{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T23:04:19Z","timestamp":1792623859835,"version":"4.5.0"},"reference-count":65,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,9,11]],"date-time":"2018-09-11T00:00:00Z","timestamp":1536624000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,9,11]],"date-time":"2018-09-11T00:00:00Z","timestamp":1536624000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000072","name":"U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["R01DE023836"],"award-info":[{"award-number":["R01DE023836"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["T90DE02198"],"award-info":[{"award-number":["T90DE02198"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000072","name":"U.S. Department of Health & Human Services | NIH | National Institute of Dental and Craniofacial Research","doi-asserted-by":"publisher","award":["F32 DE026688"],"award-info":[{"award-number":["F32 DE026688"]}],"id":[{"id":"10.13039\/100000072","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>There is no agnostic GWAS evidence for the genetic control of IL-1\u03b2 expression in periodontal disease. Here we report a GWAS for \u201chigh\u201d gingival crevicular fluid IL-1\u03b2 expression among 4910 European-American adults and identify association signals in the <jats:italic>IL37<\/jats:italic> locus. rs3811046 at this locus (<jats:italic>p<\/jats:italic>\u2009=\u20093.3\u2009\u00d7\u200910<jats:sup>\u221222<\/jats:sup>) is associated with severe chronic periodontitis (OR\u2009=\u20091.50; 95% CI\u2009=\u20091.12\u20132.00), 10-year incident tooth loss (\u22653 teeth: RR\u2009=\u20091.33; 95% CI\u2009=\u20091.09\u20131.62) and aggressive periodontitis (OR\u2009=\u20091.12; 95% CI\u2009=\u20091.01\u20131.26) in an independent sample of 4927 German\/Dutch adults. The minor allele at rs3811046 is associated with increased expression of IL-1\u03b2 in periodontal tissue. In RAW macrophages, PBMCs and transgenic mice, the <jats:italic>IL37<\/jats:italic> variant increases expression of IL-1\u03b2 and IL-6, inducing more severe periodontal disease, while IL-37 protein production is impaired and shows reduced cleavage by caspase-1. A second variant in the <jats:italic>IL37<\/jats:italic> locus (rs2708943, <jats:italic>p<\/jats:italic>\u2009=\u20094.2\u2009\u00d7\u200910<jats:sup>\u22127<\/jats:sup>) associates with attenuated <jats:italic>IL37<\/jats:italic> mRNA expression. Overall, we demonstrate that <jats:italic>IL37<\/jats:italic> variants modulate the inflammatory cascade in periodontal disease.<\/jats:p>","DOI":"10.1038\/s41467-018-05940-9","type":"journal-article","created":{"date-parts":[[2018,9,5]],"date-time":"2018-09-05T14:26:05Z","timestamp":1536157565000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":75,"title":["GWAS for Interleukin-1\u03b2 levels in gingival crevicular fluid identifies IL37 variants in periodontal inflammation"],"prefix":"10.1038","volume":"9","author":[{"given":"Steven","family":"Offenbacher","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yizu","family":"Jiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven J.","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Marchesan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin L.","family":"Moss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Jing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1290-7251","authenticated-orcid":false,"given":"Kimon","family":"Divaris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sompop","family":"Bencharit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cary S.","family":"Agler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thiago","family":"Morelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaoping","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William T.","family":"Seaman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dale","family":"Cowley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvana P.","family":"Barros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James D.","family":"Beck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Munz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arne S.","family":"Schaefer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kari E.","family":"North","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,9,11]]},"reference":[{"key":"5940_CR1","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1177\/0022034512453589","volume":"91","author":"RP Darveau","year":"2012","unstructured":"Darveau, R. P., Hajishengallis, G. & Curtis, M. A. Porphyromonas gingivalis as a potential community activist for disease. J. Dent. Res. 91, 816\u2013820 (2012).","journal-title":"J. Dent. Res."