Endometriosis: a “history” over 100 years long
Endometriosis is described more than 100 years ago as “endometrial-like tissue” outside the uterus [1, 2], endometriosis is a chronic condition characterized by an abnormality of endometrium cells (mucosa that normally covers the uterine cavity) leading to an ectopic localization of endometrial tissue, e.g. in the peritoneal cavity, causing systemic symptoms and local pathological changes [3, 4]. It is a common gynecological condition in the world and affects the 10-15% of women of reproductive age. The literature also reports cases of patients with endometriosis after menopause [5-7].
Endometriosis is considered a benign condition, called “a cancer of no kill”, also known as a “mysterious” condition because of its complexity, difficulties in formulating an early diagnosis and its nature to be prone to spread and recidivism [8,9]. Factors such as congenital, environmental, epigenetic, autoimmune and allergic factors are listed [8].
Endometriosis-related symptoms can affect a woman’s overall mental and social health and well-being [10, 11].
In 66% of women with endometriosis, the first symptoms of the disease appear before the age of 20 [12].
The symptoms associated with endometriosis are variable and present in combination, e.g. chronic pelvic pain, pain during and/or after sexual intercourse, painful urination, abdominal swelling and nausea, depression or anxiety, fatigue [13]. Infertility is relatively common in patients with endometriosis [8]. Endometriosis is difficult to treat and chronic in nature, but pharmacological, surgical or combined treatment is now possible [8].
Genetics of endometriosis: what do we know?
Several studies have examined family models to understand factors related to endometriosis [8].
In the late 1990s, dos Reis R.M. and colleagues carried out a study on the prevalence of endometriosis among first, second and third degree relatives in a group of 101 women with different symptoms related to endometriosis, diagnosed by laparoscopy and/or laparotomy. The control group consisted of 43 laparoscopy women without a diagnosis of endometriosis. Among patients with endometriosis were identified nine families with a positive family history of the condition including one mother, six sisters, three aunts and two cousins, compared to no case between controls. In conclusion, Researchers suggested a genetic contribution related to the development of endometriosis [14].
A few years later, Stefansson H. and colleagues carried out a study on the Iceland population, using a genealogical database, detecting a high risk of endometriosis between close relatives and distant relatives [15].
Linkage studies have been conducted to determine a link between a marker and a gene by analyzing inheritance within families where endometriosis occurs. Treloar and colleagues tried to identify loci susceptibility to endometriosis by conducting a linkage study on 1,176 families (931 Australian and 245 from the UK), each with at least 2 members, mainly affected sister pairs, with surgically diagnosed disease. They identified two linkage regions one on chromosome 10 and one on chromosome 20 [16].
Over 10 years ago, Genome Wide Association Studies (GWAS) were conducted to identify a correlation between SNPs (single nucleotide polymorphism – it is a variation of a single nucleotide and it is present in the population with a proportion greater than 1%) and endometriosis on several families burdened by this condition. The first studies were carried out on the Japanese population and on European women [17-19].
In 2012, an international team conducted the largest GWAS study comparing the DNA of 4604 women with endometriosis and 9393 women free from endometriosis. This meta-analysis identified two SNPs associated with an increased risk of endometriosis. The SNP, “known” as rs12700667, is located on chromosome 7 and may have a regulatory role of adjacent genes involved in the development of the uterus and its lining; the second SNP, rs7521902, is located on chromosome 1, near the WNT4 gene (Wnt Family Member 4 – https:///www.genecards.org/cgi-bin/carddisp.pl?gene=WNT4), which is involved in hormonal metabolism and the development and functioning of the woman’s genital tract. Finally, the researchers underine a significant overlap in the polygenic risk for endometriosis between cohorts study [20].
These studies have also been confirmed by other research groups [21, 22].
Three variants identified in adjacent regions genes GREB1 (Growth Regulating Estrogen Receptor Binding 1 – https://www.genecards.org/cgi-bin/carddisp.pl?gene=GREB1&keywords=GREB1) and CDKNB-AS1 (CDKN2B Antisense RNA 1 – https:///www.genecards.org/cgi-bin/carddisp.pl?genegene=CDKN2B-AS1&keywords=CDKN2B-AS1 ) showed significant associations with endometriosis [23].
