{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T10:57:11Z","timestamp":1790938631073,"version":"4.1.0"},"reference-count":28,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007104","name":"Trakya University","doi-asserted-by":"publisher","award":["2023\/205"],"award-info":[{"award-number":["2023\/205"]}],"id":[{"id":"10.13039\/501100007104","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2023\/205"],"award-info":[{"award-number":["2023\/205"]}],"id":[{"id":"https:\/\/ror.org\/00xa0xn82","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Clin. Med.","JCM"],"abstract":"<jats:p>Background\/Objectives: Matrix metalloproteinases (MMPs) are enzymes that play a key role in the disruption of blood\u2013brain barrier integrity and neuroinflammatory processes. The objective of this study is to elucidate the contribution of Matrix Metalloproteinase 1 (MMP1) rs1799750 (\u22121607 1G\/2G), Matrix Metalloproteinase 2 (MMP2) [rs243865 (\u22121306 C &gt; T), rs2285053 (\u2212735 C &gt; T)], and Matrix Metalloproteinase 3 (MMP3) rs3025058 (\u22121171 5A\/6A) genetic variants to the pathogenesis of multiple sclerosis (MS), and to evaluate their potential as genetic markers of neurodegeneration in conjunction with clinical and environmental factors. Methods: The study included 100 MS patients and 100 healthy controls. Genotype distributions of MMP1, MMP2, and MMP3 genetic variants were determined using Polymerase Chain Reaction (PCR) and Restriction Fragment Length Polymorphism (RFLP) methods. Participants\u2019 demographic data and clinical histories were recorded. The relevant MMP loci were genotyped, and genotype\u2013allele frequencies as well as haplotype combinations were evaluated. Their associations with clinical parameters were analyzed using Chi-square tests, Odds Ratios (ORs), and One-Way Analysis of Variance (One-Way ANOVA). Results: The rates of heart disease history (13% vs. 4%, p = 0.031), alcohol consumption (29% vs. 14%, p = 0.011), and smoking (35% vs. 21%, p = 0.029) were significantly higher in MS patients compared to the control group. The MMP2 rs243865 (\u22121306) TT genotype showed a strong positive association with MS, exhibiting approximately 10-fold higher odds of the disease (p &lt; 0.001). Similarly, the MMP3 rs3025058 5A\/6A genotype was associated with 2.45-fold higher odds of MS (p &lt; 0.003). Higher odds of the disease were particularly evident with the MMP2 rs243865 (\u22121306) TT and MMP3 rs3025058 6A\/6A combination (OR: 6.769, p &lt; 0.001), followed by the MMP2 rs243865 (\u22121306) TT and MMP2 rs2285053 (\u2212735) CT combination (OR: 7.169, p &lt; 0.001). No statistically significant association was found between the examined genotypes or haplotypes and clinical parameters, including attack frequency and disease duration (p &gt; 0.05). Conclusions: Our study indicates that MMP2 and MMP3 genetic variants are significantly associated with MS susceptibility, though these variants do not appear to directly influence disease severity parameters such as attack frequency and disease duration. These findings further support the potential involvement of MMPs, particularly in the immunopathological phase of the disease. Consequently, addressing modifiable lifestyle factors in individuals carrying susceptibility-associated genetic profiles and considering early interventions targeting MMP pathways may offer valuable strategic insights for personalized MS management. The data obtained suggest that MMP variations have a potential to be not merely disease markers, but also early-stage therapeutic markers that may be addressed before the first clinical attack occurs. The present study also emphasizes the necessity of transitioning from a reactive approach to a proactive, genetically based personalized medicine paradigm in MS management.<\/jats:p>","DOI":"10.3390\/jcm15197648","type":"journal-article","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T10:14:56Z","timestamp":1790936096000},"page":"7648","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic Risk Factors of Neurodegeneration: The Role of MMP1 rs1799750 (\u22121607 1G\/2G), MMP2 [rs243865 (\u22121306 C &gt; T), rs2285053 (\u2212735 C &gt; T), and MMP3 rs3025058 (\u22121171 5A\/6A) Genetic Variants in Multiple Sclerosis Pathogenesis"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8412-091X","authenticated-orcid":false,"given":"Arzu","family":"Ay","sequence":"first","affiliation":[{"name":"Department of Biophysics, Faculty of Medicine, Trakya University, Edirne 22030, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3745-8838","authenticated-orcid":false,"given":"Nevra","family":"Alkanli","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Faculty of Medicine, Hali\u00e7 University, Istanbul 