},{"key":"5940_CR2","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/j.chom.2011.10.006","volume":"10","author":"G Hajishengallis","year":"2011","unstructured":"Hajishengallis, G. et al. Low-abundance biofilm species orchestrates inflammatory periodontal disease through the commensal microbiota and complement. Cell Host Microbe 10, 497\u2013506 (2011).","journal-title":"Cell Host Microbe"},{"key":"5940_CR3","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1177\/0022034512457373","volume":"91","author":"PI Eke","year":"2012","unstructured":"Eke, P. I., Dye, B. A., Wei, L., Thornton-Evans, G. O. & Genco, R. J. Prevalence of periodontitis in adults in the United States: 2009 and 2010. J. Dent. Res. 91, 914\u2013920 (2012).","journal-title":"J. Dent. Res."},{"key":"5940_CR4","doi-asserted-by":"publisher","first-page":"1172","DOI":"10.1001\/archinte.163.10.1172","volume":"163","author":"GD Slade","year":"2003","unstructured":"Slade, G. D. et al. Relationship between periodontal disease and C-reactive protein among adults in the Atherosclerosis Risk in Communities study. Arch. Intern. Med. 163, 1172\u20131179 (2003).","journal-title":"Arch. Intern. Med."},{"key":"5940_CR5","doi-asserted-by":"publisher","first-page":"1332710","DOI":"10.1080\/20002297.2017.1332710","volume":"9","author":"P Holmstrup","year":"2017","unstructured":"Holmstrup, P. et al. Comorbidity of periodontal disease: two sides of the same coin? An introduction for the clinician. J. Oral. Microbiol. 9, 1332710 (2017).","journal-title":"J. Oral. Microbiol."},{"key":"5940_CR6","doi-asserted-by":"publisher","first-page":"1911","DOI":"10.1902\/jop.2007.060465","volume":"78","author":"S Offenbacher","year":"2007","unstructured":"Offenbacher, S. et al. Periodontal disease at the biofilm-gingival interface. J. Periodontol. 78, 1911\u20131925 (2007).","journal-title":"J. Periodontol."},{"key":"5940_CR7","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1902\/annals.1998.3.1.40","volume":"3","author":"GE Salvi","year":"1998","unstructured":"Salvi, G. E., Beck, J. D. & Offenbacher, S. PGE2, IL-1 beta, and TNF-alpha responses in diabetics as modifiers of periodontal disease expression. Ann. Periodontol. 3, 40\u201350 (1998).","journal-title":"Ann. Periodontol."},{"key":"5940_CR8","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1111\/j.1600-0765.1993.tb02090.x","volume":"28","author":"PA Heasman","year":"1993","unstructured":"Heasman, P. A., Collins, J. G. & Offenbacher, S. Changes in crevicular fluid levels of interleukin-1 beta, leukotriene B4, prostaglandin E2, thromboxane B2 and tumour necrosis factor alpha in experimental gingivitis in humans. J. Periodontal Res. 28, 241\u2013247 (1993).","journal-title":"J. Periodontal Res."},{"key":"5940_CR9","doi-asserted-by":"publisher","first-page":"324","DOI":"10.1111\/j.1600-051X.2010.01543.x","volume":"37","author":"S Offenbacher","year":"2010","unstructured":"Offenbacher, S. et al. Changes in gingival crevicular fluid inflammatory mediator levels during the induction and resolution of experimental gingivitis in humans. J. Clin. Periodontol. 37, 324\u2013333 (2010).","journal-title":"J. Clin. Periodontol."},{"key":"5940_CR10","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1111\/j.1600-051X.2010.01671.x","volume":"38","author":"PM Preshaw","year":"2011","unstructured":"Preshaw, P. M. & Taylor, J. J. How has research into cytokine interactions and their role in driving immune responses impacted our understanding of periodontitis? J. Clin. Periodontol. 38, 60\u201384 (2011).","journal-title":"J. Clin. Periodontol."