{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T18:37:53Z","timestamp":1785263873760,"version":"3.55.0"},"reference-count":26,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T00:00:00Z","timestamp":1745452800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016991","name":"University of Guadalajara","doi-asserted-by":"publisher","award":["PIN 2021-II"],"award-info":[{"award-number":["PIN 2021-II"]}],"id":[{"id":"10.13039\/100016991","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Methotrexate (MTX) is the conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) recommended as the first-choice anti-rheumatic drug for rheumatoid arthritis (RA). However, responses to MTX may be influenced by genetic variants. We aim to evaluate the association of the rs2372536, rs4673990, and rs4673993 genetic variants of the ATIC gene with therapeutic failure of MTX in patients with RA. A case\u2013control study was performed. Disease activity was measured using the disease activity score based on erythrocyte sedimentation rate (DAS28-ESR). RA patients were classified into two groups: (a) responders (DAS28-ESR \u2264 3.2), which is the group of patients who did respond to methotrexate, and (b) non-responders (DAS28-ESR &gt; 3.2), which is the group of patients who did not respond to methotrexate. Serum levels of the 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) enzyme and Interleukin-6 (IL-6) were quantified using an enzyme-linked immunosorbent assay (ELISA). Genotyping of ATIC genetic variants was performed with quantitative polymerase chain reaction (qPCR) using TaqMan probes. A total of 260 patients with RA were included. In total, 142 (54.6%) were non-responders to MTX. IL-6 levels were increased in the non-responder group (p = 0.002), while no statistical differences were observed in the AICAR levels. The variables associated with non-response were higher HAQ-Di, weekly MTX dose, glucocorticoid use, erythrocyte sedimentation rate, and carriers of the polymorphic homozygous variant of rs4673993 (OR = 4.5, 95% CI: 1.04\u201319.34; p = 0.04). The use of sulfazaline offered protective effects. Our findings indicate that the polymorphism rs4673993 gene variant of the AICAR protein may significantly influence MTX resistance. Therefore, these results support the importance of the pathway generating extracellular adenosine and its effects on promoting the immune regulation for the mechanism of MTX therapy of RA.<\/jats:p>","DOI":"10.3390\/ijms26094013","type":"journal-article","created":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T06:18:02Z","timestamp":1745475482000},"page":"4013","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Genetic Variants of the ATIC Gene and Therapeutic Response to Methotrexate in Patients with Rheumatoid Arthritis"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6831-8950","authenticated-orcid":false,"given":"Sergio Gabriel","family":"Gallardo-Moya","sequence":"first","affiliation":[{"name":"Doctorado en Farmacolog\u00eda, Departamento de Fisiolog\u00eda, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6517-6344","authenticated-orcid":false,"given":"Laura","family":"Gonzalez-Lopez","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Instituto de Terap\u00e9utica Experimental y Cl\u00ednica, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betsabe","family":"Contreras-Haro","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Biom\u00e9dicas, Centro Universitario de Tonal\u00e1 (CUT), Universidad de Guadalajara, Tonal\u00e1 45425, Jalisco, Mexico"},{"name":"Unidad de Investigaci\u00f3n Biom\u00e9dica 02, Hospital de Especialidades Centro M\u00e9dico Nacional de Occidente, IMSS, Guadalajara 44329, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8321-7883","authenticated-orcid":false,"given":"Mario Alberto","family":"Mireles-Ramirez","sequence":"additional","affiliation":[{"name":"Direcci\u00f3n de Investigaci\u00f3n y Educaci\u00f3n, Hospital de Especialidades Centro M\u00e9dico Nacional de Occidente, IMSS, Guadalajara 44329, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8261-7893","authenticated-orcid":false,"given":"Alejandra","family":"Villagomez-Vega","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Biom\u00e9dicas, Centro Universitario de Tonal\u00e1 (CUT), Universidad de Guadalajara, Tonal\u00e1 45425, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6458-9617","authenticated-orcid":false,"given":"Mar\u00eda Cristina","family":"Mor\u00e1n-Moguel","sequence":"additional","affiliation":[{"name":"Departamento de Disciplinas Filos\u00f3fico, Metodol\u00f3gicas e Instrumentales, Centro Universitario de Ciencias de la Salud (CUCS), Guadalajara 44340, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9249-7709","authenticated-orcid":false,"given":"Miriam","family":"M\u00e9ndez-Del Villar","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias Biom\u00e9dicas, Centro Universitario de Tonal\u00e1 (CUT), Universidad de Guadalajara, Tonal\u00e1 45425, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Luisa","family":"Vazquez-Villegas","sequence":"additional","affiliation":[{"name":"Instituto Regional de Investigaci\u00f3n en Salud P\u00fablica, Programa de Doctorado y Coordinaci\u00f3n del Programa de Doctorado en Salud P\u00fablica, Ciencias de la Salud P\u00fablica, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0001-3787","authenticated-orcid":false,"given":"Jorge Ivan","family":"Gamez-Nava","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Instituto de Terap\u00e9utica Experimental y Cl\u00ednica, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2272-9612","authenticated-orcid":false,"given":"Ana Miriam","family":"Salda\u00f1a-Cruz","sequence":"additional","affiliation":[{"name":"Departamento de Fisiolog\u00eda, Instituto de Terap\u00e9utica Experimental y Cl\u00ednica, Centro Universitario de Ciencias de la Salud (CUCS), Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"18001","DOI":"10.1038\/nrdp.2018.1","article-title":"Rheumatoid Arthritis","volume":"4","author":"Smolen","year":"2018","journal-title":"Nat. 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