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-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 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.

子宫内膜异位症是一种常见的慢性炎症性疾病，会导致女性盆腔疼痛和不孕，治疗选择有限，遗传率为 50%。我们利用人类和恒河猴这两种自发性子宫内膜异位症的基因分析来揭示治疗目标。我们对来自 32 个人类家族的 DNA 进行了测序，这些家族有助于染色体 7p13-15 上的遗传连锁信号，并观察到在某些情况下（主要是 III/IV 期） NPSR1（编码神经肽 S 受体 1 的基因）中预测的有害低频编码变体的显着过度表达与对照组（P = 7.8 × 10 ^-4）。在 849 只恒河猴（P= 0.0095)。对 3194 例手术证实的无关病例和 7060 例对照进行的靶向关联分析显示，常见的插入/缺失变异体 rs142885915 与 III/IV 期子宫内膜异位症显着相关（P = 5.2 × 10 ^-5；优势比，1.23；95% CI , 1.09 至 1.39)。免疫组织化学、qRT-PCR 和流式细胞术实验表明 NPSR1 在来自在位和异位子宫内膜的腺上皮中以及在腹膜液中的单核细胞上表达。NPSR1 抑制剂 SHA 68R 在体外阻断 NPSR1 介导的信号传导、促炎 TNF-α 释放和单核细胞趋化性（P < 0.01），并导致炎症细胞浸润和腹痛显着减少（P< 0.05) 在腹膜炎症的小鼠模型以及子宫内膜异位症的小鼠模型中。我们得出结论，NPSR1/NPS 系统是一种经过基因验证的非激素靶点，用于治疗子宫内膜异位症，与 III/IV 期疾病的相关性可能增加。