Neuropeptide S receptor 1 is a nonhormonal treatment target in endometriosis

Thomas Tapmeier, Nilufer Rahmioglu, Jianghai Lin, Bianca De Leo, Maik Obendorf, Muthuswamy Raveendran, Oliver M. Fischer, Cemsel Bafligil, Manman Guo, Ronald Alan Harris, Holger Hess-Stumpp, Alexis Laux-Biehlmann, Ernesto Lowy, Gerton Lunter, Jessica Malzahn, Nicholas G. Martin, Fernando O. Martinez, Sanjiv Manek, Stefanie Mesch, Grant W MontgomeryAndrew P. Morris, Jens Nagel, Heather A. Simmons, Denise Brocklebank, Catherine Shang, Susan Treloar, Graham Wells, Christian M. Becker, Udo Oppermann, Thomas M. Zollner, Stephen H Kennedy, Joseph W. Kemnitz, Jeffrey Rogers, Krina T Zondervan

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1 Citation (Scopus)

Abstract

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 NPSR1, the gene encoding neuropeptide S receptor 1, in cases (predominantly stage III/IV) versus controls (P = 7.8 × 10−4). Significant linkage to the region orthologous to human 7p13-15 was replicated in a pedigree of 849 rhesus macaques (P = 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 (P = 5.2 × 10−5; 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-αrelease, and monocyte chemotaxis in vitro (P < 0.01), and led to a significant reduction of inflammatory cell infiltrate and abdominal pain (P < 0.05) in a mouse model of peritoneal inflammation as well as in a mouse model of endometriosis. We conclude that the NPSR1/NPS system is a genetically validated, nonhormonal target for the treatment of endometriosis with likely increased relevance to stage III/IV disease.

Original languageEnglish
Article numbereabd6469
Number of pages12
JournalScience Translational Medicine
Volume13
Issue number608
DOIs
Publication statusPublished - 25 Aug 2021

Keywords

  • Endometriosis
  • NPSR1

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