rs142885915 — NPSR1 NPSR1 Endometriosis Risk Variant

NPSR1 — A Neuroinflammatory Gateway to Advanced Endometriosis

For decades, endometriosis research focused almost exclusively on hormonal mechanisms — oestrogen-driven tissue proliferation, progesterone resistance, and the surgical removal of lesions. A 2021 landmark study changed that picture by pinpointing a gene in the neuropeptide signalling system as the first genetically validated nonhormonal drug target¹¹ first genetically validated nonhormonal drug target
A drug target is "genetically validated" when genetic variation in the gene — not just pharmacological inhibition — is associated with the disease, reducing the risk that early drug failure reflects an irrelevant target for endometriosis. That gene is NPSR1 — neuropeptide S receptor 1 — and the variant at rs142885915 sits within it.

The Mechanism

NPSR1²² NPSR1
neuropeptide S receptor 1; a G-protein-coupled receptor activated by the 14-amino-acid peptide neuropeptide S (NPS), primarily expressed in inflammatory cells including macrophages, mast cells, and T-cells as well as in the nervous system mediates pro-inflammatory signalling through two parallel G-protein pathways (Gαq/PLC and Gαs/cAMP). Activation triggers calcium mobilisation, ERK cascade signalling, and — critically in the endometriosis context — expression of pro-inflammatory cytokines including TNF-α, IL-6, PTGS2, and CXCL8 in peritoneal cells.

The rs142885915 variant is an intronic insertion/deletion located within the NPSR1 gene on chromosome 7p14.3. The deletion allele (D) tags a regulatory haplotype associated with altered NPSR1 expression or splicing in inflammatory tissues. The NPSR1 gene itself is expressed at low-to-moderate levels across most adult tissues but shows notable expression in the kidney, lung, and gastrointestinal tract — all sites with documented NPSR1-mediated inflammatory phenotypes. In the peritoneal cavity, where endometriosis lesions form, NPSR1 signalling amplifies the neuroinflammatory environment that drives pain, lesion growth, and immune evasion.

The Evidence

Tapmeier et al. 2021³³ Tapmeier et al. 2021
Neuropeptide S receptor 1 is a nonhormonal treatment target in endometriosis. Sci Transl Med 13:eabd6469 combined family-based sequencing, targeted association analysis, and preclinical pharmacology to establish NPSR1 as a disease-relevant target. Starting from 32 multi-affected families with severe endometriosis, the investigators found significant overrepresentation of predicted deleterious low-frequency coding variants in NPSR1 (P=7.8×10⁻⁴). In a targeted association cohort of 3,194 surgically confirmed cases and 7,060 controls, the intronic deletion rs142885915 showed robust association specifically with stage III/IV (deep infiltrating) endometriosis: OR 1.23 (95% CI 1.09–1.39, P=5.2×10⁻⁵). Critically, the association was replicated in rhesus macaque pedigrees (849 members), linking the locus to spontaneous peritoneal disease in a non-human primate model. The therapeutic proof-of-concept was strong: the NPSR1 inhibitor SHA 68R blocked NPSR1-mediated signalling and proinflammatory TNF-α release in vitro (P<0.01), and led to a significant reduction of both inflammatory cell infiltrate and abdominal pain in mouse endometriosis models (P<0.05).

The locus was subsequently featured in the largest endometriosis GWAS to date: Rahmioglu et al. 2023⁴⁴ Rahmioglu et al. 2023
The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions. Nat Genet 55:423–436, which analysed 762,600 participants and identified multiple susceptibility regions with enriched genetic architecture shared between endometriosis, other pain conditions, and inflammatory diseases — a genetic signal that validates the neuroinflammatory framing of the NPSR1 association.

Drug development has accelerated: a 2025 medicinal chemistry study ⁵⁵ Design of peripherally biased NPSR1 antagonists. Bioorg Med Chem Lett, 2025 developed next-generation peripherally restricted NPSR1 antagonists that blocked NPS-triggered cytokine expression (IL-6, PTGS2, CXCL8) in human fibroblasts with sub-nanomolar potency, signalling active therapeutic development at this target.

Practical Actions

The NPSR1 pathway operates through neuroinflammation rather than oestrogen-driven proliferation. This distinction has practical implications for symptom management. Carriers of the deletion allele may find that hormonal treatments (combined oral contraceptives, progestins) manage some aspects of endometriosis but leave a neuroinflammatory pain component partially or fully unaddressed. Awareness of this gap can guide more targeted discussions with specialists.

Pain management approaches that target neuroinflammatory pathways — including COX-2 inhibitors (such as high-dose NSAIDs), mast cell stabilisers, and emerging NPSR1 antagonists (currently in preclinical and early drug development stages) — are mechanistically aligned with the NPSR1-driven component of endometriosis pain. Omega-3 fatty acids (EPA/DHA) reduce peritoneal prostaglandin production via competitive inhibition of the COX/PTGS2 pathway that NPSR1 activates, providing a supplementation-level intervention that addresses the relevant biology.

Because rs142885915 is specifically associated with stage III/IV endometriosis, carriers with symptoms consistent with deep infiltrating disease should discuss thorough laparoscopic staging with a specialist — the variant flags a mechanistic bias toward the advanced, inflammatory phenotype that most benefits from precise surgical characterisation.

Interactions

NPSR1 is also associated with asthma, inflammatory bowel disease, panic disorder, and post-traumatic stress disorder in the broader literature — all conditions sharing a neuroinflammatory or neuroimmune component. Carriers with endometriosis who also carry variants in inflammatory pathway genes (e.g. TNF, IL-6, COX-2 pathway variants) may experience additive neuroinflammatory burden, though no compound-genotype endometriosis risk data currently exists for NPSR1 in combination with other loci.