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Genetic analyses in humans and macaques followed by cellular and mouse studies demonstrate NPSR1 as a nonhormonal drug target in endometriosis.
\n \n\n \n \nAbstractThe normal menstrual cycle requires a delicate interplay between the hypothalamus, pituitary, and ovary. Therefore, its length is an important indicator of female reproductive health. Menstrual cycle length has been shown to be partially controlled by genetic factors, especially in the follicle stimulating hormone beta-subunit (FSHB) locus. GWAS meta-analysis of menstrual cycle length in 44,871 women of European ancestry confirmed the previously observed association with the FSHB locus and identified four additional novel signals in, or near, the GNRH1, PGR, NR5A2 and INS-IGF2 genes. These findings confirm the role of the hypothalamic-pituitary-gonadal axis in the genetic regulation of menstrual cycle length, but also highlight potential novel local regulatory mechanisms, such as those mediated by IGF2.
\n \n\n \n \nUterine leiomyomata (UL), also known as uterine fibroids, are the most common neoplasms of the reproductive tract and the primary cause for hysterectomy, leading to considerable impact on women\u2019s lives as well as high economic burden1,2. Genetic epidemiologic studies indicate that heritable risk factors contribute to UL pathogenesis3. Previous genome-wide association studies (GWAS) identified five loci associated with UL at genome-wide significance (P< 5 \u00d7 10\u22128)4\u20136. We conducted GWAS meta-analysis in 20,406 cases and 223,918 female controls of white European ancestry, identifying 24 genome-wide significant independent loci; 17 replicated in an unrelated cohort of 15,068 additional cases and 43,587 female controls. Aggregation of discovery and replication studies (35,474 cases and 267,505 female controls) revealed six additional significant loci. Interestingly, four of the 17 loci identified and replicated in these analyses have also been associated with risk for endometriosis \u2013 another common gynecologic disorder. These findings increase our understanding of the biological mechanisms underlying UL development, and suggest overlapping genetic origins with endometriosis.
\n \n\n \n \nAbstract\n\nStudy question\nIn this previous undescribed population of women, what is the prevalence of endometriosis and associated symptomatology, and how are women affected?\n\n\nSummary answer\nPrevalence of endometriosis was 5.4% (95%CI; 4.9%-5.9%). Cases suffered from worse physical health, higher use of pain medication and decreased productivity at work.\n\n\nWhat is known already\nThere is a lack of population level data on prevalence and distribution of women\u2019s health conditions, such as endometriosis, from the Eastern Mediterranean region, despite their known negative effects on quality of life. In addition, there is a complete absence of any health statistics from Northern Cyprus, an emerging region in Europe. Most current endometriosis research comes from Western populations and is not generalisable to non-Western populations due to differences in culture, lifestyle, and care seeking patterns. Therefore, it is important to investigate endometriosis in a variety of settings.\n\n\nStudy design, size, duration\nThe COHERE Initiative is a cross-sectional, population-based study that recruited 7,646 women between the ages 18-55 residing in Northern Cyprus between January 31st 2018, and January 31st 2020. Recruitment took place face-to-face (90%) and online (10%). Participants completed an expanded version of the WERF Endometriosis Phenome and Biobanking Harmonisation Project (EPHect) questionnaire, consisting of previously validated measurement instruments, such as the Short-Form-36-version-2 questionnaire (SF-36v2) and the Work Productivity and Impairment Questionnaire: General Health (WPAI:GH).