Editing Endometriosis (section)

==Risk factors==
===Genetics===
Endometriosis is a [[Genetic disorder|heritable condition]] influenced by both genetic and [[environmental factor]]s,<ref name=Fauser2011/> a genetic disorder of [[Quantitative trait locus#Quantitative traits|polygenic/multifactorial inheritance]]<ref name="GOE-2004">{{cite journal | vauthors = Bischoff F, Simpson JL | title = Genetics of endometriosis: heritability and candidate genes | journal = Best Practice & Research. Clinical Obstetrics & Gynaecology | volume = 18 | issue = 2 | pages = 219–232 | date = April 2004 | pmid = 15157639 | doi = 10.1016/j.bpobgyn.2004.01.004 }}</ref> acquired via affected genes from either [[First-degree relative|a person's father or mother]]. For example, children or siblings of women with endometriosis are at higher risk of developing endometriosis themselves; low [[progesterone]] levels may be genetic, and may contribute to a hormone imbalance.<ref name="emed">Kapoor D, Davila W (2005). [http://www.emedicine.com/med/topic3419.htm Endometriosis], {{webarchive |url=https://web.archive.org/web/20071111045258/http://www.emedicine.com/MED/topic3419.htm |date=11 November 2007 }} ''eMedicine''.</ref> Individuals with an affected first-degree relative have an approximate six-fold increase incidence of endometriosis.<ref>{{cite journal | vauthors = Giudice LC, Kao LC | title = Endometriosis | journal = Lancet | volume = 364 | issue = 9447 | pages = 1789–1799 | year = 2004 | pmid = 15541453 | doi = 10.1016/S0140-6736(04)17403-5 | s2cid = 208788714 }}</ref>

Inheritance is significant but not the sole risk factor for endometriosis. Studies attribute 50% of the risk to genetics, the other 50% to environmental factors.<ref name="Montgomery2020">{{cite journal | vauthors = Montgomery GW, Mortlock S, Giudice LC | title = Should Genetics Now Be Considered the Pre-eminent Etiologic Factor in Endometriosis? | journal = [[Journal of Minimally Invasive Gynecology]] | volume = 27 | issue = 2 | pages = 280–286 | date = February 2020 | pmid = 31683028 | pmc = 7863762 | doi = 10.1016/j.jmig.2019.10.020 }}</ref> It has been proposed that endometriosis may result from multiple mutations within target genes, in a mechanism similar to the development of cancer.<ref name=Fauser2011/> In this case, the mutations may be either [[Somatic mutation|somatic]] or [[Heritability|heritable]].<ref name=Fauser2011/>

