Endometriosis is a complex and heterogeneous disease in which extrinsic and intrinsic factors, such as genetics, provide to the disease development. Genome-wide association (GWA) studies may be ...essential to recognize genetic variants associated with the endometriosis risk. However, in the current literature there are some conflicting results between these studies. The aim of the present study was to undertake a systematic review about endometriosis GWA studies, to describe the disease-associated genes and single nucleotide polymorphisms (SNPs) to try to understand the endometriosis etiopathogenesis, besides to discuss possible bias of conflicting results among these studies. This study is a systematic review of GWA studies in endometriosis published until December 31th, 2019 by PubMed database, considering the following descriptors: endometriosis and (“polymorphism” or “SNP” or “genetic polymorphism" or “variants” or “locus”) and (“GWA” or “Genome-wide” or “Genome wide” or “Genetic association study”). The included studies were analyzed with methodological rigor (STROBE and PRISMA) to enable better quality of case-control and meta-analysis studies, respectively. Of the 88 articles found, only 15 were eligible. All articles had appropriate quality evaluated by STROBE and PRISMA checklists (77% and 81%, respectively). Overall, 35,022 endometriosis cases and 181,760 controls were analyzed. The number of participants in each study was quite different (171 to 17,045 for the cases and 308 to 150,021 for the controls), with a predominance of European ethnicity. Most endometriosis cases (86%) were diagnosed by surgery, while selection of the control group was different among studies. About 47% performed only one stage (discovery stage) and 53% performed both the discovery and replication analyses. Eleven genes/SNPs were associated with endometriosis risk in more than one article (chromosome 1, 2, 6, 7, 9 and 12; WNT4, GREB1, FN1, IL1A, ETAA1, RND3, ID4, NFE2L3, CDKN2B-AS1 and VEZT). SNPs were localized in intergenic and intronic regions, their risk allele frequencies varied among the studies and their results were conflicting. In summary, WNT4 rs7521902, GREB1 rs13394619, FN1 rs1250248, IL1A rs6542095 and VEZT rs10859871 variants are highlighted due to high frequency and pathways and function that each gene influences in the development of endometriosis. However, the replication and validation of these variants in different populations are necessary for a better understanding of the endometriosis etiopathogenesis, in order to optimize the diagnosis and improve the efficiency of clinical treatment of the disease.
This study aimed to evaluate the potential role of the PTGS2 single nucleotide polymorphisms (SNPs) -1195 A>G and +8473 T>C in endometriosis’ development, and characterizing their association with ...the prognostic features of the disease.
DNA from 254 women with endometriosis and 267 controls, recruited from two reference hospitals from the Brazilian public health system, were genotyped using TaqMan allelic discrimination assays. The association between SNPs and endometriosis features was evaluated by multivariate logistic regression, using the adjusted odds ratios (OR) with their respective 95% confidence intervals (95% CI).
There were significant differences between cases and controls regarding age (P < 0.001), body mass index (BMI) (P = 0.001), educational level (P < 0.001), physical activity (P = 0.003), smoking status (P < 0.001), contraception use (P = 0.02), family history of endometriosis (P = 0.002) and all symptoms (P < 0.001). The distribution of -1195 A > G was statistically different between the groups, suggesting a lower risk of developing the disease for the carriers of the −1195 GG genotype (OR = 0.19; 95% CI = 0.04 – 0.93). No differences were found for the +8473 T>C between the two groups and neither in prognostic features of the disease for both PTGS2 SNPs. In conclusion, PTGS2 -1195A>G SNP was negatively associated with development of endometriosis and the two groups were statistically different regarding age, BMI, educational level, physical activity, smoking status, contraception use, history of endometriosis and all endometriosis symptoms.
Endometriosis presents a pro-inflammatory microenvironment influenced by cytokines, such as interleukin (IL)-8, which expression may be influenced by genetic polymorphisms. Therefore, we aimed to ...investigate the role of interleukin (IL)-8 rs4073 polymorphism in endometriosis’ development and its related symptoms. A case-control study was conducted with 207 women with endometriosis and 193 healthy controls. Polymorphism was genotyped using a TaqMan validated assay. Associations were evaluated by binary logistic regression, using odds ratios (OR) and 95 % confidence intervals (CI), and P ≤ 0.05 was considered significant. Cases were younger (36 ± 6.8 versus 39 ± 8.4) and had lower body mass index (26.5 ± 5.3 versus 35.7 ± 6.3 Kg/m2) than controls (P < 0.001). Higher prevalence of symptoms and infertility was observed in cases, compared to controls (P < 0.001). Minor allele frequencies of IL-8 rs4073 (T) were 42.3 % and 39.9 % for cases and controls, respectively, and no associations were found between IL and 8 rs4073 polymorphism and endometriosis’ prevalence or staging. However, the polymorphism was associated with chronic pelvic pain among cases (OR = 0.54; 95 %CI = 0.29–0.98). The IL-8 rs4073A > T polymorphism may contribute to lower IL-8 expression and, consequently, decrease endometriosis-related pelvic pain. These findings can support the early diagnosis of endometriosis’ painful symptoms, preventing its complications, and allowing an individualized treatment.
