Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
34433639
TITLE
Neuropeptide S receptor 1 is a nonhormonal treatment target in endometriosis.
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 , 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 ( < 0.01), and led to a significant reduction of inflammatory cell infiltrate and abdominal pain ( < 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.
Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
DATE PUBLISHED
2021 08 25
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2020/07/03
revised 2021/02/25
accepted 2021/08/06
entrez 2021/08/26 05:37
pubmed 2021/08/27 06:00
medline 2021/11/03 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Tapmeier TT Tapmeier Thomas T TT Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria 3168, Australia.
Rahmioglu N Rahmioglu Nilufer N Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Lin J Lin Jianghai J Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou, Guangdong 510632, PR China.
De Leo B De Leo Bianca B Bayer AG Pharmaceuticals, Research & Development, Building S107, 13342 Berlin, Germany.
Obendorf M Obendorf Maik M Bayer AG Pharmaceuticals, Research & Development, Building S107, 13342 Berlin, Germany.
Raveendran M Raveendran Muthuswamy M Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Fischer OM Fischer Oliver M OM Bayer AG Pharmaceuticals, Research & Development, Building S107, 13342 Berlin, Germany.
Bafligil C Bafligil Cemsel C Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Oxford OX3 7LD, UK.
Guo M Guo Manman M Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Oxford OX3 7LD, UK.
Harris RA Harris Ronald Alan RA Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Hess-Stumpp H Hess-Stumpp Holger H Bayer AG Pharmaceuticals, Research & Development, Building S107, 13342 Berlin, Germany.
Laux-Biehlmann A Laux-Biehlmann Alexis A Bayer AG Pharmaceuticals, Research & Development, Building S107, 13342 Berlin, Germany.
Lowy E Lowy Ernesto E Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Lunter G Lunter Gerton G MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
Malzahn J Malzahn Jessica J Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Oxford OX3 7LD, UK.
Martin NG Martin Nicholas G NG QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
Martinez FO Martinez Fernando O FO Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7YH, UK.
Manek S Manek Sanjiv S Department of Pathology, Oxford University Hospitals Foundation Trust, Oxford OX3 9DU, UK.
Mesch S Mesch Stefanie S Bayer AG Pharmaceuticals, Research & Development, Building S107, 13342 Berlin, Germany.
Montgomery GW Montgomery Grant W GW Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
Morris AP Morris Andrew P AP Division of Musculoskeletal and Dermatological Sciences, University of Manchester, Manchester M13 9PL, UK.
Nagel J Nagel Jens J Bayer AG Pharmaceuticals, Research & Development, Building S107, 13342 Berlin, Germany.
Simmons HA Simmons Heather A HA Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI 53715, USA.
Brocklebank D Brocklebank Denise D Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Shang C Shang Catherine C Oxford Endometriosis CaRe Centre, Nuffield Department of Women's & Reproductive Health, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK.
Treloar S Treloar Susan S QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
Wells G Wells Graham G Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Oxford OX3 7LD, UK.
Becker CM Becker Christian M CM Oxford Endometriosis CaRe Centre, Nuffield Department of Women's & Reproductive Health, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK.
Oppermann U Oppermann Udo U Nuffield Department of Orthopedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Botnar Research Centre, Oxford OX3 7LD, UK.
Zollner TM Zollner Thomas M TM Bayer AG Pharmaceuticals, Research & Development, Building S107, 13342 Berlin, Germany.
Kennedy SH Kennedy Stephen H SH Oxford Endometriosis CaRe Centre, Nuffield Department of Women's & Reproductive Health, University of Oxford, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK.
Kemnitz JW Kemnitz Joseph W JW Department of Cell & Regenerative Biology and Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI 53706, USA.
Rogers J Rogers Jeffrey J Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Zondervan KT Zondervan Krina T KT Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
INVESTIGATORS
JOURNAL
VOLUME: 13
ISSUE: 608
TITLE: Science translational medicine
ISOABBREVIATION: Sci Transl Med
YEAR: 2021
MONTH: 08
DAY: 25
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1946-6242
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Sci Transl Med
COUNTRY: United States
ISSNLINKING: 1946-6234
NLMUNIQUEID: 101505086
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, N.I.H., Extramural
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
CommentIn Nat Rev Endocrinol. 2021 Nov;17(11):639 34508252
GRANTS
GRANTID AGENCY COUNTRY
084766/Z/08/Z Wellcome Trust United Kingdom
085235/Z/08/Z Wellcome Trust United Kingdom
085235/Z/08/A Wellcome Trust United Kingdom
R24 OD011173 NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Animals
Endometriosis genetics
Endometrium genetics
Female genetics
Humans genetics
Macaca mulatta genetics
Mice genetics
Receptors, G-Protein-Coupled genetics
Tumor Necrosis Factor-alpha genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 NPSR1 protein, human
0 Receptors, G-Protein-Coupled
0 Tumor Necrosis Factor-alpha
OTHER ID's
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