{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T18:03:52Z","timestamp":1779905032691,"version":"3.53.1"},"reference-count":26,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T00:00:00Z","timestamp":1779840000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ankara University Scientific Research Grants","award":["21B0230009"],"award-info":[{"award-number":["21B0230009"]}]},{"name":"Turkish Academy of Sciences Research Support"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"\n Background<\/jats:title>\n \n Genetic factors modulate the progression of coronavirus disease 2019 (COVID-19), but interactions between innate immune gene variants remain incompletely understood. Prior work identified Killer Immunoglobulin-like Receptor (KIR) genotypes and Neanderthal-introgressed\n OAS<\/jats:italic>\n 1\/2\/3 haplotypes as key modulators of disease severity. Given these parallel findings, we aimed to evaluate the synergistic impact of KIR motifs, Neanderthal-inherited\n OAS<\/jats:italic>\n 1\/2\/3 variants, and other immune-related SNPs on COVID-19 symptomatology and severity.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n In a cohort of 175 unvaccinated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive individuals (65 asymptomatic, 47 mild-intermediate, 63 severe), we genotyped KIR\/KIR-ligand motifs and variants in\n OAS<\/jats:italic>\n 1\/2\/3,\n IFITM3<\/jats:italic>\n ,\n DPP4<\/jats:italic>\n ,\n TLR7<\/jats:italic>\n , and\n APOE<\/jats:italic>\n . Multivariate logistic regression models assessed independent and interactive predictors of symptomatic and severe disease, and ROC curve analysis was performed to quantify their discriminative ability.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n An interaction between the absence of both the protective tAB1\/wL KIR motif and the Neanderthal-derived\n OAS<\/jats:italic>\n 1\/2\/3 alleles significantly predicted symptomatic infection (OR 3.47, P\u2009=\u20090.006) and severe disease (OR 2.41, P\u2009=\u20090.038), achieving overall classification accuracies of 75.4% and 78.9%, respectively. Independent predictors included age, male gender, rs12252 (\n IFITM3<\/jats:italic>\n ) and rs3788979 (\n DPP4<\/jats:italic>\n ) as risk factors, and blood group A and\n APOE<\/jats:italic>\n \u03b53\u03b53 status as protective factors. No rare\n TLR7<\/jats:italic>\n variants were detected.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n This study identifies, for the first time, a synergistic interaction between KIR motifs and Neanderthal-derived\n OAS<\/jats:italic>\n 1\/2\/3 variants influencing COVID-19 outcomes. These findings highlight the interplay between ancient and modern innate immune adaptations in shaping viral disease susceptibility. Future studies in larger and diverse populations are warranted to validate these immunogenetic interactions.\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1371\/journal.pone.0345137","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T17:25:31Z","timestamp":1779902731000},"page":"e0345137","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Innate immunogenetic synergy between KIR and Neanderthal-derived OAS variants predicts COVID-19 outcomes"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2461-9479","authenticated-orcid":true,"given":"Hasan Yalim","family":"Akin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timur","family":"Tuncali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emine Begum","family":"Gencer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guldane","family":"Cengiz Seval","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elif Mukime","family":"Saricaoglu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ezgi","family":"Gulten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irem","family":"Akdemir Kalkan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7635-8848","authenticated-orcid":true,"given":"Gule","family":"Cinar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osman","family":"Memikoglu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3871-8603","authenticated-orcid":true,"given":"Ridvan Goksel","family":"Anliacik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ezgi","family":"Anliacik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ergun","family":"Karaagaoglu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klara","family":"Dalva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1797-8657","authenticated-orcid":true,"given":"Meral","family":"Beksac","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,5,27]]},"reference":[{"key":"pone.0345137.ref001","article-title":"Clinical