{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:44:57Z","timestamp":1760060697380,"version":"build-2065373602"},"reference-count":35,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,12]],"date-time":"2025-09-12T00:00:00Z","timestamp":1757635200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry Of Health","award":["RC2025","PE0000006","DN. 1553 11.10.2022"],"award-info":[{"award-number":["RC2025","PE0000006","DN. 1553 11.10.2022"]}]},{"name":"#NEXTGENERATIONEU (NGEU)","award":["RC2025","PE0000006","DN. 1553 11.10.2022"],"award-info":[{"award-number":["RC2025","PE0000006","DN. 1553 11.10.2022"]}]},{"name":"Ministry of University and Research (MUR)","award":["RC2025","PE0000006","DN. 1553 11.10.2022"],"award-info":[{"award-number":["RC2025","PE0000006","DN. 1553 11.10.2022"]}]},{"name":"National Recovery and Resilience Plan (NRRP)","award":["RC2025","PE0000006","DN. 1553 11.10.2022"],"award-info":[{"award-number":["RC2025","PE0000006","DN. 1553 11.10.2022"]}]},{"name":"MNESY","award":["RC2025","PE0000006","DN. 1553 11.10.2022"],"award-info":[{"award-number":["RC2025","PE0000006","DN. 1553 11.10.2022"]}]},{"name":"Fondazione Romeo ed Enrica Invernizzi","award":["RC2025","PE0000006","DN. 1553 11.10.2022"],"award-info":[{"award-number":["RC2025","PE0000006","DN. 1553 11.10.2022"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that affects young adults with different clinical phenotypes: relapsing\u2013remitting MS (RR-MS), secondary progressive MS (SP-MS), and primary progressive MS (PP-MS). Aquaporin 4 (AQP4), a protein found in astrocytes, plays a crucial role in CNS functions. We investigated the possible association of three AQP4 gene single-nucleotide polymorphisms (SNPs), rs2075575, rs162009, and rs335929, with MS risk and rehabilitation outcomes. SNPs were genotyped in 237 people with MS (pwMS), spanning all disease forms and enrolled in an intensive, multidisciplinary rehabilitation program, and 461 healthy controls (HCs). The AQP4 rs2075575 GG genotype was significantly less frequent in male pwRR-MS compared to HCs (15.4% vs. 29.1%, p = 0.033, OR = 0.44), suggesting a protective role. Haplotype analysis identified the rs2075575(A)-rs162009(A)-rs335929(C) (A-A-C) haplotype as an MS risk factor, particularly in males (p = 0.001, OR = 2.70). Finally, the rs335929 SNP was significantly associated with EDSS improvement after rehabilitation (p = 0.011), with the CC genotype showing the highest mean \u0394EDSS in pwRR-MS (p = 0.009), especially in males (p = 0.003). AQP4 gene SNPs may influence both MS susceptibility and rehabilitation outcomes, with sex-specific effects. Further studies are needed to understand the mechanisms behind these associations and their potential for personalized treatment strategies in MS.<\/jats:p>","DOI":"10.3390\/ijms26188915","type":"journal-article","created":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T07:33:02Z","timestamp":1758007982000},"page":"8915","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sex-Specific Effects of AQP4 Gene Polymorphisms on Multiple Sclerosis Susceptibility and Response to Multidisciplinary Rehabilitation"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2022-3386","authenticated-orcid":false,"given":"Cristina","family":"Agliardi","sequence":"first","affiliation":[{"name":"IRCCS Fondazione Don Carlo Gnocchi ONLUS, Via Capecelatro 66, 20148 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9461-5927","authenticated-orcid":false,"given":"Franca Rosa","family":"Guerini","sequence":"additional","affiliation":[{"name":"IRCCS Fondazione Don Carlo Gnocchi ONLUS, Via Capecelatro 66, 20148 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Milena","family":"Zanzottera","sequence":"additional","affiliation":[{"name":"IRCCS Fondazione Don Carlo Gnocchi ONLUS, Via Capecelatro 66, 20148 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5554-1697","authenticated-orcid":false,"given":"Elisabetta","family":"Bolognesi","sequence":"additional","affiliation":[{"name":"IRCCS Fondazione Don Carlo Gnocchi ONLUS, Via Capecelatro 66, 20148 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Domenico","family":"Caputo","sequence":"additional","affiliation":[{"name":"IRCCS Fondazione Don Carlo Gnocchi ONLUS, Via Capecelatro 66, 20148 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1459-5618","authenticated-orcid":false,"given":"Elisabetta","family":"Groppo","sequence":"additional","affiliation":[{"name":"IRCCS Fondazione Don Carlo Gnocchi ONLUS, Via Capecelatro 66, 20148 Milan, Italy"},{"name":"Clinical Neurology Unit, Department of Health Sciences, Ospedale San Paolo, ASST Santi Paolo e Carlo, University of Milan, 20142 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9691-1957","authenticated-orcid":false,"given":"Marco","family":"Rovaris","sequence":"additional","affiliation":[{"name":"IRCCS Fondazione Don Carlo Gnocchi ONLUS, Via Capecelatro 66, 20148 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5920-6191","authenticated-orcid":false,"given":"Mario","family":"Clerici","sequence":"additional","affiliation":[{"name":"IRCCS Fondazione Don Carlo Gnocchi ONLUS, Via Capecelatro 66, 20148 Milan, Italy"},{"name":"Pathophysiology and Transplantation Department, University of Milan, 20122 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1007\/s00234-007-0216-2","article-title":"Idiopathic inflammatory-demyelinating diseases of the central nervous system","volume":"49","author":"Gols","year":"2007","journal-title":"Neuroradiology"},{"key":"ref_2","first-page":"529","article-title":"Multiple Sclerosis: An Update","volume":"87","author":"Faguy","year":"2016","journal-title":"Radiol. 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