\n\n\nParticipants/materials, setting, methods\nEndometriosis cases were defined using a combination of self-reported and pelvic ultrasound data. Controls were women without endometriosis. Chi-square, Fisher\u2019s exact test, Student\u2019s t-test, linear regression, and multivariable logistic regression were used for data analysis. The significance level was set at p\u2009<\u20090.05.\n\n\nMain results and the role of chance\nEndometriosis prevalence was 5.4% (95%CI; 4.9%-5.9%;n=410). The mean age women with endometriosis reported to first experience related-symptoms was 25.9-years, despite average age of first menstrual-pain occurring at 16.2-years. Average age of first gynaecologist visit was 21.0-years and endometriosis diagnostic-delay was 1.5-years. Physical health-related-quality-of-life was lower in women with endometriosis compared to those without (48.4 vs 50.2, p\u2009=\u20090.001). Cases had a higher mean percentage of activity impairment (25.8% vs 22.5%, p\u2009=\u20090.03) and reduced effectiveness whilst working (23.4% vs 19.5%, p\u2009=\u20090.006) than controls. Hormone-use was higher in women with endometriosis compared to controls for heavy-bleeding (5.9% vs 1.4%, p\u2009<\u20090.001), irregular periods (14.4% vs 7.2%, p\u2009<\u20090.001) and pelvic-pain (9.3% vs 1.7%, p\u2009<\u20090.001), though overall hormone use was low at 24.1%. Iron and vitamin-D deficiency were the most reported co-morbidities, and these proportions were significantly different from women without endometriosis (38.8% vs 28.3%, 23.9% vs 17.0% respectively, p\u2009<\u20090.001). Migraine headaches were more frequent in women with endometriosis than in those without (19.8% vs 13.2%, p\u2009<\u20090.001). Women with endometriosis were more likely to have ever used drugs for pain relief (77.1% vs 60.5%, p\u2009<\u20090.001). Further analysis will include estimation of economic burden of endometriosis and investigation into Mediterranean-specific factors including sun-exposure and dietary-habits.\n\n\nLimitations, reasons for caution\nGiven the cross-sectional nature of this study, causality cannot be inferred. The majority of endometriosis cases are self-reported which is not as reliable as hospital diagnosis/surgeries and laparoscopy is not available in Northern Cyprus. However, research has shown that women self-report endometriosis diagnoses with reasonable accuracy (>70%).\n\n\nWider implications of the findings\nThis is the first study that has estimated prevalence of endometriosis in the region and provided insight into the current-status of healthcare. It has highlighted gaps in the public\u2019s general knowledge of common gynaecological conditions. The results form the basis for targeted follow-up-studies and promotes evidence-based reproductive-medicine in the Eastern-Mediterranean-region.\n\n\nTrial registration number\nNot applicable\n
\n \n\n \n \nEndometriosis is an estrogen-dependent, progesterone-resistant, inflammatory disease with symptoms that include pelvic pain, infertility, and compromised quality of life in millions of women worldwide. Approximately 50% of the risk of developing endometriosis is due to genetic factors with the remaining 50% due to environmental (i.e., exposome) causes. Treatments are hormonal, surgical, or both, with limited efficacy in the long term. Diagnosis of pelvic endometriosis is through visual identification and confirmatory histopathology of lesions. Recent innovations in genomics, genetics and epigenetics, molecular and cell biology, imaging, and a worldwide effort to standardize patient phenotyping and biospecimen collection have contributed to understanding mechanisms underlying the pathogenesis and pathophysiology of endometriosis. Furthermore, integration of \u201cbig data\u201d obtained through these technologies holds great promise for novel targeted therapies, noninvasive diagnostics, and prognostic indicators. This chapter reviews current advances in genomics, genetics, and epigenetics of endometriosis that are providing translational approaches for preventing, diagnosing, and effectively treating this enigmatic disease.
