Neuropeptide S receptor 1 is a nonhormonal treatment target in endometriosis.

TitleNeuropeptide S receptor 1 is a nonhormonal treatment target in endometriosis.
Publication TypeJournal Article
Year of Publication2021
AuthorsTapmeier, TT, Rahmioglu, N, Lin, J, De Leo, B, Obendorf, M, Raveendran, M, Fischer, OM, Bafligil, C, Guo, M, Harris, RA, Hess-Stumpp, H, Laux-Biehlmann, A, Lowy, E, Lunter, G, Malzahn, J, Martin, NG, Martinez, FO, Manek, S, Mesch, S, Montgomery, GW, Morris, AP, Nagel, J, Simmons, HA, Brocklebank, D, Shang, C, Treloar, S, Wells, G, Becker, CM, Oppermann, U, Zollner, TM, Kennedy, SH, Kemnitz, JW, Rogers, J, Zondervan, KT
JournalSci Transl Med
Date Published2021 Aug 25
KeywordsAnimals, Endometriosis, Endometrium, Female, Humans, Macaca mulatta, Mice, Receptors, G-Protein-Coupled, Tumor Necrosis Factor-alpha

Endometriosis is a common chronic inflammatory condition causing pelvic pain and infertility in women, with limited treatment options and 50% heritability. We leveraged genetic analyses in two species with spontaneous endometriosis, humans and the rhesus macaque, to uncover treatment targets. We sequenced DNA from 32 human families contributing to a genetic linkage signal on chromosome 7p13-15 and observed significant overrepresentation of predicted deleterious low-frequency coding variants in , the gene encoding neuropeptide S receptor 1, in cases (predominantly stage III/IV) versus controls ( = 7.8 × 10). Significant linkage to the region orthologous to human 7p13-15 was replicated in a pedigree of 849 rhesus macaques ( = 0.0095). Targeted association analyses in 3194 surgically confirmed, unrelated cases and 7060 controls revealed that a common insertion/deletion variant, rs142885915, was significantly associated with stage III/IV endometriosis ( = 5.2 × 10; odds ratio, 1.23; 95% CI, 1.09 to 1.39). Immunohistochemistry, qRT-PCR, and flow cytometry experiments demonstrated that NPSR1 was expressed in glandular epithelium from eutopic and ectopic endometrium, and on monocytes in peritoneal fluid. The NPSR1 inhibitor SHA 68R blocked NPSR1-mediated signaling, proinflammatory TNF-α release, and monocyte chemotaxis in vitro (

Alternate JournalSci Transl Med
PubMed ID34433639
Grant List084766/Z/08/Z / WT_ / Wellcome Trust / United Kingdom
085235/Z/08/Z / WT_ / Wellcome Trust / United Kingdom
085235/Z/08/A / WT_ / Wellcome Trust / United Kingdom
R24 OD011173 / OD / NIH HHS / United States

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