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Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-\u03b1), and Interferon-gamma (IFN-\u03b3) are key cytokines involved in immune regulation and inflammatory responses, playing a pivotal role in the pathogenesis of hepatitis C virus (HCV), coronavirus disease 2019 (COVID-19), and co-infection with both viruses. This study aims to investigate the role of circulating leptin gene polymorphism (rs7799039, G\u2009&gt;\u2009A), together with IL-6, TNF-\u03b1, and IFN-\u03b3 biomarkers, in the context of HCV, COVID-19, and dual HCV\u2013COVID-19 infection. While previous research has examined rs7799039 in COVID-19, its contribution in co-infection remains unclear. By integrating cytokine profiling with genotypic analysis, this work provides additional insights into disease diagnosis, risk stratification, and the underlying immunopathological mechanisms of these infections. Biomarker levels were measured in plasma using enzyme-linked immunosorbent assay (ELISA). Nasopharyngeal swabs were collected for real-time polymerase chain reaction (RT-PCR) detection of COVID-19 ribonucleic acid (RNA), and blood samples were used for quantitative RT-PCR detection of HCV-RNA. Single nucleotide polymorphisms (SNP) genotyping assay for Leptin gene (rs7799039) was examined from genomic deoxyribonucleic acid (DNA) using RT-PCR. No cytokine correlations were found in HCV alone, but TNF-\u03b1 and IFN-\u03b3 correlated in dual infections. IL-6, TNF-\u03b1, and IFN-\u03b3 levels were significantly elevated in all patient groups compared to controls, with mean\u2009\u00b1\u2009SD values of IL-6: 199.2\u2009\u00b1\u200928 pg\/mL (co-infected), 171\u2009\u00b1\u200931.9 pg\/mL (COVID-19), and 46.8\u2009\u00b1\u20099 pg\/mL (HCV); TNF-\u03b1: 64.6\u2009\u00b1\u200915.4 pg\/mL, 33.5\u2009\u00b1\u20097.1 pg\/mL, and 32.9\u2009\u00b1\u20096.2 pg\/mL; IFN-\u03b3: 166.2\u2009\u00b1\u200941.9 pg\/mL, 116.8\u2009\u00b1\u200918.6 pg\/mL, and 101\u2009\u00b1\u200914.4 pg\/mL, respectively. TNF-\u03b1 and IFN-\u03b3 were significant predictors of disease status across groups (OR\u2009=\u20091.107\u20131.482,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.001). IL-6 was predictive only in HCV patients (OR\u2009=\u20091.508,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.001). TNF-\u03b1 performed well (&gt;\u200985%) in all groups. IFN-\u03b3 performed well in co-infection and COVID-19 (&gt;\u200983%), but was moderately accurate in HCV (about 60%). IL-6 showed perfect accuracy in co-infection and COVID-19. Genotype analysis of the leptin gene polymorphism (rs7799039, G\u2009&gt;\u2009A) indicated that the GA genotype was the most common across all study groups. The AA genotype of the leptin gene (rs7799039, G\u2009&gt;\u2009A) was more frequent in individuals with COVID-19, suggesting a potential association with increased disease susceptibility. Conversely, the GG genotype was more commonly observed in the control group, which may indicate a protective role against infection. Statistical analysis revealed a significant relationship between genotype and disease status (\u03c7\u00b2 = 13.52,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.035\u2009&lt;\u20090.05). This study highlights the distinct roles of IL-6, TNF-\u03b1, and IFN-\u03b3 in HCV, COVID-19, and co-infections, with more pronounced cytokine interactions in dual infections. Furthermore, the AA genotype may be associated with increased susceptibility to COVID-19, while the GG genotype was more frequent among controls, suggesting a possible protective trend that warrants further investigation. This study suggests differential roles of IL-6, TNF-\u03b1, and IFN-\u03b3 across HCV, COVID-19, and co-infections, with indications of more pronounced cytokine interactions in dual infections. Furthermore, the GA genotype appeared more common among patients, while the GG genotype was more frequent in controls, suggesting a possible protective trend. The AA genotype showed a slight increase in COVID-19 cases, but this association was not statistically significant and should be interpreted with caution.\n                  <\/jats:p>","DOI":"10.1038\/s41598-026-35418-4","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T07:35:16Z","timestamp":1770017716000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Diagnostic and immunological roles of leptin gene rs7799039 polymorphism and cytokines in COVID-19, HCV, and dual infection"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7086-6040","authenticated-orcid":false,"given":"Amany A.","family":"Sakr","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amr E.","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nabil A.","family":"Hasona","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rasha M.","family":"Abdel-Hamid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Asmaa Salman","family":"Faisal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elsaeed E.","family":"Shaaban","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sahar","family":"Mohamed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abbas Mohamed","family":"Abbas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amal A.","family":"Mohamed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,2]]},"reference":[{"key":"35418_CR1","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1016\/S0140-6736(20)30183-5","volume":"395","author":"C Huang","year":"2020","unstructured":"Huang, C. et al. 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