34060, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9608-9278","authenticated-orcid":false,"given":"Sezgin","family":"Kehaya","sequence":"additional","affiliation":[{"name":"Department of Neurology, Faculty of Medicine, Trakya University, Edirne 22030, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3631-4447","authenticated-orcid":false,"given":"Ayse Nur","family":"Cesme","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Faculty of Medicine, Trakya University, Edirne 22030, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Nemati, M.H., Yazdanpanah, E., Kazemi, R., Orooji, N., Dadfar, S., Oksenych, V., and Haghmorad, D. (2025). Microbiota-driven mechanisms in multiple sclerosis: Pathogenesis, therapeutic strategies, and biomarker potential. Biology, 14.","DOI":"10.3390\/biology14040435"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"14089","DOI":"10.1007\/s12035-025-05211-x","article-title":"Exploring the Link Between IL6 rs1800795 G > C SNP and the Severity of Epstein-Barr Virus-Associated Multiple Sclerosis: Potential Impact on Cognitive Impairment","volume":"62","author":"Hassan","year":"2025","journal-title":"Mol. Neurobiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.jneuroim.2009.06.014","article-title":"Association of MMP1, MMP3, MMP9, and MMP12 polymorphisms with risk and clinical course of multiple sclerosis in a Polish population","volume":"214","author":"Gromadzka","year":"2009","journal-title":"J. Neuroimmunol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"12865","DOI":"10.1007\/s12035-025-05027-9","article-title":"Decoding the Potential Impact of Plasma hsa-miR-24-3p and hsa-miR-181 d-3p Expression, Plasma IFN-gamma Levels, and IFNG rs2069727 T\/C Genetic Variant on Multiple Sclerosis Risk and Glatiramer Acetate Treatment","volume":"62","author":"Kalmaz","year":"2025","journal-title":"Mol. Neurobiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"10310","DOI":"10.1007\/s12035-025-04907-4","article-title":"Extracellular DNA and Deoxyribonuclease Activity as Potential Biomarkers of Inflammation in Multiple Sclerosis","volume":"62","author":"Kadlic","year":"2025","journal-title":"Mol. Neurobiol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"\u015awiderek-Matysiak, M., Oset, M., Domowicz, M., Galazka, G., Namieci\u0144ska, M., and Stasio\u0142ek, M. (2023). Cerebrospinal fluid biomarkers in differential diagnosis of multiple sclerosis and systemic inflammatory diseases with central nervous system involvement. Biomedicines, 11.","DOI":"10.3390\/biomedicines11020425"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1007\/s12035-022-03135-4","article-title":"Investigation of Relationship Between Small Noncoding RNA (sncRNA) Expression Levels and Serum Iron, Copper, and Zinc Levels in Clinical Diagnosed Multiple Sclerosis Patients","volume":"60","author":"Ay","year":"2023","journal-title":"Mol. Neurobiol."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Jansen, M.I., and Castorina, A. (2023). Identification of key genes and regulatory pathways in multiple sclerosis brain samples: A meta-analysis of micro-array datasets. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24119361"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Keller, A., Leidinger, P., Lange, J., Borries, A., Schroers, H., Scheffler, M., Lenhof, H.-P., Ruprecht, K., and Meese, E. (2009). Multiple sclerosis: MicroRNA expression profiles accurately differentiate patients with relapsing-remitting disease from healthy controls. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0007440"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.jaut.2019.04.002","article-title":"Small non-coding RNAs as important players, biomarkers and therapeutic targets in multiple sclerosis: A comprehensive overview","volume":"101","author":"Piket","year":"2019","journal-title":"J. Autoimmun."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Matusiak, M., Ozi\u0119b\u0142o, D., O\u0142dak, M., Rejmak, E., Kaczmarek, L., and Skar\u017cy\u0144ski, H. (2023). Longitudinal changes in BDNF and MMP-9 protein plasma levels in children after cochlear implantation. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24043714"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Mohammadhosayni, M., Khosrojerdi, A., Lorian, K., Aslani, S., Imani, D., Razi, B., Babaie, F., and Torkamandi, S. (2020). Matrix metalloproteinases (MMPs) family gene polymorphisms and the risk of multiple sclerosis: Systematic review and meta-analysis. BMC Neurol., 20.","DOI":"10.1186\/s12883-020-01804-2"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Castellazzi, M., Ligi, D., Contaldi, E., Quartana, D., Fonderico, M., Borgatti, L., Bellini, T., Trentini, A., Granieri, E., and Fainardi, E. (2018). Multiplex Matrix Metalloproteinases Analysis in the Cerebrospinal Fluid Reveals Potential Specific Patterns in Multiple Sclerosis Patients. Front. Neurol., 9.","DOI":"10.3389\/fneur.2018.01080"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1080\/08820139.2016.1180303","article-title":"Functional Promoter Polymorphisms of MMP2 C-735T and MMP9 C-1562T and Their Synergism with MMP7 A-181G in Multiple Sclerosis","volume":"45","author":"Rahimi","year":"2016","journal-title":"Immunol. Investig."