{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T12:09:34Z","timestamp":1788869374790,"version":"build-2803163510"},"reference-count":39,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Age-associated immune\u2013inflammatory remodeling may be influenced by regulatory variation in the macrophage migration inhibitory factor gene (MIF). We conducted an exploratory cross-sectional comparison to assess whether MIF rs755622 (\u2212173G\/C) genotype distributions differ between predefined younger and older age groups in a Turkish population and to characterize the observed pattern using genetic-model and in silico analyses. We evaluated 368 individuals: 245 older adults aged 65\u2013102 years and 123 younger controls aged 20\u201346 years. None of the 26 main association tests remained statistically significant after global multiplicity correction (minimum FDR q = 0.062; minimum Bonferroni-adjusted p = 0.108). Before correction, GC frequency was higher in the older group and increased across the ordered age categories, and sex-adjusted analyses yielded concordant nominal estimates. However, these nominal patterns were sensitive to younger-control genotype reclassification and were not supported by an allele-level or additive association. Younger controls showed Hardy\u2013Weinberg disequilibrium (p &lt; 0.001), without sequencing confirmation, and deterministic and scenario-based Monte Carlo genotype-reclassification analyses indicated sensitivity of the nominal signal to uncertainty in control genotype classification. GTEx data provide C-allele-oriented expression context but do not validate function in this cohort. These preliminary findings warrant independent genotype verification, ancestry-matched replication, and direct functional investigation in future studies.<\/jats:p>","DOI":"10.3390\/ijms27177818","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T09:48:36Z","timestamp":1788256116000},"page":"7818","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MIF Promoter Variant rs755622 (\u2212173G\/C) in Younger and Older Turkish Adults: An Exploratory Cross-Sectional Genetic and in Silico Analysis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7129-5024","authenticated-orcid":false,"given":"Kursat","family":"Ozdilli","sequence":"first","affiliation":[{"name":"Department of Medical Biology, Faculty of Medicine, Istanbul Medipol University, Istanbul 34810, Turkey"},{"name":"Pediatric Bone Marrow Transplantation Unit, Medipol Mega University Hospital, 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ageing","volume":"464","author":"Kenyon","year":"2010","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/j.mad.2004.08.028","article-title":"Genes involved in immune response\/inflammation, IGF1\/insulin pathway and response to oxidative stress play a major role in the genetics of human longevity: The lesson of centenarians","volume":"126","author":"Franceschi","year":"2005","journal-title":"Mech. Ageing Dev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1038\/s41569-018-0064-2","article-title":"Inflammageing: Chronic inflammation in ageing, cardiovascular disease, and frailty","volume":"15","author":"Ferrucci","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.mad.2006.11.016","article-title":"Inflammaging and anti-inflammaging: A systemic perspective on aging and longevity emerged from studies in humans","volume":"128","author":"Franceschi","year":"2007","journal-title":"Mech. Ageing Dev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.3389\/fimmu.2017.01960","article-title":"Immunosenescence and Inflamm-Aging As Two Sides of the Same Coin: Friends or Foes?","volume":"8","author":"Fulop","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Aiello, A., Farzaneh, F., Candore, G., Caruso, C., Davinelli, S., Gambino, C.M., Ligotti, M.E., Zareian, N., and Accardi, G. (2019). Im-munosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic In-tervention. Front. Immunol., 10.","DOI":"10.3389\/fimmu.2019.02247"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1038\/nri1200","article-title":"Macrophage migration inhibitory factor: A regulator of innate immunity","volume":"3","author":"Calandra","year":"2003","journal-title":"Nat. Rev. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1677\/joe.0.1790015","article-title":"Macrophage migration inhibitory factor: A neuroendocrine modulator of chronic inflammation","volume":"179","author":"Baugh","year":"2003","journal-title":"J. Endocrinol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1016\/S1286-4579(02)01560-5","article-title":"Macrophage migration inhibitory factor (MIF): Mechanisms of action and role in disease","volume":"4","author":"Lue","year":"2002","journal-title":"Microbes Infect."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1006\/scbi.2000.0328","article-title":"Tumor growth-promoting properties of macrophage migration inhibitory factor (MIF)","volume":"10","author":"Mitchell","year":"2000","journal-title":"Semin. Cancer Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1084\/jem.20030286","article-title":"MIF signal transduction initiated by binding to CD74","volume":"197","author":"Leng","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1038\/nm1567","article-title":"MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment","volume":"13","author":"Bernhagen","year":"2007","journal-title":"Nat. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1038\/sj.gene.6363867","article-title":"A functional promoter polymorphism in the macrophage migration inhibitory factor (MIF) gene associated with disease severity in rheu-matoid arthritis","volume":"3","author":"Baugh","year":"2002","journal-title":"Genes Immun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1782","DOI":"10.1002\/1529-0131(200108)44:8<1782::AID-ART314>3.0.CO;2-#","article-title":"A novel 5\u2032-flanking region polymorphism of macrophage migration inhibitory factor is associated with systemic-onset juvenile idiopathic arthritis","volume":"44","author":"Donn","year":"2001","journal-title":"Arthritis Rheum."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1398","DOI":"10.1002\/art.10882","article-title":"Functional and prognostic relevance of the -173 polymorphism of the macrophage migration inhibitory factor gene in sys-temic-onset juvenile idiopathic arthritis","volume":"48","author":"Meazza","year":"2003","journal-title":"Arthritis Rheum."