Abstract Objectives: to describe the epidemiological and clinical profile of women with endometriosis and to determine the association with the prognostic characteristics of the disease. Methods: ...retrospective descriptive study involving 237 women attended at two referral hospitals for endometriosis, between 2011 and 2017. Associations between groups were estimated using logistic regression models. Results: most women (65.4%) were of reproductive age (29-39 years), with a body mass index in the range of 18.5-24.9 kg/m2 and a high prevalence (23-81%) of symptoms of the disease, with 49.5% being infertile. The average time of diagnosis was 5 years. Ovarian endometrioma and/or deep infiltrative endometriosis (DIE) were the most frequent type of endometriosis (87%), and 59% of patients were in the III/IV stage of the disease. Approximately 87% of women with surgical diagnosis were aged over 30, married (70%) and had lower parity. Dyspareunia was negatively associated with superficial endometriosis. Infertility was positively associated with age (30-39 years) and DIE in the uterine tubes; dysmenorrhea with DIE in the uterosacral ligament; cyclic intestinal complaints with DIE in the rectosigmoid and intestine, and with DIE classification and III/IVstage. Conclusions: knowing the epidemiological and clinical profile of Brazilian women with endometriosis can help in diagnosis and treatment planning.
Resumo Objetivos: descrever o perfil epidemiológico e clínico de mulheres com endometriose e determinar a associação com as características prognósticas da doença. Métodos: estudo descritivo retrospectivo envolvendo 237 mulheres atendidas em dois hospitais de referência em endometriose, no período entre 2011 e 2017. As associações entre os grupos foram estimadas utilizando modelos de regressão logística. Resultados: a maioria das mulheres (65,4%) estava em idade reprodutiva (29-39 anos), com índice de massa corporal entre 18,5-24,9 kg/m2 e alta prevalência (23-81%) dos sintomas clínicos da doença, sendo que 49,5% eram inférteis. O tempo médio de diagnóstico foi de 5 anos. O endometrioma ovariano e/ou endometriose profunda infiltrativa (EPI) foram os tipos mais frequentes de endometriose (87%), sendo que 59% das pacientes estavam no estágio III/IVda doença. Aproximadamente 87% das mulheres com diagnóstico cirúrgico apresentavam idade acima dos 30 anos, eram casadas (70%) e apresentavam menor paridade. A dispareunia foi associada negativamente à endometriose superficial. A infertilidade foi associada positivamente com a idade (30-39 anos) e com a EPI nas tubas uterinas; a dismenorreia com a EPI no ligamento uterosacral; as queixas intestinais cíclicas com a EPI no retosigmóide e intestino, e com a classificação EPI e estágio III/IV. Conclusões: conhecer o perfil epidemiológico e clínico das mulheres brasileiras com endometriose pode auxiliar no diagnóstico e no planejamento do tratamento.
DROSHA and DICER1 enzymes participate in the main stages of microRNA synthesis. Polymorphisms can influence mRNAs stability and genes expression, and hence affect the binding of miRNAs. Thus, the ...present study evaluated the association of DROSHA and DICER1 polymorphisms in the development of endometriosis and other diseases.
A total of 240 endometriosis cases and 242 controls were genotyped for the DROSHA rs10719 G > A and DICER1 rs3742330 A > G polymorphisms using the TaqMan system. The association between polymorphisms and endometriosis was estimated by binary logistic regression. A literature review was also performed including all published articles (PubMed database) until December 2020, regarding the association of the studied polymorphisms and different diseases.
DICER1 rs3742330GG was only found in endometriosis cases (2.1%) and deep infiltrative endometriosis (DIE) (2.5%). The DICER1 rs3742330GG genotype was significantly associated with endometriosis (P < 0.05), suggesting a tendency to present an increased risk for disease. DROSHA rs10719A and DICER1 rs3742330G allele frequencies varied among populations (6%–79% and 10.2%–55.1%, respectively). In the Brazilian population, the frequencies of these alleles were 42.3% and 7.3%, respectively. Both polymorphisms were risk factors for nonsyndromic orofacial clefts, tuberculosis, stroke ischemia and mortality after stroke, recurrent idiopathic pregnancy loss, and some types of cancer. Moreover, the DICER1 rs3742330 polymorphism was a protective factor for precancerous cervical lesions, different types of cancer and tuberculosis.