},{"key":"5940_CR11","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1016\/j.immuni.2013.11.010","volume":"39","author":"C Garlanda","year":"2013","unstructured":"Garlanda, C., Dinarello, C. A. & Mantovani, A. The interleukin-1 family: back to the future. Immunity 39, 1003\u20131018 (2013).","journal-title":"Immunity"},{"key":"5940_CR12","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1038\/sj.gene.6364162","volume":"6","author":"AJ de Craen","year":"2005","unstructured":"de Craen, A. J. et al. Heritability estimates of innate immunity: an extended twin study. Genes Immun. 6, 167\u2013170 (2005).","journal-title":"Genes Immun."},{"key":"5940_CR13","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1038\/nri2691","volume":"10","author":"JE Sims","year":"2010","unstructured":"Sims, J. E. & Smith, D. E. The IL-1 family: regulators of immunity. Nat. Rev. Immunol. 10, 89\u2013102 (2010).","journal-title":"Nat. Rev. Immunol."},{"key":"5940_CR14","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1002\/eji.201545828","volume":"46","author":"CA Dinarello","year":"2016","unstructured":"Dinarello, C. A. et al. Suppression of innate inflammation and immunity by interleukin-37. Eur. J. Immunol. 46, 1067\u20131081 (2016).","journal-title":"Eur. J. Immunol."},{"key":"5940_CR15","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1002\/1531-8249(200003)47:3<365::AID-ANA13>3.0.CO;2-G","volume":"47","author":"JA Nicoll","year":"2000","unstructured":"Nicoll, J. A. et al. Association of interleukin-1 gene polymorphisms with Alzheimer\u2019s disease. Ann. Neurol. 47, 365\u2013368 (2000).","journal-title":"Ann. Neurol."},{"key":"5940_CR16","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.1002\/art.27325","volume":"62","author":"I Meulenbelt","year":"2010","unstructured":"Meulenbelt, I. et al. Interleukin-1 gene cluster variants with innate cytokine production profiles and osteoarthritis in subjects from the Genetics, Osteoarthritis and Progression Study. Arthritis Rheum. 62, 1119\u20131126 (2010).","journal-title":"Arthritis Rheum."},{"key":"5940_CR17","doi-asserted-by":"publisher","first-page":"e0153480","DOI":"10.1371\/journal.pone.0153480","volume":"11","author":"H Rai","year":"2016","unstructured":"Rai, H., Sinha, N., Kumar, S., Sharma, A. K. & Agrawal, S. Interleukin-1 gene cluster polymorphisms and their association with coronary artery disease: separate evidences from the largest case-control study amongst North Indians and an updated meta-analysis. PLoS ONE 11, e0153480 (2016).","journal-title":"PLoS ONE"},{"key":"5940_CR18","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1038\/sj.gene.6363719","volume":"1","author":"R Bergholdt","year":"2000","unstructured":"Bergholdt, R. et al. Characterization of new polymorphisms in the 5\u2032 UTR of the human interleukin-1 receptor type 1 (IL1R1) gene: linkage to type 1 diabetes and correlation to IL-1RI plasma level. Genes Immun. 1, 495\u2013500 (2000).","journal-title":"Genes Immun."},{"key":"5940_CR19","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1007\/s12028-013-9899-x","volume":"21","author":"KJ Becker","year":"2014","unstructured":"Becker, K. J. et al. Stroke, IL-1ra, IL1RN, infection and outcome. Neurocrit. Care. 21, 140\u2013146 (2014).","journal-title":"Neurocrit. Care."},{"key":"5940_CR20","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1042\/BJ20040217","volume":"381","author":"P Bufler","year":"2004","unstructured":"Bufler, P., Gamboni-Robertson, F., Azam, T., Kim, S. H. & Dinarello, C. A. Interleukin-1 homologues IL-1F7b and IL-18 contain functional mRNA instability elements within the coding region responsive to lipopolysaccharide. Biochem. J. 381, 503\u2013510 (2004).","journal-title":"Biochem. J."},{"key":"5940_CR21","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1086\/512821","volume":"80","author":"S Zollner","year":"2007","unstructured":"Zollner, S. & Pritchard, J. K. Overcoming the winner\u2019s curse: estimating penetrance parameters from case-control data. Am. J. Hum. Genet. 80, 605\u2013615 (2007).","journal-title":"Am. J. Hum. Genet."},{"key":"5940_CR22","doi-asserted-by":"crossref","unstructured":"Rudloff, I., Cho, S.X., Lao, J.C., Ngo, D., McKenzie, M., Nold-Petry, C.A., Nold, M.F. Monocytes and dendritic cells are the primary sources of interleukin 37 in human immune cells. J. Leukoc. Biol.