002555, respectively) and frozen embryo (allele G of AMHR2 rs11170555) were found to be statistically associated. Considering COH, serum AMH and AFC were a positive predictor to OHSS. Regarding serum AMH and assisted reproduction outcomes, a positive correlation with all variables studied was found. Comparing AFC and AMH as predictors of human reproduction outcomes, the AFC was less effective than serum AMH. Considering pregnancy rates, no marker was positively associated. CONCLUSION: AMHR2 polymorphisms were associated with estradiol, AMH and FSH measurements, as well as number and quality of embryos, while AMH polymorphisms was associated with number of embryos produced. Serum AMH was correlated with nearly all variables analyzed in assisted reproductive treatment, demonstrating that it represents a better biomarker of OHSS and human reproduction outcomes compared to AMH and AMHR2 polymorphisms.

Association of the +331G/A progesterone receptor gene (PgR) polymorphism with risk of endometrial cancer in Caucasian women: a meta-analysis.

PURPOSE: The +331G/A progesterone receptor (PgR) gene polymorphism may influence risk of endometrial cancer. However, data from published studies have been controversial. To evaluate whether combined evidence shows an association between this polymorphism and endometrial cancer, we considered all available studies in a meta-analysis. METHODS: We searched PubMed and EMBASE and identified eight studies representing data for 3,790 cases and 6,458 controls. We estimated risk [odds ratio (OR) and 95 % confidence interval] of these associations, which were non-significant in the entire body of results. RESULTS: Overall effects indicated increased risks, slightly pronounced in the homozygous and recessive models (OR 1.16-1.17, p = 0.57-0.60). These effects were exacerbated when confined to studies in Hardy-Weinberg Equilibrium (OR 1.33-1.36, p = 0.33-0.35) and in the underpowered subgroup (OR 1.62-1.68, p = 0.27-0.30). The exception is the powered subgroup which showed reduced risk (OR 0.96-0.97, p = 0.92-0.93). None of the comparisons were heterogeneous, in fact, 10 of the 16 comparisons had zero heterogeneity (I (2) = 0 %). CONCLUSION: In summary, the non-significant results suggest that the PgR +331G/A polymorphism might not be a conspicuous low-penetrant risk factor for developing endometrial cancer.

Complex small supernumerary marker chromosome with a 15q/16p duplication: clinical implications.

BACKGROUND: Complex small supernumerary marker chromosomes (sSMCs) consist of chromosomal material derived from more than one chromosome and have been implicated in reproductive problems such as recurrent pregnancy loss. They may also be associated with congenital abnormalities in the offspring of carriers. Due to its genomic architecture, chromosome 15 is frequently associated with rearrangements and the formation of sSMCs. Recently, several different CNVs have been described at 16p11.2, suggesting that this region is prone to rearrangements. RESULTS: We detected the concomitant occurrence of partial trisomy 15q and 16p, due to a complex sSMC, in a 6-year-old girl with clinical phenotypic. The karyotype was analyzed by G and C banding, NOR staining, FISH and SNP array and defined as 47,XX,+der(15)t(15;16)(q13;p13.2)mat. The array assay revealed an unexpected complex sSMC containing material from chromosomes 15 and 16, due to an inherited maternal translocation (passed along over several generations). The patient's phenotype included microsomia, intellectual disability, speech delay, hearing impairment, dysphagia and other minor alterations. DISCUSSION: This is the first report on the concomitant occurrence of partial trisomy 15q and 16p. The wide range of phenotypes associated with complex sSMCs represents a challenge for genotype-phenotype correlation studies, accurate clinical assessment of patients and genetic counseling.

PRODH polymorphisms, cortical volumes and thickness in schizophrenia.

