Genetics Of Endometriosis Research Articles

The Genetics of Endometriosis.

Mapping genetic risk factors for endometriosis continues from early studies on women's health initiated by Nick Martin and Susan Treloar. Their initial recruitment of endometriosis cases and family members received a major boost and became a flagship project within the Cooperative Research Centre (CRC) for the Discovery of Common Human Disease. We extended the study through a formal collaboration with Professor Stephen Kennedy and his group in Oxford. Our first joint scientific meeting was held in Brisbane and was sadly memorable as the day the planes were flown into the Twin Towers in New York. Our initial collaboration expanded into the International Endometriosis Genetics Consortium (IEGC). The IEGC now has 15 groups around the world, and the most recent meta-analysis will be published this year.

Recent advances in molecular genetics of endometriosis

Endometriosis (MIM 131200) is a prevalent and complex gynecological disease polygenically inherited with multifactorial pathogenesis. It is increasingly recognized as a major women's health issue. ...

Genetics of Endometriosis.

Endometriosis is a complex, puzzling disease in women of reproductive age. The exact cause of the disease is unknown; however, different genetic and environmental factors contribute to the evolution of the disorder. Further investigation has led to the discovery of inheritance as a complex genetic trait. Candidate genes were identified to isolate regions of genes that affect disease risk. Additional linkage studies have been performed to map specific genes along the entire genome. Recent advances to determine the genetic component of endometriosis include genome-wide association studies. This chapter focuses on different approaches to identify the genetic links of endometriosis and its pathogenesis.

Genetics of endometriosis.

Endometriosis is a heritable complex disorder that is influenced by multiple genetic and environmental factors. Identification of these genetic factors will aid a better understanding of the underlying biology of the disease. In this article, we describe different methods of studying genetic variation of endometriosis, summarize results from genetic studies performed to date and provide recommendations for future studies to uncover additional factors contributing to the heritable component of endometriosis.

Advances in the genetics of endometriosis

Endometriosis is a gynecological disease characterized by implantation of endometrial tissue outside of the uterus. Early familial aggregation and twin studies noted a higher risk of endometriosis among relatives. Studies on the roles of the environment, genetics and aberrant regulation in the endometrium and endometriotic lesions of women with endometriosis suggest that endometriosis arises from the interplay between genetic variants and environmental factors. Elucidating the hereditary component has proven difficult because multiple genes seem to produce a susceptibility to developing endometriosis. Molecular techniques, including linkage and genome-wide analysis, have identified candidate genes located near known loci related to development and regulation of the female reproductive tract. As new candidate genes are discovered and hereditary pathways identified using technologies such as genome-wide analysis, the possibility of prevention and treatment becomes more tangible for millions of women affected by endometriosis. Here, we discuss the advances of genetic research in endometriosis and describe technologies that have contributed to the current understanding of the genetic variability in endometriosis, variability that includes regulatory polymorphisms in key genes.

Genetics of Endometriosis

Genetics of Endometriosis

Recent Advances in Molecular Genetics of Endometriosis

Endometriosis (MIM 131200) is a prevalent and complex gynecological disease polygenically inherited with multifactorial pathogenesis. It is increasingly recognized as a major women's health issue. Endometriosis is characterized by the presence of endometrial-like tissue in sites outside the uterus, mainly the pelvic peritoneum, ovaries and rectovaginal septum causing severe dysmenorrhoea, dyspareunia, chronic pelvic pain and subfertility. Recent advances in molecular technologies have provided many evidences about the underlying biological events that are likely to be involved in the development of endometriosis. Different chromosomal regions, genes and other molecules, such as microRNAs, have been identified as potentially involved in endometriosis pathogenesis. Moreover, genome-wide analyses of endometriosis have showed novel molecular signatures or individual genes that had not been previously associated with the disease. The goal of these studies is to provide information that might, in turn, lead to new therapies. In this review, some previous studies were updated supporting the polygenic/multifactorial inheritance and the association with malignant neoplasias. We have also emphasized the importance of identifying the causative genes and determining novel diagnostic and predictive biomarkers.

Genetics of endometriosis: current status and prospects

Family and twin studies have shown that heritability accounts for endometriosis development to an extent similar to other complex genetic diseases. Both linkage analysis and association studies have been performed to identify genetic determinants for the disease. Results from the linkage scan of 1,176 families collected thanks to a joint effort between an Australian and a UK group supported significant linkage to a novel susceptibility locus on chromosome 10q26. Although gene variants with effects on the disease predisposition have been proposed to exist and several candidates have been put forward, their effects have not been or are yet to be confirmed. The main categories of candidate genes studied have been those involved in detoxification processes, sex steroid biosynthesis and action, immune system regulation. Genetic studies on endometriosis face numerous challenges as the disease has several manifestations and different forms. Moreover, strong gene-environmental interactions might definitively influence approaches to identify genetic variants involved. Genome-wide association studies that survey most of the genome for causal genetic variants provide the potential for future progress.

Genetics of endometriosis: a role for the progesterone receptor gene polymorphism PROGINS?