\n \n\n \n \nEndometriosis is a complex condition that is caused by both multiple genetic and environmental factors. The heritable component for endometriosis is estimated at ~50%. Here we provide a summary of genome-wide associations studies (GWAS) performed to date to identify common genetic variants for endometriosis. Largest GWAS meta-analysis conducted by the International Endogene Genomics Consortium (IEGC) included a total of 58, 115 endometriosis cases and 733, 480 controls and has identified 27 loci genome-wide significantly associated with endometriosis. Positionally, the lead SNPs for the identified genetic loci reside near genes that are involved in sex-steroid hormone, WNT signaling, cell adhesion/migration, cell growth/carcinogenesis, and inflammation-related pathways. Furthermore, genetic variants associated with subtypes of endometriosis are described. In particular, eight genome-wide significant signals were associated with stage III/IV disease and 21 of 27 loci had larger effect sizes in stage III/IV disease compared to stage I/II disease suggesting that particular variants may confer risk for different subtypes of endometriosis through different pathways. Together, the 27 loci explained 2.15% of variance for overall endometriosis and 3.83% for stage III/IV disease which highlight that there remain many more genetic loci to be revealed for endometriosis in larger, deeply phenotyped datasets. Furthermore, future research needs to focus on fine-mapping of the identified loci to reveal the causal variants for each of the 27 loci and functional follow-up examining their effects on multiomics data in tissues and cells relevant to endometriosis, i.e., endometrium and its cellular components.
\n \n\n \n \nAbstractEndometriosis is a common gynaecological disease of women in reproductive age, and is thought to arise from retrograde menstruation and implantation of endometrial tissue, mostly into the peritoneal cavity. The condition is characterized by a chronic, unresolved inflammatory process thereby contributing to pain as cardinal symptom in endometriosis. Elevated reactive oxygen species (ROS) and oxidative stress have been postulated as factors in endometriosis pathogenesis. We here set out for a systematic study to identify novel mechanisms and pathways relating to oxidative stress in ectopic peritoneal lesions. Using combined proteomic and transcriptomic approaches, we identified novel targets including upregulated pro-oxidative enzymes, such as amine oxidase 3/vascular adhesion protein 1 (AOC3/VAP1) as well as downregulated protective factors, in particular alkenal reductase PTGR1 and methionine sulfoxide reductase. Consistent with an altered ROS landscape, we observed hemoglobin / iron overload, ROS production and lipid peroxidation in ectopic lesions. ROS-derived 4-hydroxy-2-nonenal induced interleukin IL-8 release from monocytes. Notably, AOC3 inhibitors provoked analgesic effects in inflammatory pain models in vivo, suggesting potential translational applicability.
\n \n\n \n \n\nIntroduction\nCaesarean section (C-section) is a life-saving procedure when medically indicated but unmet need and overuse can add to avoidable morbidity and mortality. It is not clear whether C-section has a negative impact on breastfeeding and there is limited data available on rates of C-section or breastfeeding from Northern Cyprus, an emerging region in Europe. This study aimed to investigate prevalence, trends and associations of C-section and breastfeeding in this population.\n\n\nMethods\nUsing self-reported data from the representative Cyprus Women\u2019s Health Research (COHERE) Initiative, we used 2,836 first pregnancies to describe trends in C-section and breastfeeding between 1981 and 2017. Using modified Poisson regression, we examined the relationship between year of pregnancy and C-section and breastfeeding, as well as the association between C-section and breastfeeding prevalence and duration.\n\n\nResults\nC-section prevalence in first pregnancies increased from 11.1% in 1981 to 72.5% in 2017 with a relative risk of 2.60 (95%CI; 2.14\u20132.15) of babies being delivered by C-section after 2005 compared to before 1995, after full adjustment for demographic and maternal medical and pregnancy related factors. Prevalence of ever breastfeeding remained steady throughout the years at 88.7% and there was no significant association between breastfeeding initiation and the year of pregnancy, or demographic and maternal medical and pregnancy related variables. After full adjustment, women who gave birth after 2005 were 1.24 (95%CI; 1.06\u20131.45) times more likely to breastfeed for >12 weeks compared to women who gave birth before 1995. There was no association between C-section and breastfeeding prevalence or length.\n\n\nConclusion\nPrevalence of C-section in this population is much higher than WHO recommendations. Public awareness campaigns surrounding choice during pregnancy and change in legal framework to allow for midwife-led continuity models of birthing care should be implemented. Further research is required to understand the reasons and drivers behind this high rate.\n