The results suggest that only the DICER1 rs3742330 A > G polymorphism may be associated with susceptibility to endometriosis. The frequencies of both polymorphisms were significantly different among populations, and there were discrepancies in the risk associations with the development of diseases.
Abstract
Purpose
To evaluate the magnitude of the association of the polymorphisms of the genes
PGR, CYP17A1
and
CYP19A1
in the development of endometriosis.
Methods
This is a retrospective ...case-control study involving 161 women with endometriosis (cases) and 179 controls. The polymorphisms were genotyped by real-time polymerase chain reaction using the TaqMan system. The association of the polymorphisms with endometriosis was evaluated using the multivariate logistic regression.
Results
The endometriosis patients were significantly younger than the controls (36.0 ± 7.3 versus 38.0 ± 8.5 respectively,
p
= 0.023), and they had a lower body mass index (26.3 ± 4.8 versus 27.9 ± 5.7 respectively,
p
= 0.006), higher average duration of the menstrual flow (7.4 ± 4.9 versus 6.1 ± 4.4 days respectively,
p
= 0.03), and lower average time intervals between menstrual periods (25.2 ± 9.6 versus 27.5 ± 11.1 days respectively,
p
= 0.05). A higher prevalence of symptoms of dysmenorrhea, dyspareunia, chronic pelvic pain, infertility and intestinal or urinary changes was observed in the case group when compared with the control group. The interval between the onset of symptoms and the definitive diagnosis of endometriosis was 5.2 ± 6.9 years. When comparing both groups, significant differences were not observed in the allelic and genotypic frequencies of the polymorphisms
PGR +331C
>
T
,
CYP17A1 -34A
>
G
and
CYP19A1 1531G
>
A
, even when considering the symptoms, classification and stage of the endometriosis. The combined genotype
PGR +331TT/CYP17A1 -34AA
/
CYP19A11531AA
is positively associated with endometriosis (odds ratio OR = 1.72; 95% confidence interval 95%CI = 1.09–2.72).
Conclusions
The combined analysis of the polymorphisms
PGR-CYP17A1-CYP19A1
suggests a gene-gene interaction in the susceptibility to endometriosis. These results may contribute to the identification of biomarkers for the diagnosis and/or prognosis of the disease and of possible molecular targets for individualized treatments.
The aim of the study was to investigate whether genetic variants in VEGF and KDR genes can be correlated with susceptibility of tendinopathy in volleyball athletes. This study was conducted at the ...Brazilian Volleyball Federation, and comprised 179 volleyball athletes: 88 had a confirmed diagnosis of tendinopathy (cases), whereas 91 had no evidence of the disease (controls). The VEGF (-2578C>A, -460T>C and +936C>T) and KDR (-604C>T, 1192G>A and 1719T>A) polymorphisms were determined by TaqMan real-time polymerase chain reaction. The odds ratio (OR) with their 95% confidence intervals (CI) were calculated using an unconditional logistic regression model. The evaluation of demographic and clinical characteristics revealed the athlete age (P < 0.001), years of practice in volleyball (P < 0.001) and presence of pain (P = 0.001) were risk factors for tendinopathy. KDR 1192 GA and GA + AA genotypes were associated with lower risk of tendinopathy (OR: 0.41, 95% CI: 0.19-0.88 and OR: 0.47, 95% CI: 0.23-0.98, respectively). The KDR (-604C>T, 1192G>A and 1719T>A) haplotypes CGA and CAT were associated with decreased tendinopathy risk (OR: 0.46, 95% CI: 0.21-0.99 and OR: 0.23, 95% CI: 0.07-0.76, respectively). With regards to pain, traumatic lesion and away from training due to injury, VEGF and KDR polymorphisms were not associated with clinical symptoms complaints. The present results provide evidence that the KDR polymorphisms were associated with development of tendinopathy, and can contribute to identify new therapeutic targets or personalized training programs to avoid tendinopathy development in athletes.