A 2019 [[genome-wide association study]] (GWAS) review enumerated 36 genes with mutations associated with endometriosis development.<ref name="Vassilopoulou2019">{{cite journal | vauthors = Vassilopoulou L, Matalliotakis M, Zervou MI, Matalliotaki C, Krithinakis K, Matalliotakis I, Spandidos DA, Goulielmos GN | title = Defining the genetic profile of endometriosis | journal = Experimental and Therapeutic Medicine | volume = 17 | issue = 5 | pages = 3267–3281 | date = May 2019 | pmid = 30988702 | pmc = 6447774 | doi = 10.3892/etm.2019.7346 }}</ref> Nine [[Locus (genetics)|chromosome loci]] were robustly replicated:<ref>{{cite journal | vauthors = Rahmioglu N, Nyholt DR, Morris AP, Missmer SA, Montgomery GW, Zondervan KT | title = Genetic variants underlying risk of endometriosis: insights from meta-analysis of eight genome-wide association and replication datasets | journal = Human Reproduction Update | volume = 20 | issue = 5 | pages = 702–716 | date = September 2014 | pmid = 24676469 | pmc = 4132588 | doi = 10.1093/humupd/dmu015 }}</ref><ref name="Gene94025">{{cite web|url=https://www.ncbi.nlm.nih.gov/gene/94025|title=MUC16 mucin 16, cell surface associated [Homo sapiens (human)] - Gene - NCBI|website=ncbi.nlm.nih.gov|access-date=13 November 2018|archive-date=13 November 2018|archive-url=https://web.archive.org/web/20181113225150/https://www.ncbi.nlm.nih.gov/gene/94025|url-status=live}}</ref><ref name="Gene2335">{{cite web|url=https://www.ncbi.nlm.nih.gov/gene/2335|title=FN1 fibronectin 1 [Homo sapiens (human)] - Gene - NCBI|website=ncbi.nlm.nih.gov|access-date=13 November 2018|archive-date=8 June 2019|archive-url=https://web.archive.org/web/20190608083214/https://www.ncbi.nlm.nih.gov/gene/2335|url-status=live}}</ref><ref name="Sapkota Steinthorsdottir Morris Fassbender p. ">{{cite journal | vauthors = Sapkota Y, Steinthorsdottir V, Morris AP, Fassbender A, Rahmioglu N, De Vivo I, Buring JE, Zhang F, Edwards TL, Jones S, O D, Peterse D, Rexrode KM, Ridker PM, Schork AJ, MacGregor S, Martin NG, Becker CM, Adachi S, Yoshihara K, Enomoto T, Takahashi A, Kamatani Y, Matsuda K, Kubo M, Thorleifsson G, Geirsson RT, Thorsteinsdottir U, Wallace LM, Yang J, Velez Edwards DR, Nyegaard M, Low SK, Zondervan KT, Missmer SA, D'Hooghe T, Montgomery GW, Chasman DI, Stefansson K, Tung JY, Nyholt DR | title = Meta-analysis identifies five novel loci associated with endometriosis highlighting key genes involved in hormone metabolism | journal = Nature Communications | volume = 8 | issue = 1 | pages = 15539 | date = May 2017 | pmid = 28537267 | pmc = 5458088 | doi = 10.1038/ncomms15539 | publisher = Springer Science and Business Media LLC | bibcode = 2017NatCo...815539S }}</ref>
{| class="wikitable"
|-
!Chromosome
!Gene/cytoband
!Gene Product
!Function
|-
|1
|''[[WNT4]]''/1p36.12
|Wingless-type MMTV integration site family member 4
|Vital for the development of the female reproductive organs
|-
|2
|''[[GREB1]]''/2p25.1
|Growth regulation by [[estrogen]] in [[breast cancer]] 1/Fibronectin 1
|Early response gene in the estrogen regulation pathway/Cell adhesion and migration processes
|-
|2
|''ETAA1''/2p14
|(ETAA1 Activator Of ATR Kinase) is a protein-coding gene.
|Diseases associated with ETAA1 include Adult [[Lymphoma]] and [[Restless legs syndrome|Restless Legs Syndrome]]
|-
|2
|''IL1A''/2q13
|[[Interleukin 1 alpha]] (IL-1α) is encoded by the ''IL1A'' gene.
|Interleukin 1 alpha (IL-1α) is encoded by the ''IL1A'' gene.
|-
|4
|''KDR''/4q12
|''KDR'' is the human gene encoding [[kinase insert domain receptor]] also known as vascular endothelial growth factor receptor 2 (VEGFR-2)
|Primary mediator of [[VEGF receptor|VEGF-induced]] [[Endothelium|endothelial]] proliferation, survival, migration, tubular morphogenesis and sprouting<ref>{{cite web |title=GeneCards®: The Human Gene Database |url=https://www.genecards.org/cgi-bin/carddisp.pl?gene=KDR&keywords=kdr |website=www.genecards.org |publisher=Weizmann Institute of Science |access-date=7 February 2024 |archive-date=7 February 2024 |archive-url=https://web.archive.org/web/20240207163420/https://www.genecards.org/cgi-bin/carddisp.pl?gene=KDR&keywords=kdr |url-status=live }}</ref>
|-
|6
|''[[ID4]]''/6p22.3
|Inhibitor of DNA binding 4
|Ovarian oncogene, biological function unknown
|-
|7
|7p15.2
|[[Transcription factor]]s
|Influence transcriptional regulation of uterine development
|-
|9
|''[[CDKN2BAS]]''/9p21.3
|Cyclin-dependent kinase inhibitor 2B antisense RNA
|Regulation of tumour suppressor genes
|-
|12
|''[[VEZT]]''/12q22
|Vezatin, an adherens junction transmembrane protein
|Tumor suppressor gene
|}
There are many findings of altered [[gene expression]] and [[epigenetics]], but both of these can also be a secondary result of, for example, environmental factors and altered metabolism. Examples of altered gene expression include that of [[miRNA]]s.<ref name=Fauser2011/>

