{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T10:30:25Z","timestamp":1790505025586,"version":"4.1.0"},"reference-count":46,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,6,25]],"date-time":"2019-06-25T00:00:00Z","timestamp":1561420800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["K08AR065500"],"award-info":[{"award-number":["K08AR065500"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32HL07899"],"award-info":[{"award-number":["T32HL07899"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000862","name":"Doris Duke Charitable Foundation","doi-asserted-by":"publisher","award":["2015099"],"award-info":[{"award-number":["2015099"]}],"id":[{"id":"10.13039\/100000862","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University of Wisconsin School of Medicine and Public Health from the Wisconsin Partnership Program","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Autoantibodies against citrullinated proteins are a hallmark of rheumatoid arthritis, a destructive inflammatory arthritis. Peptidylarginine deiminase 4 (PAD4) has been hypothesized to contribute to rheumatoid arthritis by citrullinating histones to induce neutrophil extracellular traps (NETs), which display citrullinated proteins that are targeted by autoantibodies to drive inflammation and arthritis. Consistent with this theory, PAD4-deficient mice have reduced NETs, autoantibodies, and arthritis. However, PAD4\u2032s role in human rheumatoid arthritis is less clear. Here, we determine if single nucleotide polymorphism rs2240335 in PADI4, whose G allele is associated with reduced PAD4 in neutrophils, correlates with NETs, anti-histone antibodies, and rheumatoid arthritis susceptibility in North Americans. Control and rheumatoid arthritis subjects, divided into anti-cyclic citrullinated peptide (CCP) antibody positive and negative groups, were genotyped at rs2240335. In homozygotes, in vitro NETosis was quantified in immunofluorescent images and circulating NET and anti-histone antibody levels by enzyme linked immunosorbent assay (ELISA). Results were compared by t-test and correlation of rheumatoid arthritis diagnosis with rs2240335 by Armitage trend test. NET levels did not significantly correlate with genotype. G allele homozygotes in the CCP\u2212 rheumatoid arthritis group had reduced anti-native and anti-citrullinated histone antibodies. However, the G allele conferred increased risk for rheumatoid arthritis diagnosis, suggesting a complex role for PAD4 in human rheumatoid arthritis.<\/jats:p>","DOI":"10.3390\/ijms20123093","type":"journal-article","created":{"date-parts":[[2019,6,25]],"date-time":"2019-06-25T10:52:31Z","timestamp":1561459951000},"page":"3093","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Reduced Anti-Histone Antibodies and Increased Risk of Rheumatoid Arthritis Associated with a Single Nucleotide Polymorphism in PADI4 in North Americans"],"prefix":"10.3390","volume":"20","author":[{"given":"Aisha M.","family":"Mergaert","sequence":"first","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4113-8669","authenticated-orcid":false,"given":"Mandar","family":"Bawadekar","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thai Q.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5647-4617","authenticated-orcid":false,"given":"Laura","family":"Massarenti","sequence":"additional","affiliation":[{"name":"Institute for Inflammation Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital, Rigshospitalet, DK-2100 Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caitlyn L.","family":"Holmes","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Rebernick","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2304-8528","authenticated-orcid":false,"given":"Steven J.","family":"Schrodi","sequence":"additional","affiliation":[{"name":"Center for Precision Medicine Research, Marshfield Clinic Research Institute, Marshfield, WI 54449, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8842-0303","authenticated-orcid":false,"given":"Miriam A.","family":"Shelef","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"William S. 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