Abstract Objective Endometriosis is a multifactorial gynecological disease, whose pathogenesis is crucially dependent on angiogenesis, which is signaled via vascular endothelial growth factor (VEGF) ...and its receptor (VEGFR2). We hypothesize that single nucleotide polymorphisms (SNPs) in VEGF and VEGFR2 genes may influence the onset and/or the progression of endometriosis. The main aim of this study was to investigate the contribution of VEGF and VEGFR2 SNPs as risk factors for endometriosis, as well as their association with endometriosis symptoms. Study design A case-control study was conducted, involving 293 endometriosis patients and 223 controls, who were submitted to laparoscopic or laparotomy surgery at hospitals from the Brazilian public health system. Genotyping of VEGF ( −2578C > A, −460T > C, −1154G > A, +405G > C and +936C > T ) and VEGFR2 ( −604T > C, 1192C > T ) SNPs was performed by TaqMan real-time polymerase chain reaction. The association between SNPs and endometriosis, deep infiltrating endometriosis (DIE) or endometriosis symptoms was estimated by odds ratios (OR) with their 95% confidence intervals (CI), which were calculated using multivariate logistic regression models. Results VEGF variant alleles −2578A and −1154A were associated with increased endometriosis risk (OR: 1.39, 95% CI: 1.04–1.87 and OR: 1.63, 95% CI: 1.12–2.37, respectively), whereas VEGF 405C and VEGFR2 1192T were associated with lower risk of endometriosis (OR: 0.66, 95% CI: 0.43–1.00 and OR: 0.58, 95% CI: 0.40–0.84, respectively). The combination of wild-type genotypes of both VEGF −2578C > A and −1154G > A with variant genotypes of both VEGF +405G > C and VEGFR2 1192C > T showed the best protective effect against the development of endometriosis, either considering all cases (OR: 0.33, 95% CI: 0.12–0.89) or only DIE (OR: 0.30, 95% CI: 0.10–0.87). The combination of variant genotypes of VEGF −2578C > A, −1154G > A, +405G > C and VEGFR2 1192C > T was also protective against DIE (OR: 0.67, 95% CI: 0.46–0.96). VEGFR2 1192C > T were associated with reduced cyclical urinary complaints (OR: 0.40, 95% CI: 0.18–0.88). Conclusions Our results indicate that VEGF SNPs −2578C > A and − 1154G > A increase endometriosis risk, whereas VEGF +405G > C and VEGFR2 1192C > T are protective against disease development, with VEGFR2 1192C > T also reducing cyclical urinary symptoms. The combined analysis of VEGF–VEGFR2 genotypes suggests a gene–gene interaction in endometriosis susceptibility.
To investigate the contribution of CYP2C19 polymorphisms and body mass index (BMI) in the development of endometriosis.
This is a case-control study that includes 356 women (187 cases and 169 ...controls) recruited from two hospitals in the Brazilian public health system. The genotyping analyses of the CYP2C19*2 and CYP2C19*17 polymorphisms were performed using TaqMan allelic discrimination assays, and the association of the studied polymorphisms with endometriosis was evaluated by multivariate logistic regression. Pearson correlation coefficients were used to investigate the interaction between BMI and CYP2C19 polymorphisms.
The variant allele frequencies of CYP2C19*2 were significantly different between cases and controls, and after adjusting for confounding factors, the CYP2C19*2 polymorphism was more frequent in women with endometriosis, considering all cases (CYP2C19*2: OR=1.83; 95% CI=1.17–2.85) and only deeply infiltrating endometriosis (DIE) cases (CYP2C19*2: OR=2.32; 95% CI=1.42–3.77). BMI was significantly lower in endometriosis patients (26.5±4.68) than in controls (27.8±5.65, P<0.02). Among obese women (BMI 30–40), the CYP2C19*2 polymorphism had a greater association with endometriosis (CYP2C19*2: OR=3.27; 95% CI=1.55–6.89). There was a positive correlation between CYP2C19*2 and BMI 30–40 (P=0.004).
The findings of our study suggest that CYP2C19*2 is positively associated with endometriosis and that BMI may have a significant interaction with CYP2C19*2 and the risk of endometriosis.
Mercury (Hg) pollution is a global public health concern because of its adverse effects on the environment and health. Single-nucleotide polymorphisms (SNPs) have been associated with Hg levels and ...outcomes. The aim of this review was to describe the research and discuss the evidence on the genetic susceptibility of Hg-exposed individuals to the development of neurocognitive disorders. A systematic review was performed to identify the genes/SNPs associated with Hg toxicokinetics and that, therefore, affect neurological function in exposed populations. Observational and experimental studies were identified by screening three databases. Thirteen articles were included (quality score 82-100%) and 8124 individuals were evaluated. Hg exposure was mainly fish consumption (77%) and, in 31% of the studies, the Hg levels exceeded the reference limits. Genetic susceptibility to higher Hg levels and neurotoxicity risk in Hg poisoning were associated with eight (
rs1800435,
rs2740574,
rs776746,
rs2257401,
rs1695,
rs8052394,
rs2270836, and
rs11643815) and three (
rs8052394,
rs2270837, and
rs10636) SNPs, respectively, and rs8052394 was associated with both outcomes. The
rs8052394 SNP may be used as a susceptibility biomarker to identify individuals at greater risk for higher Hg levels and the development of neurocognitive disorders in metal-exposed populations.
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