Schizophrenia is a neurodevelopmental disorder with high heritability. Several lines of evidence indicate that the PRODH gene may be related to the disorder. Therefore, our study investigates the effects of 12 polymorphisms of PRODH on schizophrenia and its phenotypes. To further evaluate the roles of the associated variants in the disorder, we have conducted magnetic resonance imaging (MRI) scans to assess cortical volumes and thicknesses. A total of 192 patients were evaluated using the Structured Clinical Interview for DSM-IV (SCID), Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale, Global Assessment of Functioning (GAF) and Clinical Global Impression (CGI) instruments. The study included 179 controls paired by age and gender. The samples were genotyped using the real-time polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP)-PCR and Sanger sequencing methods. A sample of 138 patients and 34 healthy controls underwent MRI scans. One polymorphism was associated with schizophrenia (rs2904552), with the G-allele more frequent in patients than in controls. This polymorphism is likely functional, as predicted by PolyPhen and SIFT, but it was not associated with brain morphology in our study. In summary, we report a functional PRODH variant associated with schizophrenia that may have a neurochemical impact, altering brain function, but is not responsible for the cortical reductions found in the disorder.

Aberrant telomerase expression in the endometrium of infertile women with deep endometriosis.

BACKGROUND AND AIMS: Considering the complex cellular and molecular mechanisms involved in endometriosis formation and progression and the similarities concerning the association of endometriosis with tumorigenesis and metastasis, we hypothesized a possible relationship between telomerase and the development/progression of endometriosis. The present study aimed to evaluate the expression of telomerase in the endometrium and peritoneal endometriotic lesions from women with endometriosis and controls. METHODS: A case-control study was performed comprising 25 infertile women with endometriosis and 44 fertile women without endometriosis as controls. Samples of endometrium and endometriotic peritoneal lesions of the same patient were harvested in the late luteal phase of the cycle. The expression of hTERT and GAPDH genes was measured by mRNA using qRT-PCR based on TaqMan methodology. Student t test was used to compare the values between the groups; p >0.05 was accepted as statistically significant. RESULTS: The mean expression of hTERT in the endometriosis group was significantly high when compared to the control group (1.24 ± 4.67 vs. 0.31 ± 1.10, p = 0.026). When the expression of hTERT was compared in relation to disease stage, the group of moderate/severe endometriosis showed increased expression in relation to control group (2.59 ± 7.35 vs. 0.31 ± 1.10, p = 0.026). Regarding endometriotic peritoneal lesions, only one 1/25 expressed hTERT mRNA. This patient had deep endometriosis. CONCLUSIONS: There was an association between the expression of telomerase (hTERT mRNA) and the genesis and progression of endometriosis.

ZDHHC8 gene may play a role in cortical volumes of patients with schizophrenia.

ZDHHC8 rs175174 polymorphism is located in 22q11.2 region and its role in brain volume has not been fully addressed. A total of 282 schizophrenia patients and 379 controls were genotyped. A sample of 138 patients underwent brain MRI scan. No association was found between schizophrenia and genotypes. Nevertheless, GG-genotype carriers presented gray matter volume (GMV) reduction in frontal lobe compared to A-allele carriers, and cerebellar hemispheres GMV reductions were found in G-allele carriers compared to AA-genotype. Moreover, A-allele carriers presented posterior brain GMV reductions when compared to GG-genotype. These data suggest that ZDHHC8 may play a role in cortical volumes.

Variants in endothelial nitric oxide synthase (eNOS) gene in idiopathic infertile Brazilian men.

PURPOSE: In recent years, considerable concern has been expressed about the deleterious effects of reactive oxygen species (ROS) on sperm function, because ROS at high levels is potentially detrimental to sperm function and quality. Nitric oxide (NO) is a powerful anti-oxidant present in seminal plasma. The aim of the study was to analyze the distribution of the of endothelial nitric oxide synthase (eNOS) gene (T-786C, G894T, e 4a/b) polymorphisms in idiopathic infertile Brazilian men and evaluate the possible role of these polymorphisms in sperm count. METHODS: A case-control study was performed comprising 208 infertile men [n=74 with non-obstructive azoospermia and n=134 with severe oligozoospermia] and 201 fertile men as controls. Genotyping of eNOS polymorphisms was performed by real time (T-786C and G894T) and conventional PCR (4a/b). The results were analyzed statistically and a p-value<0.05 was considered significant. RESULTS: According to the sperm count, relatively similar eNOS polymorphism genotypes and allele frequencies were found among the groups. Combined genotypes of the eNOS polymorphisms did not identify a haplotype associated with idiopathic infertility, even when the patients were separated in non-obstructive azoospermia or severe oligozoospermia. CONCLUSION: In conclusion, the findings demonstrate that, in Brazilian population studied, genetic variations, T-786C, G894T, and e 4a/b, of the eNOS gene are not associated with male infertility.

