The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions

Rahmioğlu, Nilüfer; Mortlock, Sally; Ghiasi, Marzieh; Møller, Peter L.; Stefánsdóttir, Lilja; Turman, Constance; Danning, Rebecca; Law, Matthew H.; Sapkota, Yadav; Christofidou, Paraskevi; Skarp, Sini; Giri, Ayush; Banasik, Karina; Krassowski, Michal; Lepamets, Maarja; Marciniak, Błażej; Nõukas, Margit; Perro, Danielle; Sliz, Eeva; Sobalska‐Kwapis, Marta; Þorleifsson, Guðmar; Selçuki, Nura Fitnat Topbaş; Vitonis, Allison F.; Westergaard, David; Arnadottir, Ragnheidur; Burgdorf, Kristoffer Sølvsten; Campbell, Archie; Cheuk, Cecilia S. K.; Cook, James P.; Vivo, Immaculata De; DiVasta, Amy D.; Dorien, O; Donoghue, Jacqueline; Edwards, Todd L.; Fung, Jenny N.; Geirsson, Reynir Tómas; Girling, Jane E.; Harris, Holly R.; Healey, Martin; Holdsworth-Carson, Sarah J.; Hostettler, Isabel C.; Houlden, Henry; Houshdaran, Sahar; Irwin, Juan C.; Järvelin, Marjo‐Riitta; Kamatani, Yoichiro; Kennedy, Stephen; Kępka, Ewa; Kubo, Michiaki; Kulig, Bartosz; Laivuori, Hannele; Laufer, Marc R.; Lindgren, Cecilia M.; MacGregor, Stuart; Mangino, Massimo; Martin, Nicholas G.; Matalliotaki, Charoula; Matalliotakis, Michail; Murray, Alison; Ndungu, Anne; Nezhat, Camran; Olsen, Catherine M.; Opoku‐Anane, Jessica; Padmanabhan, Sandosh; Paranjpe, Manish; Peters, Maire; Polak, Grzegorz; Porteous, David J.; Rabban, Joseph T.; Rexrode, Kathryn M.; Romanowicz, Hanna; Saare, Merli; Saavalainen, Liisu; Schork, Andrew J.; Sen, Sushmita; Shafrir, Amy; Siewierska-Górska, Anna; Słomka, Marcin; Smith, Blair H.; Smolarz, Beata; Szaflik, Tomasz; Szyłło, Krzysztof; Takahashi, Atsushi; Terry, Kathryn L.; Tomassetti, Carla; Treloar, Susan A.; Vanhie, Arne; Vincent, Katy; Vo, Kim Chi; Werring, David J.; Zeggini, Eleftheria; Zervou, Maria I.; Nyegaard, Mette; Härkki, Päivi; Heikinheimo, Oskari; Kettunen, Johannes; Kurra, Venla; Laivuori, Hannele; Galarneau, Geneviève; Clementi, Caterina; Fontanillas, Pierre; Adachi, Sosuke; Buring, Julie E.; Ridker, Paul M.; D’Hooghe, Thomas; Goulielmos, George N.; Hapangama, Dharani; Hayward, Caroline; Horne, Andrew; Low, Siew‐Kee; Martikainen, Hannu; Chasman, Daniel I.; Rogers, Peter A. W.; Saunders, Philippa; Sirota, Marina; Spector, Tim D.; Strapagiel, Dominik; Tung, Joyce Y.; Whiteman, David C.; Giudice, Linda C.; Velez-Edwards, Digna; Uimari, Outi; Kraft, Peter; Salumets, Andres; Nyholt, Dale R.; Mägi, Reedik; Stefánsson, Kāri; Becker, Christian M.; Yurttas-Beim, Piraye; Steinthórsdóttir, Valgerður; Nyegaard, Mette; Missmer, Stacey A.; Montgomery, Grant W.; Morris, Andrew P.; Zondervan, Krina T.

doi:10.1038/s41588-023-01323-z

Cited by 104 publications

(100 citation statements)

References 100 publications

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“…Interestingly, BMP2 levels were decreased in the peritoneal fluid of women with endometriosis 111 . Recent large-scale genome-wide association studies (GWAS) also identified BMPR2 as one of the endometriosis risk loci 67 . In women with recurrent implantation loss, BMP7 was identified to harbor a deleterious mutation that was predicted to be disease-causing 112 .…”