\u00a0101, 901\u2013911 (2017).","DOI":"10.1189\/jlb.3MA0616-287R"},{"key":"5940_CR23","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1093\/abbs\/gmv058","volume":"47","author":"W Wu","year":"2015","unstructured":"Wu, W. et al. IL-37b suppresses T cell priming by modulating dendritic cell maturation and cytokine production via dampening ERK\/NF-kappaB\/S6K signalings. Acta Biochim. Biophys. Sin. 47, 597\u2013603 (2015).","journal-title":"Acta Biochim. Biophys. Sin."},{"key":"5940_CR24","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1902\/jop.2016.160379","volume":"88","author":"T Morelli","year":"2017","unstructured":"Morelli, T. et al. Derivation and validation of the periodontal and tooth profile classification system for patient stratification. J. Periodontol. 88, 153\u2013165 (2017).","journal-title":"J. Periodontol."},{"key":"5940_CR25","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1902\/jop.2002.73.5.517","volume":"73","author":"Y Fu","year":"2002","unstructured":"Fu, Y., Korostoff, J. M., Fine, D. H. & Wilson, M. E. Fc gamma receptor genes as risk markers for localized aggressive periodontitis in African-Americans. J. Periodontol. 73, 517\u2013523 (2002).","journal-title":"J. Periodontol."},{"key":"5940_CR26","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1034\/j.1600-051X.2002.290701.x","volume":"29","author":"RM Scarel-Caminaga","year":"2002","unstructured":"Scarel-Caminaga, R. M., Trevilatto, P. C., Souza, A. P., Brito, R. B. & Line, S. R. Investigation of an IL-2 polymorphism in patients with different levels of chronic periodontitis. J. Clin. Periodontol. 29, 587\u2013591 (2002).","journal-title":"J. Clin. Periodontol."},{"key":"5940_CR27","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1111\/j.1600-051X.2005.00697.x","volume":"32","author":"M Donati","year":"2005","unstructured":"Donati, M. et al. Association of the -159 CD14 gene polymorphism and lack of association of the -308 TNFA and Q551R IL-4RA polymorphisms with severe chronic periodontitis in Swedish Caucasians. J. Clin. Periodontol. 32, 474\u2013479 (2005).","journal-title":"J. Clin. Periodontol."},{"key":"5940_CR28","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1902\/jop.2004.75.1.30","volume":"75","author":"LI Holla","year":"2004","unstructured":"Holla, L. I. et al. Analysis of the interleukin-6 gene promoter polymorphisms in Czech patients with chronic periodontitis. J. Periodontol. 75, 30\u201336 (2004).","journal-title":"J. Periodontol."},{"key":"5940_CR29","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1034\/j.1600-051X.2003.10274.x","volume":"30","author":"T Berglundh","year":"2003","unstructured":"Berglundh, T., Donati, M., Hahn-Zoric, M., Hanson, L. A. & Padyukov, L. Association of the -1087 IL 10 gene polymorphism with severe chronic periodontitis in Swedish Caucasians. J. Clin. Periodontol. 30, 249\u2013254 (2003).","journal-title":"J. Clin. Periodontol."},{"key":"5940_CR30","doi-asserted-by":"publisher","first-page":"1724","DOI":"10.1016\/j.jacc.2013.12.030","volume":"63","author":"S Tsimikas","year":"2014","unstructured":"Tsimikas, S. et al. Pro-inflammatory interleukin-1 genotypes potentiate the risk of coronary artery disease and cardiovascular events mediated by oxidized phospholipids and lipoprotein(a). J. Am. Coll. Cardiol. 63, 1724\u20131734 (2014).","journal-title":"J. Am. Coll. Cardiol."},{"key":"5940_CR31","doi-asserted-by":"publisher","first-page":"2116","DOI":"10.2337\/db14-1098","volume":"64","author":"OM Finucane","year":"2015","unstructured":"Finucane, O. M. et al. Monounsaturated fatty acid-enriched high-fat diets impede adipose NLRP3 inflammasome-mediated IL-1beta secretion and insulin resistance despite obesity. Diabetes 64, 2116\u20132128 (2015).","journal-title":"Diabetes"},{"key":"5940_CR32","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1016\/j.smim.2013.10.004","volume":"25","author":"CA Dinarello","year":"2013","unstructured":"Dinarello, C. A. & Bufler, P. Interleukin-37. Semin. Immunol. 25, 466\u2013468 (2013).","journal-title":"Semin. Immunol."