\n \n\n \n \nResponse to medication is highly variable, unpredictable and, at times, may be fatal. All drugs are more effective in certain groups of the population while showing no or minimal benefit in other groups. Although the current data on the subject are piecemeal, anecdotal evidence suggests that, in line with other common multifactorial traits, a myriad of genomic as well as environmental factors underpin population variability in drug response. Pharmacogenomics is the study of how variations in the human genome affect the variability in response to medication. Efforts to personalize treatment based on results from pharmacogenomics studies have the potential to increase efficacy, lower the overall cost of treatment, and decrease the incidence of adverse drug reactions, and are one of the major challenges of the modern era. The classical twin design has traditionally been used to assess the relative contribution of genetic and environmental factors to population variation in common, complex phenotypes, including drug response. Twins are not commonly regarded as providing the optimal design in genomic studies. However, we argue that, through their precise \u2018matching\u2019 for confounding variables (age, sex, cohort and common environmental effects), their amenability to numerous nonclassical study designs (genome-wide association studies or the role of epigenetic factors), and the availability of large, established registries worldwide, the twin model represents a flexible study design for systems-biology studies of drug response in humans. In this review, we describe the \u2018classical twin model\u2019 and its application in traditional pharmacogenetics studies, discuss the value of the twin design in the modern systems biology era, and highlight the potential of existing twin registries in formulating future strategies in pharmacogenomics research. We argue that the usefulness of this design goes beyond its traditional applications. Moreover, the flexibility of the model in concert with the amenability of large, established registries of twins worldwide to the collecting of new phenotypes will mean that the study of identical and nonidentical twins will play a considerable role in shaping our understanding of the important factors that underpin population variability in common, complex phenotypes, including response to medication.
\n \n\n \n \nBACKGROUND: Endometriosis is an estrogen-dependent, chronic inflammatory disease that affects 10% of women during the reproductive ages. Despite the estimated 50% heritability for the condition, only 26% was associated with common genetic variants. Thus, necessity of identifying rare variants for the missing heritability is implicated in the literature. Therefore, our study aimed to identify novel rare genetic variants involved in the pathogenesis of endometriosis utilizing a family of multiple affected members. METHODS: A family composed of four affected women along with their two unaffected mothers were recruited at a single gynecology and infertility clinic specialized in endometriosis. All patients presented with endometriomas, which was visualized by transvaginal ultrasonography. Two affected individuals had received laparoscopic endometrioma excision and therefore were diagnosed with recurrent disease. One mother had a history of endometrial serous adenocarcinoma (ESC) for which she underwent hysterectomy with bilateral oophorectomy. Three endometriosis cases were whole exome sequenced on Illumina NextSeq 550 platform with an average of 90% coverage. Candidate genes were confirmed by Sanger sequencing and followed-up with family segregation. RESULTS: Novel rare variants were identified in TNFRSF1B (NM_001066.3: c.1072G>A, p.(Ala358Thr)) and GEN1 (NM_001130009.3: c.1574C>T, p.(Ser525Leu)) as possible genetic causes of endometriosis. A third novel rare variant was identified in CRABP1 (NM_004378.3:c.54G>C, p.(Glu18Asp)) only on the mother with ESC history and her daughters. CONCLUSION: Novel candidate genetic variants that might contribute to endometriosis were suggested that need replication through independent cohorts or validation by functional studies. The family has also received genetic counseling and that the affected daughters are on clinical follow-up, accordingly.