===Environmental toxins===

Some factors associated with endometriosis include:
* Prolonged exposure to naturally synthesized estrogen; for example, from late [[menopause]]<ref name="Clinical practice. Endometriosis">{{cite journal | vauthors = Giudice LC | title = Clinical practice. Endometriosis | journal = The New England Journal of Medicine | volume = 362 | issue = 25 | pages = 2389–98 | date = June 2010 | pmid = 20573927 | pmc = 3108065 | doi = 10.1056/NEJMcp1000274 }}</ref> or early [[menarche]]<ref>{{cite journal | vauthors = Treloar SA, Bell TA, Nagle CM, Purdie DM, Green AC | title = Early menstrual characteristics associated with subsequent diagnosis of endometriosis | journal = American Journal of Obstetrics and Gynecology | volume = 202 | issue = 6 | pages = 534.e1–6 | date = June 2010 | pmid = 20022587 | doi = 10.1016/j.ajog.2009.10.857 | url = http://hdl.cqu.edu.au/10018/58278 }}{{Dead link|date=March 2024 |bot=InternetArchiveBot |fix-attempted=yes }}</ref><ref>{{cite journal | vauthors = Nnoaham KE, Webster P, Kumbang J, Kennedy SH, Zondervan KT | title = Is early age at menarche a risk factor for endometriosis? A systematic review and meta-analysis of&nbsp;case-control studies | journal = Fertility and Sterility | volume = 98 | issue = 3 | pages = 702–712.e6 | date = September 2012 | pmid = 22728052 | pmc = 3502866 | doi = 10.1016/j.fertnstert.2012.05.035 }}</ref>
* Obstruction of menstrual outflow; for example, in [[Müllerian anomalies]]<ref name="Clinical practice. Endometriosis"/>

Potential [[toxin]]s:
* [[Dioxins and dioxin-like compounds|Dioxins]] - Several studies have investigated the potential link between exposure to dioxins and endometriosis, but evidence is equivocal and potential mechanisms are poorly understood.<ref name="pmid17981650">{{cite journal | vauthors = Anger DL, Foster WG | title = The link between environmental toxicant exposure and endometriosis | journal = Frontiers in Bioscience | volume = 13 | issue = 13| pages = 1578–93 | date = January 2008 | pmid = 17981650 | doi = 10.2741/2782 | s2cid = 12813384 | doi-access = free | title-link = doi }}</ref> A 2004 review of studies of dioxin and endometriosis concluded that "the human data supporting the dioxin-endometriosis association are scanty and conflicting",<ref>{{cite journal | vauthors = Guo SW | title = The link between exposure to dioxin and endometriosis: a critical reappraisal of primate data | journal = Gynecologic and Obstetric Investigation | volume = 57 | issue = 3 | pages = 157–73 | year = 2004 | pmid = 14739528 | doi = 10.1159/000076374 | s2cid = 29701466 }}</ref> and a 2009 follow-up review also found that there was "insufficient evidence" in support of a link between dioxin exposure and developing endometriosis.<ref>{{cite journal | vauthors = Guo SW, Simsa P, Kyama CM, Mihályi A, Fülöp V, Othman EE, D'Hooghe TM | title = Reassessing the evidence for the link between dioxin and endometriosis: from molecular biology to clinical epidemiology | journal = Molecular Human Reproduction | volume = 15 | issue = 10 | pages = 609–24 | date = October 2009 | pmid = 19744969 | doi = 10.1093/molehr/gap075 | doi-access = free | title-link = doi }}</ref>
* [[Endocrine disruptor#Types|Endocrine-disrupting chemicals (EDCs)]]- A wider class of hormonally active agents, to which dioxin belongs, consists of both natural and manmade compounds, e.g., bisphenols, [[phthalates]], pesticides ([[chlorpyrifos]], [[hexachlorobenzene]]) and [[polychlorinated biphenyl]]s (PCBs).<ref name="Ahn-2023">{{cite journal | vauthors = Ahn C, Jeung EB | title = Endocrine-Disrupting Chemicals and Disease Endpoints | journal = International Journal of Molecular Sciences | volume = 24 | issue = 6 | page = 5342 | date = March 2023 | pmid = 36982431 | pmc = 10049097 | doi = 10.3390/ijms24065342 | doi-access = free }}</ref> Dietary uptake represents a significant source of EDC exposure via consumption of food, water and beverages, but exposure can also occur through ingestion of EDC dust and inhalation of its gases or particles in the air.<ref name="Ahn-2023" /> Most EDCs are [[Lipophilicity|lipophilic]], allowing them to [[Bioaccumulation|bioaccumulate]] in [[adipose tissue]] (body fat) and increase in concentration.<ref name="Rumph2020" /> [[Bisphenol A]] (BPA), [[bisphenol S]] (BPS), [[phthalate]]s, [[pesticide]]s and [[Polychlorinated biphenyl|PCBs]] all have a suspected linkage to endometriosis,<ref name="Ahn-2023" /> though have not been definitively proven as being causative.<ref name="Rumph2020">{{cite book | vauthors = Rumph JT, Stephens VR, Archibong AE, Osteen KG, Bruner-Tran KL | chapter = Environmental Endocrine Disruptors and Endometriosis | title = Advances in Anatomy, Embryology, and Cell Biology | volume = 232 | pages = 57–78 | date = 2020 | pmid = 33278007 | pmc = 7978485 | doi = 10.1007/978-3-030-51856-1_4 | isbn = 978-3-030-51855-4 | series = Advances in Anatomy, Embryology and Cell Biology }}</ref>