},{"key":"5940_CR33","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/j.immuni.2015.06.016","volume":"43","author":"JL Halliley","year":"2015","unstructured":"Halliley, J. L. et al. Long-lived plasma cells are contained within the CD19(\u2212)CD38(hi)CD138(+) subset in human bone marrow. Immunity 43, 132\u2013145 (2015).","journal-title":"Immunity"},{"key":"5940_CR34","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1111\/j.1600-051X.2005.00820.x","volume":"32","author":"T Berglundh","year":"2005","unstructured":"Berglundh, T. & Donati, M. Aspects of adaptive host response in periodontitis. J. Clin. Periodontol. 32, 87\u2013107 (2005).","journal-title":"J. Clin. Periodontol."},{"key":"5940_CR35","doi-asserted-by":"publisher","first-page":"705","DOI":"10.1007\/s00418-008-0435-6","volume":"129","author":"R Moll","year":"2008","unstructured":"Moll, R., Divo, M. & Langbein, L. The human keratins: biology and pathology. Histochem. Cell. Biol. 129, 705\u2013733 (2008).","journal-title":"Histochem. Cell. Biol."},{"key":"5940_CR36","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1006\/cyto.2002.0873","volume":"18","author":"S Kumar","year":"2002","unstructured":"Kumar, S. et al. Interleukin-1F7B (IL-1H4\/IL-1F7) is processed by caspase-1 and mature IL-1F7B binds to the IL-18 receptor but does not induce IFN-gamma production. Cytokine 18, 61\u201371 (2002).","journal-title":"Cytokine"},{"key":"5940_CR37","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1038\/ni.3103","volume":"16","author":"CA Nold-Petry","year":"2015","unstructured":"Nold-Petry, C. A. et al. IL-37 requires the receptors IL-18Ralpha and IL-1R8 (SIGIRR) to carry out its multifaceted anti-inflammatory program upon innate signal transduction. Nat. Immunol. 16, 354\u2013365 (2015).","journal-title":"Nat. Immunol."},{"key":"5940_CR38","doi-asserted-by":"publisher","first-page":"27069","DOI":"10.1074\/jbc.M110.203398","volume":"286","author":"S Carta","year":"2011","unstructured":"Carta, S. et al. The rate of interleukin-1beta secretion in different myeloid cells varies with the extent of redox response to Toll-like receptor triggering. J. Biol. Chem. 286, 27069\u201327080 (2011).","journal-title":"J. Biol. Chem."},{"key":"5940_CR39","doi-asserted-by":"publisher","first-page":"2650","DOI":"10.1073\/pnas.1324140111","volume":"111","author":"AM Bulau","year":"2014","unstructured":"Bulau, A. M. et al. Role of caspase-1 in nuclear translocation of IL-37, release of the cytokine, and IL-37 inhibition of innate immune responses. Proc. Natl Acad. Sci. USA 111, 2650\u20132655 (2014).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"5940_CR40","doi-asserted-by":"publisher","first-page":"1014","DOI":"10.1038\/ni.1944","volume":"11","author":"MF Nold","year":"2010","unstructured":"Nold, M. F. et al. IL-37 is a fundamental inhibitor of innate immunity. Nat. Immunol. 11, 1014\u20131022 (2010).","journal-title":"Nat. Immunol."},{"key":"5940_CR41","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1038\/nprot.2009.2","volume":"4","author":"LA Kelley","year":"2009","unstructured":"Kelley, L. A. & Sternberg, M. J. Protein structure prediction on the Web: a case study using the Phyre server. Nat. Protoc. 4, 363\u2013371 (2009).","journal-title":"Nat. Protoc."},{"key":"5940_CR42","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1038\/35006081","volume":"404","author":"EM El-Omar","year":"2000","unstructured":"El-Omar, E. M. et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 404, 398\u2013402 (2000).","journal-title":"Nature"},{"key":"5940_CR43","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1111\/imr.12605","volume":"281","author":"G Cavalli","year":"2018","unstructured":"Cavalli, G. & Dinarello, C. A. Suppression of inflammation and acquired immunity by IL-37. Immunol. Rev. 281, 179\u2013190 (2018).","journal-title":"Immunol. Rev."},{"key":"5940_CR44","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1002\/cre2.61","volume":"3","author":"A Zekeridou","year":"2017","unstructured":"Zekeridou, A., Giannopoulou, C., Cancela, J., Courvoisier, D. & Mombelli, A. Effect of initial periodontal therapy on gingival crevicular fluid cytokine profile in subjects with chronic periodontitis. Clin. Exp. Dent. Res. 3, 62\u201368 (2017).","journal-title":"Clin. Exp. Dent. Res."