TYK2 rs34536443 polymorphism is associated with a decreased susceptibility to endometriosis-related infertility.

INTRODUCTION: Tyrosine kinase 2 gene (TYK2) is part of the janus kinase (JAK) that binds to the type I interferon-α receptor (IFNAR) on the cell surface of IFN-producing cells, and have crucial importance in the etiology of autoimmune and inflammatory diseases. Many polymorphisms of the TYK2 gene have been identified, and recently, a number of case-control studies were conducted to investigate the association of these polymorphisms with autoimmune and inflammatory diseases, with conflicting results. Based on these observations, we hypothesized that the TYK2 polymorphisms (rs34536443, rs2304256, rs280523, rs12720270 and rs12720356) might be involved in the pathogenesis of endometriosis and/or infertility. METHODS: Genetic association study comprising 275 infertile women with endometriosis, 92 women with idiopathic infertility and 307 fertile women as controls. TYK2 polymorphisms were identified by TaqMan PCR. Genotype distribution, allele frequency and haplotype analysis of the TYK2 polymorphisms were performed. A p-value <0.05 was considered significant. RESULTS: Single-marker analysis revealed that TYK2 rs34536443 was significantly associated with protection against endometriosis-related infertility, especially in moderate/severe disease (p = 0.002; OR = 0.24, 95% IC = 0.09-0.62). No difference was found considering the infertile group without endometriosis. No associations were found considering rs2304256, rs280523, rs12720270 and rs12720356 either for endometriosis-related infertility group or idiopathic infertility group. Haplotype analysis of five TYK2 polymorphisms identified a haplotype "CTATG" associated with protection against endometriosis-related infertility, especially in moderate/severe disease (p = 0.027). CONCLUSION: This is the first study to report an association between TYK2 polymorphisms and endometriosis and/or infertility. These findings require replication in other populations but suggest the TYK2 rs34536443 polymorphisms and "CTATG" haplotype can be associated with a decreased susceptibility to endometriosis-related infertility in Brazilian women.

The nuclear factor-kB functional promoter polymorphism is associated with endometriosis and infertility.

INTRODUCTION: An aberrant immunologic mechanism has been suggested to be involved in the pathogenesis of endometriosis. Nuclear factor-kB (NF-kB) plays a key role in the immune and inflammatory response and modulates cell proliferation, apoptosis, adhesion, invasion, and angiogenesis in many cell types involved in the development of endometriosis. We hypothesized a possible relationship between the NFKB1 promoter regulatory polymorphism and endometriosis and/or infertility. METHODS: A genetic association study comprising 172 infertile women with endometriosis, 77 women with idiopathic infertility and 189 controls was performed. Detection of the -94 insertion/deletion ATTG (rs28362491) polymorphism in the NFKB1 gene was done using the RFLP-PCR (Restriction Fragment Length Polymorphism-Polymerase Chain Reaction) technique. The results were statistically analyzed, and a p-value <0.05 was considered significant. RESULTS: Single-marker analysis revealed a significant association between the -94 insertion/deletion ATTG polymorphism and endometriosis-related infertility (p=0.014, OR=1.47, 95% CI=1.09-1.97), especially in moderate/severe disease cases. Considering the idiopathic infertility group, a significant association was also found (p=<0.001, OR=2.01, 95% CI=1.35-2.98), suggesting that the -94 insertion/deletion ATTG polymorphism is associated with endometriosis and/or infertility. CONCLUSION: In the population sample studied, the -94 insertion/deletion ATTG polymorphism in the NFKB1 gene was positively associated both with moderate/severe endometriosis and idiopathic infertility.

