{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T03:35:57Z","timestamp":1779334557845,"version":"3.51.4"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,20]],"date-time":"2025-03-20T00:00:00Z","timestamp":1742428800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Objectives<\/jats:title><jats:p>This research aims to reveal the mechanisms of the effect of the Paraoxonase 1 (<jats:italic>PON1<\/jats:italic>) gene on response to leflunomide (LEF) in rheumatoid arthritis (RA) patients, in terms of single nucleotide polymorphism (SNP), DNA methylation levels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A total of 240 RA patients enrolled were categorized into the good response group and the non-response group according to the difference in DAS28 scores between baseline and 6\u00a0months after LEF administration. The identified LEF-response cytosine-phosphate-guanines (CpGs) island (cg17330251) and its internal SNPs (rs705379, etc.) located at the <jats:italic>PON1<\/jats:italic> promoter were detected by Sanger sequencing and methyl target sequencing.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A total of 12 CpG sites at cg17330251 could be identified in our RA patients. There were significant difference between the responders and non-responders in nine CpG sites: cg17330251_2, cg17330251_3, cg17330251_4, cg17330251_6, cg17330251_7, cg17330251_8, cg17330251_9, cg17330251_10, cg17330251_12, [OR (95CI%) = 0.492 (0.250, 0.969), 0.478 (0.243, 0.940), 0.492 (0.250, 0.969), 0.461 (0.234, 0.907), 0.492 (0.250, 0.969), 0.437 (0.225, 0.849), 0.478 (0.243, 0.941), 0.421 (0.212, 0.836), 0.424 (0.213, 0.843), <jats:italic>P<\/jats:italic> &amp;lt; 0.05, respectively]. At all these nine CpG sites, the proportions of low methylation levels in the responders were higher than those in the non-responders (<jats:italic>P<\/jats:italic> &amp;lt; 0.05). In a dominant model, there was a significant difference in rs705379 wildtype CC and mutant genotypes (CT + TT) between the responders and non-responders (<jats:italic>P<\/jats:italic> &amp;lt; 0.05). The average methylation level of 12 CpG sites was lowest in rs705379-CC (median 0.229, IQR 0.195\u20130.287), then rs705379-CT (median 0.363, IQR 0.332\u20130.395), and rs705379-TT (median:0.531, IQR:0.496\u20130.557). The average methylation levels of 12 CpG sites were significantly negative correlated with \u0394DAS28 (<jats:italic>r<\/jats:italic> = \u22120.13, <jats:italic>P<\/jats:italic> &amp;lt; 0.05). The Logistic regression indicated that combined effect of rs705379, DNA methylation of the <jats:italic>PON1<\/jats:italic> gene [OR (95CI%) = 1.277 [1.003, 1.626)], systemic inflammation index (SIRI) [OR (95CI%) = 1.079 (1.018, 1.143)] served as protective factors on response to LEF in RA patients.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The RA patients with SNP-rs705379-CC, the low methylation level of <jats:italic>PON1<\/jats:italic>-cg17330251 and more SIRI would be susceptible of response to LEF and more suitable to choose LEF treatment.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1499723","type":"journal-article","created":{"date-parts":[[2025,3,20]],"date-time":"2025-03-20T05:34:06Z","timestamp":1742448846000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["The interaction between a leflunomide-response methylation site (cg17330251) and variant (rs705379) on response to leflunomide in patients with rheumatoid arthritis"],"prefix":"10.3389","volume":"16","author":[{"given":"Feng","family":"Zhao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yulan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haina","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lei","family":"Jin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Feng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bingbing","family":"Dai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuxin","family":"Yao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruobing","family":"Liao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junyi","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bingjia","family":"Qu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingyu","family":"Fu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"10018","DOI":"10.1002\/jcp.27860","article-title":"Strategies toward rheumatoid arthritis therapy; the old and the new","volume":"234","author":"Abbasi","year":"2019","journal-title":"J. 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