Endometriosis is a steroid-dependent disease with a particular genetic background, but the locations of possible genomic aberrations are still poorly clarified. We have investigated the potential association between endometriosis and the PROGINS 306 base pair insertion polymorphism in intron G of the progesterone receptor (PR) gene, which has been reported previously to segregate with this disease. In a case-control study, we examined the PROGINS polymorphism of the progesterone receptor gene in 131 Italian women affected by endometriosis diagnosed according to published criteria for the definition of the definite disease. Control subjects were represented by 127 Italian women without laparoscopic evidence of the disease. Peripheral blood samples, DNA extraction and polymerase chain reaction (PCR) were used to genotype women for the presence of the PROGINS polymorphism. We found a statistically significant difference in the distribution of PROGINS genotypes between patients with and without endometriosis. The frequency of the PROGINS allele T2 was 17.2% and 11%, respectively, in affected women and in controls [odds ratio (OR) = 1.7, 95% confidence interval (CI) 1.0-2.8]. This association was stronger in patients with more severe forms of endometriosis, such as an infiltrating disease or a disease characterized by severe pelvic adhesions (OR 2.4, 95% CI 1.2-4.8; and OR 2.7, 95% CI 1.4-5.3, respectively). Combination of the results from an earlier study and the current data indicates that carrying the allele variant T2 is associated with a twofold increase in the risk of developing endometriosis (OR 2.0, 95% CI 1.3-2.9). Our results further support the idea that the PROGINS polymorphism of the progesterone receptor may be associated with an increased risk of endometriosis.

Genetics of endometriosis: heritability and candidate genes

Endometriosis is a complex gynecologic disorder that affects as many as 10–15% of premenopausal women. Epidemiologic studies have confirmed that this disease is a genetic disorder of polygenic/multifactorial inheritance. The disorder has long been recognized to show heritable tendencies with recurrence risks of 5–7% for first-degree relatives. The current investigational goal is to determine the number and location of causative genes, a process that has been made possible by recent advances in molecular technology. This chapter discusses heritability studies supporting polygenic/multifactorial inheritance, the scientific basis of genome-wide strategies for identifying causative genes and potential candidate genes.

Genetics of endometriosis: a review of the positional cloning approaches.

There is increasing evidence that endometriosis is inherited as a complex genetic trait in which multiple genes conferring disease susceptibility interact with each other and the environment to produce the phenotype. Research groups worldwide are trying to identify such susceptibility genes through a "positional cloning" approach. This involves mapping their approximate chromosomal localization using linkage analysis by studying the segregation of DNA markers with disease in families without any knowledge of disease mechanisms. The next stage involves choosing a candidate gene in that region, based upon some theoretical or actual knowledge of disease mechanisms, and showing that polymorphisms in that gene occur more frequently in affected individuals than in controls. The approach should produce a clearer understanding of the molecular and cellular mechanisms involved in disease etiology and pathogenesis. It is unlikely that endometriosis is a single disease entity, and it should be possible to categorize the disease into subtypes on the basis of genetic information. The strategy should lead to the discovery of new drug targets, which will be a major advance given that treatment to date has focused upon crude manipulation of ovarian function.

The epidemiology of endometriosis.

Advances in understanding the epidemiology of endometriosis have lagged behind other diseases because of methodologic problems related to disease definition and control selection. Nevertheless, a better picture of the epidemiology of endometriosis has emerged over the past few decades. Prevalence estimates of the disease in clinic populations vary from about a 4% occurrence of largely asymptomatic endometriosis found in women undergoing tubal ligation to 50% of teenagers with intractable dysmenorrhea. General population incidence during the 1970s in this country has been suggested to be 1.6 per 1000 white females aged 15-49, while a more current study based upon hospital discharges finds endometriosis as a first listed diagnosis in 1.3 per 1000 discharges in women aged 15-44. There is a clinical impression that blacks have lower rates of endometriosis and Orientals have higher rates than whites. A variety of personal risk factors for endometriosis have also been described. Women with endometriosis may be taller and thinner. Menstrual factors reported to increase risk include dysmenorrhea, early menarche, and shorter cycle lengths. There is support for the idea that lifestyle exposures that might raise or lower estrogen levels could affect risk, including a decreased risk associated with smoking and exercise and an increased risk associated with caffeine or alcohol use. These risk factors appear to be compatible with the central importance of retrograde menstruation influenced by outflow obstruction that might affect its amount, immune factors that might affect its ability to be cleared, or hormonal stimuli that might affect its growth. In this model, dysmenorrhea could be either a disease symptom or a manifestation of outflow obstruction. Nulliparity could be either a consequence of disease or a cause since nulliparous women would not have the benefit of cervical dilation associated with labor and delivery. Since there is evidence that family history is a risk factor for disease, a challenge is how to integrate genetic factors into the model. The genetics of endometriosis might be advanced if we could identify an "endometriosis phenotype". We propose that this may consist of early menarche, short cycles, painful periods, subfertility, and possibly tall stature that could be explained by genetic factors that predispose to poor endowment of germ cells and canalization defects of the cervix. The value of establishing an "endometriosis phenotype" is that, as candidates for genetic markers are identified, particular genotypes can be correlated with these factors even if a formal diagnosis of endometriosis has not been made. Additional well-designed case-control and cohort studies will be necessary to test theories related to pathogenesis, establish the precise relationship between reproductive morbidity and endometriosis, identify specific genetic factors, and establish long-term risks.

The genetics of endometriosis

There is mounting evidence that endometriosis is inherited as a complex trait, like diabetes or asthma. This implies there are environmental factors, such as dioxin, that are interacting with multiple genetic susceptibility loci to produce the phenotype. The Oxford Endometriosis Gene (OXEGENE) study, an international collaborative project, seeks to identify the susceptibility loci using linkage analysis; the aim then is to use positional cloning techniques to identify genes that predispose women to the disease. Analysis of the biochemical function of the gene products will lead to a better understanding of the pathophysiology and aetiology of endometriosis. New therapies may be designed based upon knowledge of the gene function and disease associated genetic markers may be used to identify women at high risk of developing the disease.