Literature data indicate a significant role of estrogen receptor genes, in particular the ESR2 (Estrogen Receptor 2 – https:///www.genecards.org/cgi-bin/carddisp.pl?gene=geneESR2&keywords=ESR2) and CYP19A1 genes (Cytochrome P450 Family 19 Subfamily A Member 1 – https:///www.genecards.org/cgi-bin/carddisp.pl?genegene=CYP19A1&keywords=CYP19A1) related to a predisposition and development of endometriosis [24, 25].
An important role is also played by the polymorphisms of the gene HLA-G (Major Histocompatibility Complex, Class I, G – https://www.genecards.org/cgi-bin/carddisp.pl?gene=HL-G&words=HLA-G) and LILRB1 (Leukocyte Immunoglobulin Like Receptor B1 – https:///www.genecards.org/cgi-bin/carddisp.pl?gene=geneLILRB1&keywords=LILRB1) and LILRB2 (Leukocyte Immunoglobulin Like Receptor B2 – https//www.genecards.org/cgi-/bincard.pl”=LIkeykeyILRB2) for the development of endometriosis [24].
Reports on the development of diagnostic tools based on non-coding RNA (ncRNA) are reported in the literature as they are important regulators of cell function and have been implicated in many chronic diseases. Several studies show that ncRNAs are key contributors to the endometriosis process [26].
Endometriosis: not just a medical and social condition.
Endometriosis is an important condition not only from a medical and social point of view, but also from an economic point of view. In 2012, a multicentric study was conducted to calculate the costs and quality of life of women with symptoms associated with endometriosis treated in the reference centers. The annual costs of endometriosis treatment in Europe ranged from EUR 0.8 billion to EUR 12.5 billion depending on the country, comparable to other chronic diseases such as diabetes [27].
Consequently, also by virtue of this study, it is necessary to shed light on the biology and molecular mechanisms of endometriosis, through genomic studies and other omic sciences, to understand the relationship between gene expression and polymorphism and endometriosis, contributing to the stratification of patients and the identification of molecular targets to develop new personalized and effective therapeutic strategies.
Bibliografy
1. Perforating hemorrhagic (chocolate) cysts of the ovary: Dr. John A. Sampson, of Albany, New York, read a paper entitled, calling. DOI: https://doi.org/10.1016/S0002-9378(21)90294-1
2. https://collections.nlm.nih.gov/catalog/nlm:nlmuid-101489149-bk
3. Giudice, L.C. & Kao, L.C. Endometriosis. The Lancet, volume 364, pages1789–1799 (2004). DOI: https://doi.org/10.1016/S0140-6736(04)17403-5
4. Nezhat, C. et al. Pathophysiology and management of urinary tract endometriosis. Nature Reviews Urology volume 14, pages359–372 (2017). DOI: 10.1038/nrurol.2017.58
5. Maggiore, U.L.R. et al. A systematic review on endometriosis during pregnancy: diagnosis, misdiagnosis, complications and outcomes. Hum Reprod Update volume 22, pages: 70-103 (2016). DOI: 10.1093/humupd/dmv045
6. Defrère, S. et al. Potential involvement of iron in the pathogenesis of peritoneal endometriosis. Mol Hum Reprod. Volume 14, pages 377-85 (2008). DOI: 10.1093/molehr/gan033
7. Zondervan, K.T. et al. Endometriosis. N Engl J Med volume 382, pages: 1244-1256 (2020). DOI: 10.1056/NEJMra1810764
8. Smolarz, B. et al. Endometriosis: Epidemiology, Classification, Pathogenesis, Treatment and Genetics (Review of Literature). Int. J. Mol. Sci. Volume 22, pages 10554 (2021). DOI: https://doi.org/10.3390/ijms221910554
9. Hsu, C.F. et al. The Double Engines and Single Checkpoint Theory of Endometriosis. Biomedicines, volume 10, page 1403 (2022). DOI: https://doi.org/10.3390/biomedicines10061403
10. Vessey, M.P. et al. Epidemiology of endometriosis in women attending family planning clinics. BMJ. volume 306, pages: 182–184 (1993). DOI: 10.1136/bmj.306.6871.182
11. Viganò, P. et al. Endometriosis: epidemiology and aetiological factors. Best Pract Res Clin Obstet Gynaecol. volume 18, pages: 177-200 (2004). DOI: 10.1016/j.bpobgyn.2004.01.007
12. Bourdel, N. et al. Endometriosis in teenagers. Gynécologie Obstétrique & Fertilité. Volume 34, pages: 727–734 (2006). DOI: 10.1016/j.gyobfe.2006.07.008
14. dos Reis, R.M. et al. Familial risk among patients with endometriosis. J Assist Reprod Genet. Volume 16, pages: 500-3 (1999). DOI: 10.1023/a:1020559201968.
