{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T10:46:52Z","timestamp":1785322012185,"version":"3.55.0"},"reference-count":61,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T00:00:00Z","timestamp":1694131200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"institutional funds"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Around 50% of rheumatoid arthritis (RA) patients show some extra-articular manifestation, with the lung a usually affected organ; in addition, the presence of anti-citrullinated protein antibodies (ACPA) is a common feature, which is caused by protein citrullination modifications, catalyzed by the peptidyl arginine deiminases (PAD) enzymes. We aimed to identify single nucleotide variants (SNV) in PADI2 and PADI4 genes (PAD2 and PAD4 proteins, respectively) associated with susceptibility to interstitial lung disease (ILD) in RA patients and the PAD2 and PAD4 levels. Material and methods: 867 subjects were included: 118 RA-ILD patients, 133 RA patients, and 616 clinically healthy subjects (CHS). Allelic discrimination was performed in eight SNVs using qPCR, four in PADI2 and four in PADI4. The ELISA technique determined PAD2 and PAD4 levels in serum and bronchoalveolar lavage (BAL) samples, and the population structure was evaluated using 14 informative ancestry markers. Results: The rs1005753-GG (OR = 4.9) in PADI2 and rs11203366-AA (OR = 3.08), rs11203367-GG (OR = 2.4) in PADI4 are associated with genetic susceptibility to RA-ILD as well as the ACTC haplotype (OR = 2.64). In addition, the PAD4 protein is increased in RA-ILD individuals harboring the minor allele homozygous genotype in PADI4 SNVs. Moreover, rs1748033 in PADI4, rs2057094, and rs2076615 in PADI2 are associated with RA susceptibility. In conclusion, in RA patients, single nucleotide variants in PADI4 and PADI2 are associated with ILD susceptibility. The rs1748033 in PADI4 and two different SNVs in PADI2 are associated with RA development but not ILD. PAD4 serum levels are increased in RA-ILD patients.<\/jats:p>","DOI":"10.3390\/cells12182235","type":"journal-article","created":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T07:57:17Z","timestamp":1694159837000},"page":"2235","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Molecular Factors in PAD2 (PADI2) and PAD4 (PADI4) Are Associated with Interstitial Lung Disease Susceptibility in Rheumatoid Arthritis Patients"],"prefix":"10.3390","volume":"12","author":[{"given":"Karol J.","family":"Nava-Quiroz","sequence":"first","affiliation":[{"name":"HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cos\u00edo Villegas, Tlalpan, Mexico City 14080, Mexico"},{"name":"Programa de Maestr\u00eda y Doctorado en Ciencias M\u00e9dicas Odontol\u00f3gicas y de la Salud, Universidad Nacional Aut\u00f3noma de M\u00e9xico (UNAM), Mexico City 04100, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Rojas-Serrano","sequence":"additional","affiliation":[{"name":"Rheumatology Clinic, Instituto Nacional de Enfermedades Respiratorias Ismael Cos\u00edo Villegas, Tlalpan, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6876-1012","authenticated-orcid":false,"given":"Gloria","family":"P\u00e9rez-Rubio","sequence":"additional","affiliation":[{"name":"HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cos\u00edo Villegas, Tlalpan, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2825-506X","authenticated-orcid":false,"given":"Ivette","family":"Buendia-Roldan","sequence":"additional","affiliation":[{"name":"Translational Research Laboratory on Aging and Pulmonary Fibrosis, Instituto Nacional de Enfermedades Respiratorias Ismael Cos\u00edo Villegas, Tlalpan, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9969-9872","authenticated-orcid":false,"given":"Mayra","family":"Mej\u00eda","sequence":"additional","affiliation":[{"name":"Diffuse Interstitial Lung Disease Clinic, Instituto Nacional de Enfermedades Respiratorias Ismael Cos\u00edo Villegas, Tlalpan, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3680-4193","authenticated-orcid":false,"given":"Juan Carlos","family":"Fern\u00e1ndez-L\u00f3pez","sequence":"additional","affiliation":[{"name":"Consorcio de Gen\u00f3mica Computacional, Instituto Nacional de Medicina Gen\u00f3mica (INMEGEN), Tlalpan, Mexico City 14610, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro","family":"Rodr\u00edguez-Henr\u00edquez","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Hospital General Dr. Manuel Gea Gonz\u00e1lez, Tlalpan, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"No\u00e9","family":"Ayala-Alcantar","sequence":"additional","affiliation":[{"name":"Banco de Sangre, Instituto Nacional de Enfermedades Respiratorias Ismael Cos\u00edo Villegas, Tlalpan, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4361-821X","authenticated-orcid":false,"given":"Espiridi\u00f3n","family":"Ramos-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Experimental Medicine Research Unit, Facultad de Medicina, Universidad Nacional Aut\u00f3noma de M\u00e9xico, Mexico City 06720, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0922-1590","authenticated-orcid":false,"given":"Luis Alberto","family":"L\u00f3pez-Flores","sequence":"additional","affiliation":[{"name":"HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cos\u00edo Villegas, Tlalpan, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4464-4396","authenticated-orcid":false,"given":"Alma D.","family":"Del \u00c1ngel-Pablo","sequence":"additional","affiliation":[{"name":"HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cos\u00edo Villegas, Tlalpan, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6877-8124","authenticated-orcid":false,"given":"Ramc\u00e9s","family":"Falf\u00e1n-Valencia","sequence":"additional","affiliation":[{"name":"HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cos\u00edo Villegas, Tlalpan, Mexico City 14080, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,9,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1378\/chest.13-1394","article-title":"Functional Impact of a Spectrum of Interstitial Lung Abnormalities in Rheumatoid Arthritis","volume":"146","author":"Doyle","year":"2014","journal-title":"Chest"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1007\/s00296-004-0472-y","article-title":"Pulmonary Involvement in Rheumatoid Arthritis","volume":"25","author":"Bilgici","year":"2005","journal-title":"Rheumatol. 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