[Research Articles] Neuropeptide S receptor 1 is a nonhormonal treatment target in endometriosis

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 x 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 x 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-α release, 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 m...

Source: Science Translational Medicine - August 25, 2021 Category: Biomedical Science Authors: Tapmeier, T. T., Rahmioglu, N., Lin, J., De Leo, B., Obendorf, M., Raveendran, M., Fischer, O. M., Bafligil, C., Guo, M., Harris, R. A., Hess-Stumpp, H., Laux-Biehlmann, A., Lowy, E., Lunter, G., Malzahn, J., Martin, N. G., Martinez, F. O., Manek, S., Mes Tags: Research Articles Source Type: research