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"e70517","DOI":"10.1111\/ene.70517","article-title":"Vascular Comorbidities and an Increased Comorbidity Score Are Associated With Disability and Disability Progression in Secondary Progressive Multiple Sclerosis","volume":"33","author":"John","year":"2026","journal-title":"Eur. J. Neurol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Hollingworth, B.Y.A., Pallier, P.N., Jenkins, S.I., and Chen, R. (2025). Hypoxic Neuroinflammation in the Pathogenesis of Multiple Sclerosis. Brain Sci., 15.","DOI":"10.3390\/brainsci15030248"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s12974-025-03629-7","article-title":"Cigarette smoke-induced lung-brain barrier dysfunction drives neurocognitive impairment via inflammatory spill-over","volume":"23","author":"Yu","year":"2025","journal-title":"J. Neuroinflamm."},{"key":"ref_18","first-page":"58","article-title":"Alcohol and multiple sclerosis: An immune system-based review","volume":"12","author":"Fahim","year":"2020","journal-title":"Int. J. Physiol. Pathophysiol. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.semcdb.2007.06.003","article-title":"MMPs in the central nervous system: Where the good guys go bad","volume":"19","author":"Agrawal","year":"2008","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.pneurobio.2016.08.002","article-title":"The multifaceted role of metalloproteinases in physiological and pathological conditions in embryonic and adult brains","volume":"155","author":"Herrero","year":"2017","journal-title":"Prog. Neurobiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2738","DOI":"10.1093\/brain\/awg285","article-title":"Analyses of all matrix metalloproteinase members in leukocytes emphasize monocytes as major inflammatory mediators in multiple sclerosis","volume":"126","author":"Nuttall","year":"2003","journal-title":"Brain"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Tanase, D.M., Valasciuc, E., Anton, I.-B., Gosav, E.M., Dima, N., Cucu, A.I., Costea, C.F., Floria, D.E., Hurjui, L.L., and Tarniceriu, C.C. (2025). Matrix Metalloproteinases: Pathophysiologic Implications and Potential Therapeutic Targets in Cardiovascular Disease. Biomolecules, 15.","DOI":"10.3390\/biom15040598"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.jns.2007.09.037","article-title":"Association of the MMP3 5A\/6A gene polymorphism with multiple sclerosis in patients from Serbia","volume":"267","year":"2008","journal-title":"J. Neurol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1016\/j.bbrc.2006.07.174","article-title":"Allele-specific MMP-3 transcription under in vivo conditions","volume":"348","author":"Zhu","year":"2006","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2408","DOI":"10.1161\/01.STR.0000031929.05665.DA","article-title":"Matrix metalloproteinase 1 and matrix metalloproteinase 3 gene promoter polymorphisms are associated with carotid artery stenosis","volume":"33","author":"Ghilardi","year":"2002","journal-title":"Stroke"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1038\/sj.gene.6364050","article-title":"Association of matrix metalloproteinase 3 promoter genotype with disease outcome in rheumatoid arthritis","volume":"5","author":"Mattey","year":"2004","journal-title":"Genes Immun."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1002\/art.10336","article-title":"Stromelysin 1 (matrix metalloproteinase 3) and HLA-DRB1 gene polymorphisms: Association with severity and progression of rheumatoid arthritis in a prospective study","volume":"46","author":"Constantin","year":"2002","journal-title":"Arthritis Rheum."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"586","DOI":"10.1177\/1073858402238517","article-title":"Matrix Metalloproteinases and Neuroinflammation in Multiple Sclerosis","volume":"8","author":"Rosenberg","year":"2002","journal-title":"Neuroscientist"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/19\/7648\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T10:22:32Z","timestamp":1790936552000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/19\/7648"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,2]]},"references-count":28,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["jcm15197648"],"URL":"https:\/\/doi.org\/10.3390\/jcm15197648","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,2]]}}}