15. Stefansson, H. et al. Genetic factors contribute to the risk of developing endometriosis. Human Reproduction, Volume 17, Pages 555–559 (2022). DOI: https://doi.org/10.1093/humrep/17.3.555
16. Treloar, S.A. et al. Genomewide Linkage Study in 1,176 Affected Sister Pair Families Identifies a Significant Susceptibility Locus for Endometriosis on Chromosome 10q26. ASHG, volume 77, pages: 365-376 (2005). DOI: https://doi.org/10.1086/432960
17. Satoko, U. et al. A genome-wide association study identifies genetic variants in the CDKN2BAS locus associated with endometriosis in Japanese. Nature Genetics, volume 42, pages: 707–710 (2010). DOI: 10.1038/ng.612
18. Sosuke, A. et al. Meta-analysis of genome-wide association scans for genetic susceptibility to endometriosis in Japanese population. Journal of Human Genetics, volume 55, pages: 816–821 (2010). DOI: 10.1038/jhg.2010.118
19. Painter, J.N. et al. Genome-wide association study identifies a locus at 7p15.2 associated with endometriosis. Nature Genetics, volume 43, pages: 51–54 (2011). DOI: 10.1038/ng.731
20. Dale, R.N. et al. Genome-wide association meta-analysis identifies new endometriosis risk loci. Nature Genetics, volume 44, pages: 1355–1359 (2012). DOI: 10.1038/ng.2445
21. Pagliardini, L. et al. An Italian association study and meta-analysis with previous GWAS confirm WNT4, CDKN2BAS and FN1 as the first identified susceptibility loci for endometriosis. J Med Genet. Volume 50, pages: 43-6 (2013). DOI: 10.1136/jmedgenet-2012-101257
22. Sundquvist, J. et al. Replication of endometriosis-associated single-nucleotide polymorphisms from genome-wide association studies in a Caucasian population. Hum Reprod. volume 28, pages: 835-9 (2013). DOI: 10.1093/humrep/des457
23. Sapkota, Y. et al. Independent Replication and Meta-Analysis for Endometriosis Risk Loci. Twin Res Hum Genet. Volume 18, pages: 518-25 (2015). DOI: 10.1017/thg.2015.61
24. Bilinska, A. et al. The impact of HLA-G, LILRB1 and LILRB2 gene polymorphisms on susceptibility to and severity of endometriosis. Molecular Genetics and Genomics volume 293, pages: 601–613 (2018). DOI: 10.1007/s00438-017-1404-3
25. Szaflik, T. et al. Polymorphisms in the 3′UTR Region of ESR2 and CYP19A1 Genes in Women With Endometriosis. Eur J Obstet Gynecol Reprod Biol. volume 250, pages: 241-245 (2020). DOI: 10.1016/j.ejogrb.2020.05.023
26. Panir, K. et al. Non-coding RNAs in endometriosis: a narrative review. Human Reproduction Update, Volume 24, Pages 497–515 (2018). DOI: https://doi.org/10.1093/humupd/dmy014
27. Simoens, S. et al. The burden of endometriosis: costs and quality of life of women with endometriosis and treated in referral centres. Human Reproduction, Volume 27, Pages 1292–1299 (2012). DOI: https://doi.org/10.1093/humrep/des073