Section: Discussionmentioning

confidence: 99%

Impaired bone morphogenetic protein signaling pathways disrupt decidualization in endometriosis

Liao,

Tang,

Jiang

et al. 2023

Preprint

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It is hypothesized that impaired endometrial decidualization contributes to decreased fertility in individuals with endometriosis. To identify the molecular defects that underpin defective decidualization in endometriosis, we subjected endometrial stromal cells from individuals with or without endometriosis to time course in vitro decidualization with estradiol, progesterone, and 8-bromo-cyclic-AMP (EPC) for 2, 4, 6, or 8 days. Transcriptomic profiling identified differences in key pathways between the two groups, including defective bone morphogenetic protein (BMP)/SMAD4 signaling (ID2, ID3, FST), oxidate stress response (NFE2L2, ALOX15, SLC40A1), and retinoic acid signaling pathways (RARRES, RARB, ALDH1B1). Genome-wide binding analyses identified an altered genomic distribution of SMAD4 and H3K27Ac in the decidualized stromal cells from individuals without endometriosis relative to those with endometriosis, with target genes enriched in pathways related to signaling by transforming growth factor beta (TGFbeta), neurotrophic tyrosine kinase receptors (NTRK), and nerve growth factor (NGF)-stimulated transcription. We found that direct SMAD1/5/4 target genes control FOXO, PI3K/AKT, and progesterone-mediated signaling in decidualizing cells and that BMP2 supplementation in endometriosis patient-derived assembloids elevated the expression of decidualization markers. In summary, transcriptomic and genome-wide binding analyses of patient-derived endometrial cells and assembloids identified that a functional BMP/SMAD1/5/4 signaling program is crucial for engaging decidualization.

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Section: Discussionmentioning

confidence: 99%

Impaired bone morphogenetic protein signaling pathways disrupt decidualization in endometriosis

Liao,

Tang,

Jiang

et al. 2023

Preprint

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show abstract

“…It was identified 42 genome-wide significant loci with 49 distinct signals that had larger effect size for advanced stage endometriosis, explaining up to 5.01% of disease variance. Furthermore, the authors found an interesting genetic correlation between endometriosis and pain and inflammatory conditions, which may demonstrate the genetic basis of shared pathogenesis (Rahmioglu et al, 2023).…”

Section: Introductionmentioning

confidence: 91%

Recent insights explaining susceptibility to endometriosis—From genetics to environment

Pais

Almeida‐Santos

2023

WIREs Mechanisms of Disease

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Endometriosis is a disease with a heterogeneous pathogenesis, explained by multiple theories, and also with a polymorphic presentation. The purpose of this literature review is to systematize the genetic, inflammatory, and environmental factors related to the pathophysiology of endometriosis. Current evidence suggests that endometriosis is a complex inherited genetic condition, in which the genes that determine susceptibility to the disease interact with the environment to develop different phenotypes. Genetic variants associated with risk of endometriosis have been identified in several genome‐wide association studies, in addition to a group of genes related to the pathophysiology of endometriosis, namely the estrogen, progesterone and androgen receptors and the cytochrome P450 gene, as well as the p53 gene. The role of inflammation is controversial; however, it is an essential process, both in the initiation and perpetuation of the disease, in and outside the pelvis. Alterations in reactive oxygen species pathways that consequently determine oxidative stress are typical in the inflammatory environment of endometriosis. The role of environmental factors is a relatively new and broad‐spectrum topic, with inconsistent evidence. Multiple factors have been studied such as endocrine‐disrupting chemicals, metals, intrauterine exposure to diethylstilbesterol and lifestyle risk factors. In conclusion, endometriosis remains a mysterious condition, with multifactorial factors involved in its pathophysiology. The progress that has been made in the genetic predisposition to endometriosis may allow the establishment of new therapeutic targets. On the other hand, understanding the role of the environment in this disease may allow preventive intervention, minimizing its incidence and/or severity.This article is categorized under: Reproductive System Diseases > Molecular and Cellular Physiology Reproductive System Diseases > Environmental Factors Reproductive System Diseases > Genetics/Genomics/Epigenetics