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Illescas, O., Gomez-Verjan, J.C., Garcia-Velazquez, L., Govezensky, T., and Rodriguez-Sosa, M. (2018). Macrophage Migration Inhibitory Factor -173 G\/C Polymorphism: A Global Meta-Analysis across the Disease Spectrum. Front. Genet., 9.","DOI":"10.3389\/fgene.2018.00055"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Vera, P.L., and Meyer-Siegler, K.L. (2011). Association between macrophage migration inhibitory factor promoter region polymorphism (-173 G\/C) and cancer: A meta-analysis. BMC Res. Notes, 4.","DOI":"10.1186\/1756-0500-4-395"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1038\/s41598-019-56949-z","article-title":"MIF gene rs755622 polymorphism positively associated with acute coronary syndrome in Chinese Han population: Case-control study","volume":"10","author":"Du","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"The 1000 Genomes Project Consortium (2015). A global reference for human genetic variation. Nature, 526, 68\u201374.","DOI":"10.1038\/nature15393"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/s13059-016-0974-4","article-title":"The Ensembl Variant Effect Predictor","volume":"17","author":"McLaren","year":"2016","journal-title":"Genome Biol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Averdunk, L., Bernhagen, J., Fehnle, K., Surowy, H., Ludecke, H.J., Mucha, S., Meybohm, P., Wieczorek, D., Leng, L., and Marx, G. (2020). The Macrophage Migration Inhibitory Factor (MIF) Promoter Polymorphisms (rs3063368, rs755622) Predict Acute Kidney Injury and Death after Cardiac Surgery. J. Clin. Med., 9.","DOI":"10.3390\/jcm9092936"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s13075-017-1260-x","article-title":"Chromatin landscapes and genetic risk for juvenile idi-opathic arthritis","volume":"19","author":"Zhu","year":"2017","journal-title":"Arthritis Res. Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1126\/science.aaz1776","article-title":"The GTEx Consortium atlas of genetic regulatory effects across human tissues","volume":"369","author":"Consortium","year":"2020","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e160024","DOI":"10.1172\/jci.insight.160024","article-title":"The MIF promoter SNP rs755622 is associated with immune activation in glioblastoma","volume":"8","author":"Alban","year":"2023","journal-title":"JCI Insight"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","article-title":"The STRING database in 2023: Protein-protein association networks and functional enrichment analyses for any se-quenced genome of interest","volume":"51","author":"Szklarczyk","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.cellsig.2019.01.006","article-title":"Evolving complexity of MIF signaling","volume":"57","author":"Jankauskas","year":"2019","journal-title":"Cell Signal."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1186\/s10020-026-01490-9","article-title":"LARS promotes hepatocellular carcinoma progression via the PI3K\/AKT\/mTOR pathway and interaction with RPS5, and serves as a prognostic biomarker","volume":"32","author":"Chen","year":"2026","journal-title":"Mol. Med."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Teng, Y.C., Wang, J.Y., Chi, Y.H., and Tsai, T.F. (2020). Exercise and the Cisd2 Prolongevity Gene: Two Promising Strategies to Delay the Aging of Skeletal Muscle. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21239059"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1007\/s10238-016-0439-9","article-title":"Association of genetic poly-morphisms in MIF with breast cancer risk in Chinese women","volume":"17","author":"Lin","year":"2017","journal-title":"Clin. Exp. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"577120","DOI":"10.1016\/j.jneuroim.2019.577120","article-title":"MIF-173G\/C polymorphism is associated with NMO disease severity","volume":"339","author":"Brill","year":"2020","journal-title":"J. Neuroimmunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2436","DOI":"10.1096\/fj.09-152223","article-title":"Macrophage migration inhibitory factor-knockout mice are long lived and respond to caloric restriction","volume":"24","author":"Harper","year":"2010","journal-title":"FASEB J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"22488","DOI":"10.1038\/srep22488","article-title":"Macrophage Migration Inhibitory Factor (MIF) Deficiency Exacerbates Aging-Induced Cardiac Remodeling and Dysfunction Despite Improved Inflammation: Role of Autophagy Regulation","volume":"6","author":"Xu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1177\/147323001003800108","article-title":"Association of macrophage migration inhibitory factor gene promoter polymorphisms with multiple sclerosis in Turkish patients","volume":"38","author":"Akcali","year":"2010","journal-title":"J. Int. Med. Res."},{"key":"ref_36","first-page":"283","article-title":"The MIF rs755622 variant may increase susceptibility of breast cancer but not gastrointestinal cancer in a Turkish population","volume":"35","author":"Pehlivan","year":"2020","journal-title":"Turk. J. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1002\/gepi.20410","article-title":"STrengthening the REporting of Genetic Association Studies (STREGA)\u2014An extension of the STROBE statement","volume":"33","author":"Little","year":"2009","journal-title":"Genet. Epidemiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1086\/429864","article-title":"A note on exact tests of Hardy-Weinberg equilibrium","volume":"76","author":"Wigginton","year":"2005","journal-title":"Am. J. Hum. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1093\/ije\/dyi184","article-title":"A method to automate probabilistic sensitivity analyses of misclassified binary variables","volume":"34","author":"Fox","year":"2005","journal-title":"Int. J. Epidemiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7818\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T11:25:29Z","timestamp":1788866729000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/17\/7818"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,31]]},"references-count":39,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["ijms27177818"],"URL":"https:\/\/doi.org\/10.3390\/ijms27177818","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,31]]}}}