},{"key":"5940_CR45","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1684\/ecn.2011.0288","volume":"22","author":"D Boraschi","year":"2011","unstructured":"Boraschi, D. et al. IL-37: a new anti-inflammatory cytokine of the IL-1 family. Eur. Cytokine Netw. 22, 127\u2013147 (2011).","journal-title":"Eur. Cytokine Netw."},{"key":"5940_CR46","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1111\/all.12566","volume":"70","author":"L Lunding","year":"2015","unstructured":"Lunding, L. et al. IL-37 requires IL-18Ralpha and SIGIRR\/IL-1R8 to diminish allergic airway inflammation in mice. Allergy 70, 366\u2013373 (2015).","journal-title":"Allergy"},{"key":"5940_CR47","doi-asserted-by":"publisher","first-page":"2889","DOI":"10.1038\/onc.2016.444","volume":"36","author":"C Luo","year":"2017","unstructured":"Luo, C. et al. Intracellular IL-37b interacts with Smad3 to suppress multiple signaling pathways and the metastatic phenotype of tumor cells. Oncogene 36, 2889\u20132899 (2017).","journal-title":"Oncogene"},{"key":"5940_CR48","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1902\/jop.2000.71.2.164","volume":"71","author":"GC Armitage","year":"2000","unstructured":"Armitage, G. C. et al. Low prevalence of a periodontitis-associated interleukin-1 composite genotype in individuals of Chinese heritage. J. Periodontol. 71, 164\u2013171 (2000).","journal-title":"J. Periodontol."},{"key":"5940_CR49","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1902\/jop.1999.70.4.418","volume":"70","author":"SR Diehl","year":"1999","unstructured":"Diehl, S. R. et al. Linkage disequilibrium of interleukin-1 genetic polymorphisms with early-onset periodontitis. J. Periodontol. 70, 418\u2013430 (1999).","journal-title":"J. Periodontol."},{"key":"5940_CR50","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1902\/jop.2000.71.2.156","volume":"71","author":"MJ McDevitt","year":"2000","unstructured":"McDevitt, M. J. et al. Interleukin-1 genetic association with periodontitis in clinical practice. J. Periodontol. 71, 156\u2013163 (2000).","journal-title":"J. Periodontol."},{"key":"5940_CR51","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1902\/annals.1998.3.1.327","volume":"3","author":"KS Kornman","year":"1998","unstructured":"Kornman, K. S. & di Giovine, F. S. Genetic variations in cytokine expression: a risk factor for severity of adult periodontitis. Ann. Periodontol. 3, 327\u2013338 (1998).","journal-title":"Ann. Periodontol."},{"key":"5940_CR52","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1111\/j.1600-051X.2008.01298.x","volume":"35","author":"GK Nikolopoulos","year":"2008","unstructured":"Nikolopoulos, G. K., Dimou, N. L., Hamodrakas, S. J. & Bagos, P. G. Cytokine gene polymorphisms in periodontal disease: a meta-analysis of 53 studies including 4178 cases and 4590 controls. J. Clin. Periodontol. 35, 754\u2013767 (2008).","journal-title":"J. Clin. Periodontol."},{"key":"5940_CR53","doi-asserted-by":"publisher","first-page":"16711","DOI":"10.1073\/pnas.1111982108","volume":"108","author":"EN McNamee","year":"2011","unstructured":"McNamee, E. N. et al. Interleukin 37 expression protects mice from colitis. Proc. Natl Acad. Sci. USA 108, 16711\u201316716 (2011).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"5940_CR54","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1034\/j.1600-0757.2003.03110.x","volume":"31","author":"CM Champagne","year":"2003","unstructured":"Champagne, C. M. et al. Potential for gingival crevice fluid measures as predictors of risk for periodontal diseases. Periodontol 2000. 31, 167\u2013180 (2003).","journal-title":"Periodontol 2000."},{"key":"5940_CR55","doi-asserted-by":"publisher","first-page":"2011","DOI":"10.1902\/jop.2006.060047","volume":"77","author":"S Offenbacher","year":"2006","unstructured":"Offenbacher, S. et al. Effects of periodontal therapy during pregnancy on periodontal status, biologic parameters, and pregnancy outcomes: a pilot study. J. Periodontol. 77, 2011\u20132024 (2006).","journal-title":"J. Periodontol."},{"key":"5940_CR56","doi-asserted-by":"publisher","first-page":"2312","DOI":"10.1093\/hmg\/ddt065","volume":"22","author":"K Divaris","year":"2013","unstructured":"Divaris, K. et al. Exploring the genetic basis of chronic periodontitis: a genome-wide association study. Hum. Mol. Genet. 