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“…In a further meta-analysis, Sapkota et al ( 38 ) identified five novel endometriosis risk loci exhibiting significance in GWA, namely fibronectin 1 ( FN1 ), Coiled-coil domain containing 17 ( CCDC170 ), estrogen receptor 1 ( ESR1 ), spectrin repeat-containing nuclear envelope protein 1 ( SYNE1 ) and follicle-stimulating hormone beta subunit ( FSHB ), with all of them being involved in sex steroid hormone pathways. In the largest GWAS and replication meta-analysis of endometriosis that has been performed to date, enrolling 60,674 cases and 701,926 controls of European and East Asian ancestry, 42 genome-wide significant loci were identified, including 31 novel ones, such as ADP ribosylation factor like GTPase 14 effector protein ( ARL14EP ), Bcl-2-modifying factor ( BMF ), homeobox A10 ( HOXA10 ), long intergenic non-protein coding RNA 629 ( LINC00629 ), alpha 1–3-N-acetylgalactosaminyltransferase and alpha 1–3-galactosyltransferase ( ABO ), bassoon presynaptic cytomatrix protein ( BSN ), PDZ and LIM domain 5 ( PDLIM5 ), potassium channel tetramerization domain containing 9 ( KCTD9 ), MLLT10 histone lysine methyltransferase DOT1L cofactor ( MLLT10 ), actin like 9 ( ACTL9 ) and inhibitor of DNA binding 4 ( ID4 ) ( 39 ). The majority of SNPs exhibited larger effect sizes for stage III/IV disease, and when combined, they explained 5.61% of stage III/IV disease variance.…”

Section: Genetics Of As and Endometriosismentioning

confidence: 99%

“…Accumulating evidence has indicated that inflammation plays a critical role in pathologic bone formation in patients with AS ( 52 ). Considering that AS represents a disease that is associated with chronic inflammation, it is characterized by the key role of dendritic cells, natural killer (NK) cells, macrophages and cells of adaptive immunity, with all these cells producing a variety of cytokines that lead to the development of the disease ( 39 ). Thus, elevated levels of pro-inflammatory cytokines, including IL-1B, IL-6, IL-8, IL-10, IL-17, IL-21 and IL-23 have been observed in patients with AS compared with normal subjects, whereas increased levels of interferon (IFN)-γ and TNF-α have been also reported in some patients as a result of aggressive inflammatory responses ( 5 ).…”

Section: Influence Of Autoimmunity Angiogenesis and Inflammation In A...mentioning

confidence: 99%

Genetic factors involved in the co‑occurrence of endometriosis with ankylosing spondylitis (Review)

et al. 2023

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Previous research has revealed an association between endometriosis and various autoimmune diseases, while recent data suggest, for the first time, an association between endometriosis and the risk of developing ankylosing spondylitis (AS). AS, the prototype of spondyloarthritides diseases, is a systemic, chronic, immune-mediated inflammatory arthritis, which primarily affects the spine and sacroiliac joints, as well as the axial skeleton with or without extraspinal manifestations. AS is of polygenic inheritance and numerous immunologically relevant genes contribute to its development. Endometriosis is an enigmatic, relatively common, benign, estrogen-dependent, heterogeneous gynecological disease, influenced by multiple genetic, epigenetic and environmental factors. It is characterized by the growth of endometrial tissue occurring in sites other than the uterine cavity, most commonly in the pelvic cavity, including the ovaries and the uterosacral ligaments, affecting up to 10% of the female population of childbearing age, causing pain and infertility. The present review discusses whether a partially shared genetic background may explain the co-occurrence of these disorders, as well as potential similarities regarding the underlying pathogenetic mechanisms and specific molecular and cellular pathways.

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The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions

Cited by 104 publications

References 100 publications

Impaired bone morphogenetic protein signaling pathways disrupt decidualization in endometriosis

Impaired bone morphogenetic protein signaling pathways disrupt decidualization in endometriosis

Recent insights explaining susceptibility to endometriosis—From genetics to environment

Genetic factors involved in the co‑occurrence of endometriosis with ankylosing spondylitis (Review)

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