\n \n\n \n \nSTUDY QUESTION: Is there a shared genetic or causal association of endometriosis with asthma or what biological mechanisms may underlie their potential relationships? SUMMARY ANSWER: Our results confirm a significant but non-causal association of endometriosis with asthma implicating shared genetic susceptibility and biological pathways in the mechanisms of the disorders, and potentially, their co-occurrence. WHAT IS KNOWN ALREADY: Some observational studies have reported a pattern of co-occurring relationship between endometriosis and asthma; however, there is conflicting evidence and the aetiology, as well as the underlying mechanisms of the relationship, remain unclear. STUDY DESIGN, SIZE, DURATION: We applied multiple statistical genetic approaches in the analysis of well-powered, genome-wide association study (GWAS) summary data to comprehensively assess the relationship of endometriosis with asthma. Endometriosis GWAS from the International Endogene Consortium (IEC, 17\u200a054 cases and 191\u200a858 controls) and asthma GWAS from the United Kingdom Biobank (UKB, 26\u200a332 cases and 375\u200a505 controls) were analysed. Additional asthma data from the Trans-National Asthma Genetic Consortium (TAGC, 19\u200a954 cases and 107\u200a715 controls) were utilized for replication testing. PARTICIPANTS/MATERIALS, SETTING, METHODS: We assessed single-nucleotide polymorphism (SNP)-level genetic overlap and correlation between endometriosis and asthma using SNP effect concordance analysis (SECA) and linkage disequilibrium score regression analysis (LDSC) methods, respectively. GWAS meta-analysis, colocalization (GWAS-PW), gene-based and pathway-based functional enrichment analysis methods were applied, respectively, to identify SNP loci, genomic regions, genes and biological pathways shared by endometriosis and asthma. Potential causal associations between endometriosis and asthma were assessed using Mendelian randomization (MR) methods. MAIN RESULTS AND THE ROLE OF CHANCE: SECA revealed significant concordance of SNP risk effects across the IEC endometriosis and the UKB asthma GWAS. Also, LDSC analysis found a positive and significant genetic correlation (rG = 0.16, P = 2.01 \u00d7 10-6) between the two traits. GWAS meta-analysis of the IEC endometriosis and UKB asthma GWAS identified 14 genome-wide significant (Pmeta-analysis < 5.0 \u00d7 10-8) independent loci, five of which are putatively novel. Three of these loci were consistently replicated using TAGC asthma GWAS and reinforced in colocalization and gene-based analyses. Additional shared genomic regions were identified in the colocalization analysis. MR found no evidence of a significant causal association between endometriosis and asthma. However, combining gene-based association results across the GWAS for endometriosis and asthma, we identified 17 shared genes with a genome-wide significant Fisher's combined P-value (FCPgene) <2.73 \u00d7 10-6. Additional analyses (independent gene-based analysis) replicated evidence of gene-level genetic overlap between endometriosis and asthma. Biological mechanisms including 'thyroid hormone signalling', 'abnormality of immune system physiology', 'androgen biosynthetic process' and 'brain-derived neurotrophic factor signalling pathway', among others, were significantly enriched for endometriosis and asthma in a pathway-based analysis. LARGE SCALE DATA: The GWAS for endometriosis data were sourced from the International Endogen Consortium (IEC) and can be accessed by contacting the consortium. The GWAS data for asthma are freely available online at Lee Lab (https://www.leelabsg.org/resources) and from the Trans-National Asthma Genetic Consortium (TAGC). LIMITATIONS, REASONS FOR CAUTION: Given we analysed GWAS datasets from mainly European populations, our results may not be generalizable to other ancestries. WIDER IMPLICATIONS OF THE FINDINGS: This study provides novel insights into mechanisms underpinning endometriosis and asthma, and potentially their observed relationship. Findings support a co-occurring relationship of endometriosis with asthma largely due to shared genetic components. Agents targeting 'selective androgen receptor modulators' may be therapeutically relevant in both disorders. Moreover, SNPs, loci, genes and biological pathways identified in our study provide potential targets for further investigation in endometriosis and asthma. STUDY FUNDING/COMPETING INTEREST(S): National Health and Medical Research Council (NHMRC) of Australia (241,944, 339,462, 389,927, 389,875, 389,891, 389,892, 389,938, 443,036, 442,915, 442,981, 496,610, 496,739, 552,485, 552,498, 1,026,033 and 1,050,208), Wellcome Trust (awards 076113 and 085475) and the Lundbeck Foundation (R102-A9118 and R155-2014-1724). All researchers had full independence from the funders. Authors do not have any conflict of interest.
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