Variants in follicle-stimulating hormone receptor gene in infertile Brazilian men and the correlation to FSH serum levels and sperm count.

The aim of the study was to analyze the distribution of the follicle-stimulating hormone (FSH) receptor (FSHR) Ala307Thr and Asn680Ser polymorphisms in infertile Brazilian men and evaluate the possible role of these polymorphisms on the serum levels of FSH and in sperm count. A case-control study was performed comprising138 infertile men with nonobstructive azoospermia (n = 53) or severe oligozoospermia (n = 85), and 217 fertile men as controls. Genotyping of FSHR polymorphisms was performed by real-time polymerase chain reaction (PCR). The results were analyzed statistically and a P value <.05 was considered significant. According to the sperm count, relatively similar FSHR polymorphisms genotype and allele frequencies were found among the groups, and combined genotypes of 2 polymorphisms did not identify a haplotype associated with sperm count. Considering FSH serum level according to genotypes of the Ala307Thr and Asn680Ser polymorphisms individually, statistical analysis showed no difference among the groups. When the combined genotypes of the FSHR polymorphisms were compared to FSH serum levels, no difference was also found among the groups. In conclusion, the findings demonstrate that, in Brazilian population studied, genetic variations, Asn680Ser and Thr307Ala, of the FSHR gene are not correlated with serum FSH levels or sperm count in male infertility.

Genetic association study of polymorphisms FOXP3 and FCRL3 in women with endometriosis.

OBJECTIVE: To consider a possible cumulative effect of two genetic polymorphisms (FOXP3 C-2383T/rs3761549 and FCRL3 C-169T/rs7528684) that were previously shown to be associated with endometriosis. DESIGN: Genetic association study. SETTING: Human reproduction outpatient clinic of Faculdade de Medicina do ABC. PATIENT(S): One hundred eighty-eight infertile women with endometriosis and 169 controls. INTERVENTION(S): Detection of polymorphisms FOXP3 (C-2383T/rs3761549) and FCRL3 (C-169T/rs7528684) by TaqMan real-time polymerase chain reaction. The results were analyzed statistically. MAIN OUTCOME MEASURE(S): Genotype distribution, allele frequency, and combination analysis of the FOXP3 and FCRL3 polymorphisms. RESULT(S): Single-marker analysis revealed a significant association of FOXP3 C-2383T and FCRL3 C-169T, independently, with endometriosis-related infertility, regardless of the stage of the disease. Considering the combined genotypes of FCRL3 and FOXP3 polymorphisms, a positive association was found between genotypes FCRL3TT/FOXP3CT, FCRL3CT/FOXP3CT, and FCRL3CC/FOXP3CT and the risk of endometriosis development. Moreover, a progression of the disease risk was observed according to the presence of one or two copies of risk allele FCRL3 C and only one copy of risk allele FOXP3 T (odds ratio [OR] = 2.14, OR = 3.25, and OR = 6.0, respectively, for genotypes FCRL3TT/FOXP3CT, FCRL3CT/FOXP3CT, and FCRL3CC/FOXP3CT). CONCLUSION(S): Our findings support a possible gene-gene interaction leading to a cumulative effect on endometriosis development.

The possible role of genetic variants in autoimmune-related genes in the development of endometriosis.

Numerous hypotheses have been put forward to explain the presence of ectopic endometrial tissue and stroma. The immune system participates in the homeostasis of the peritoneal cavity, and modifications in its functioning have been advanced to explain endometriosis and its consequences. Recently, the powerful anti-inflammatory effect of progesterone was recognized as a potential causal factor for endometriosis and could contribute to the autoimmune nature of endometriosis, as well as to more specific local and systemic changes. Autoimmune and inflammatory diseases are a diverse group of complex diseases characterized by loss of self-tolerance causing immune-mediated tissue destruction. Just as in autoimmune diseases, in endometriosis similar immunologic alterations occur, such as an increase in the number and cytotoxicity of macrophages, polyclonal increase in the activity of B lymphocytes, abnormalities in the functions and concentrations of B and T lymphocytes, and reduction in number or activity of natural killer cells. Furthermore, the presence of specific antiendometrial and antiovary antibodies was found both in endometriosis and infertility. Genetic factors play a role in the pathogenesis of endometriosis, and autoimmunity genes are therefore reasonable candidate genes for endometriosis and endometriosis-associated infertility. Single nucleotide polymorphisms are common in the human genome and affect the function of crucial components of the T-cell-antigen-receptor signaling pathways; they could have profound effects on the function of the immune system and thus on the development of autoimmune diseases. Here, we conducted a critical medical literature review about the possible role of genetic variants in autoimmune-related genes in the development of endometriosis.