22, 2312\u20132324 (2013).","journal-title":"Hum. Mol. Genet."},{"key":"5940_CR57","doi-asserted-by":"publisher","first-page":"21S","DOI":"10.1177\/0022034512447951","volume":"91","author":"K Divaris","year":"2012","unstructured":"Divaris, K. et al. Genome-wide association study of periodontal pathogen colonization. J. Dent. Res. 91, 21S\u201328S (2012).","journal-title":"J. Dent. Res."},{"key":"5940_CR58","doi-asserted-by":"publisher","first-page":"882","DOI":"10.1177\/0022034514544506","volume":"93","author":"K Rhodin","year":"2014","unstructured":"Rhodin, K. et al. Chronic periodontitis genome-wide association studies: gene-centric and gene set enrichment analyses. J. Dent. Res. 93, 882\u2013890 (2014).","journal-title":"J. Dent. Res."},{"key":"5940_CR59","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-11-134","volume":"11","author":"YS Aulchenko","year":"2010","unstructured":"Aulchenko, Y. S., Struchalin, M. V. & van Duijn, C. M. ProbABEL package for genome-wide association analysis of imputed data. BMC Bioinf. 11, 134 (2010).","journal-title":"BMC Bioinf."},{"key":"5940_CR60","doi-asserted-by":"publisher","first-page":"2336","DOI":"10.1093\/bioinformatics\/btq419","volume":"26","author":"RJ Pruim","year":"2010","unstructured":"Pruim, R. J. et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336\u20132337 (2010).","journal-title":"Bioinformatics"},{"key":"5940_CR61","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1038\/nmeth0410-248","volume":"7","author":"IA Adzhubei","year":"2010","unstructured":"Adzhubei, I. A. et al. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248\u2013249 (2010).","journal-title":"Nat. Methods"},{"key":"5940_CR62","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.ajhg.2010.11.011","volume":"88","author":"J Yang","year":"2011","unstructured":"Yang, J., Lee, S. H., Goddard, M. E. & Visscher, P. M. GCTA: a tool for genome-wide complex trait analysis. Am. J. Hum. Genet. 88, 76\u201382 (2011).","journal-title":"Am. J. Hum. Genet."},{"key":"5940_CR63","doi-asserted-by":"publisher","first-page":"2577","DOI":"10.1093\/hmg\/ddx151","volume":"26","author":"M Munz","year":"2017","unstructured":"Munz, M. et al. A genome-wide association study identifies nucleotide variants at SIGLEC5 and DEFA1A3 as risk loci for periodontitis. Hum. Mol. Genet. 26, 2577\u20132588 (2017).","journal-title":"Hum. Mol. Genet."},{"key":"5940_CR64","doi-asserted-by":"publisher","unstructured":"American Academy of Periodontology Task Force report on the update to the 1999 classification of periodontal diseases and conditions. J. Periodontol. 86, 835\u2013838, https:\/\/doi.org\/10.1902\/jop.2015.157001 (2015).","DOI":"10.1902\/jop.2015.157001"},{"key":"5940_CR65","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1016\/j.chom.2013.04.005","volume":"13","author":"Y Jiao","year":"2013","unstructured":"Jiao, Y. et al. Induction of bone loss by pathobiont-mediated Nod1 signaling in the oral cavity. Cell. Host. Microbe 13, 595\u2013601 (2013).","journal-title":"Cell. Host. Microbe"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-018-05940-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-018-05940-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-018-05940-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,20]],"date-time":"2022-12-20T17:43:31Z","timestamp":1671558211000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-018-05940-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,9,11]]},"references-count":65,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["5940"],"URL":"https:\/\/doi.org\/10.1038\/s41467-018-05940-9","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,9,11]]},"assertion":[{"value":"25 January 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 July 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 September 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Dr. Cowley is employed by, has equity ownership in, and serves on the board of directors of TransViragen, the company which has been contracted by UNC-Chapel Hill to manage its Animal Models Core Facility. The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"3686"}}