Genetic variants in fibrinolytic system-related genes in infertile women with and without endometriosis.

AIMS: The aim of this study was to evaluate urokinase-type plasminogen activator gene (uPA) and thrombin-activatable fibrinolysis inhibitor gene (TAFI) genotypes in a group of infertile women with and/or without endometriosis and controls. METHODS: A case-control study comprising 180 infertile women with endometriosis, 68 women with idiopathic infertility, and 152 fertile women as controls was carried out. Detection of uPA (C422T/rs2227564) and TAFI (G438A/rs2146881) polymorphisms was performed by TaqMan polymerase chain reaction. The results were statistically analyzed and a p-value of <0.05 was considered significant. RESULTS: We found no association among both uPA or TAFI polymorphisms and endometriosis-related infertility (p=0.920 and p=0.356, respectively) or idiopathic infertility (p=0.502 and p=0.392, respectively) comparing to controls, even considering minimal/mild and moderate/severe endometriosis separately. Both uPA and TAFI polymorphisms were in Hardy-Weinberg equilibrium for all studied groups. The combinatory analysis of both uPA and TAFI polymorphisms to endometriosis-related infertility, idiopathic infertility, and control group showed no statistical difference to any combination. CONCLUSION: The data suggest that, in the Brazilian population, genetic variations in both uPA and TAFI were not relevant to endometriosis and/or infertility.

Mechanisms of ring chromosome formation, ring instability and clinical consequences.

BACKGROUND: The breakpoints and mechanisms of ring chromosome formation were studied and mapped in 14 patients. METHODS: Several techniques were performed such as genome-wide array, MLPA (Multiplex Ligation-Dependent Probe Amplification) and FISH (Fluorescent in situ Hybridization). RESULTS: The ring chromosomes of patients I to XIV were determined to be, respectively: r(3)(p26.1q29), r(4)(p16.3q35.2), r(10)(p15.3q26.2), r(10)(p15.3q26.13), r(13)(p13q31.1), r(13)(p13q34), r(14)(p13q32.33), r(15)(p13q26.2), r(18)(p11.32q22.2), r(18)(p11.32q21.33), r(18)(p11.21q23), r(22)(p13q13.33), r(22)(p13q13.2), and r(22)(p13q13.2). These rings were found to have been formed by different mechanisms, such as: breaks in both chromosome arms followed by end-to-end reunion (patients IV, VIII, IX, XI, XIII and XIV); a break in one chromosome arm followed by fusion with the subtelomeric region of the other (patients I and II); a break in one chromosome arm followed by fusion with the opposite telomeric region (patients III and X); fusion of two subtelomeric regions (patient VII); and telomere-telomere fusion (patient XII). Thus, the r(14) and one r(22) can be considered complete rings, since there was no loss of relevant genetic material. Two patients (V and VI) with r(13) showed duplication along with terminal deletion of 13q, one of them proved to be inverted, a mechanism known as inv-dup-del. Ring instability was detected by ring loss and secondary aberrations in all but three patients, who presented stable ring chromosomes (II, XIII and XIV). CONCLUSIONS: We concluded that the clinical phenotype of patients with ring chromosomes may be related with different factors, including gene haploinsufficiency, gene duplications and ring instability. Epigenetic factors due to the circular architecture of ring chromosomes must also be considered, since even complete ring chromosomes can result in phenotypic alterations, as observed in our patients with complete r(14) and r(22).