features of covid-19","volume":"369","author":"P Vetter","year":"2020","journal-title":"The BMJ"},{"issue":"6","key":"pone.0345137.ref002","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1038\/s41431-020-0636-6","article-title":"The COVID-19 Host Genetics Initiative, a global initiative to elucidate the role of host genetic factors in susceptibility and severity of the SARS-CoV-2 virus pandemic","volume":"28","author":"COVID-19 Host Genetics Initiative","year":"2020","journal-title":"Eur J Hum Genet"},{"issue":"10229","key":"pone.0345137.ref003","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1016\/S0140-6736(20)30566-3","article-title":"Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study","volume":"395","author":"F Zhou","year":"2020","journal-title":"Lancet"},{"issue":"4","key":"pone.0345137.ref004","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1016\/j.htct.2022.11.001","article-title":"Correlation between ABO blood type, susceptibility to SARS-CoV-2 infection and COVID-19 disease severity: A systematic review","volume":"45","author":"DMB Soares","year":"2023","journal-title":"Hematol Transfus Cell Ther"},{"issue":"6","key":"pone.0345137.ref005","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1007\/s00251-021-01227-4","article-title":"A model integrating Killer Immunoglobulin-like Receptor (KIR) haplotypes for risk prediction of COVID-19 clinical disease severity","volume":"73","author":"M Beksac","year":"2021","journal-title":"Immunogenetics"},{"issue":"8","key":"pone.0345137.ref006","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0255608","article-title":"Natural killer-cell immunoglobulin-like receptors trigger differences in immune response to SARS-CoV-2 infection","volume":"16","author":"R Littera","year":"2021","journal-title":"PLoS One"},{"key":"pone.0345137.ref007","doi-asserted-by":"crossref","first-page":"845474","DOI":"10.3389\/fgene.2022.845474","article-title":"Individualized Constellation of Killer Cell Immunoglobulin-Like Receptors and Cognate HLA Class I Ligands that Controls Natural Killer Cell Antiviral Immunity Predisposes COVID-19","volume":"13","author":"S Maruthamuthu","year":"2022","journal-title":"Front Genet"},{"issue":"7835","key":"pone.0345137.ref008","doi-asserted-by":"crossref","first-page":"610","DOI":"10.1038\/s41586-020-2818-3","article-title":"The major genetic risk factor for severe COVID-19 is inherited from Neanderthals","volume":"587","author":"H Zeberg","year":"2020","journal-title":"Nature"},{"issue":"9","key":"pone.0345137.ref009","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2026309118","article-title":"A genomic region associated with protection against severe COVID-19 is inherited from Neandertals","volume":"118","author":"H Zeberg","year":"2021","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"2","key":"pone.0345137.ref010","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1038\/s41588-021-00996-8","article-title":"Multi-ancestry fine mapping implicates OAS1 splicing in risk of severe COVID-19","volume":"54","author":"JE Huffman","year":"2022","journal-title":"Nat Genet"},{"issue":"1","key":"pone.0345137.ref011","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1186\/s13059-016-1098-6","article-title":"Adaptively introgressed Neandertal haplotype at the OAS locus functionally impacts innate immune responses in humans","volume":"17","author":"AJ Sams","year":"2016","journal-title":"Genome Biol"},{"key":"pone.0345137.ref012","unstructured":"dbSNP - NCBI. https:\/\/www.ncbi.nlm.nih.gov\/snp\/"},{"key":"pone.0345137.ref013","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1038\/ncomms2433","article-title":"Interferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with severe influenza in Chinese individuals","volume":"4","author":"Y-H Zhang","year":"2013","journal-title":"Nat Commun"},{"key":"pone.0345137.ref014","doi-asserted-by":"crossref","first-page":"119410","DOI":"10.1016\/j.lfs.2021.119410","article-title":"Dipeptidylpeptidase-4 levels and DPP4 gene polymorphisms in patients with COVID-19. Association with disease and with severity","volume":"276","author":"R Posadas-S\u00e1nchez","year":"2021","journal-title":"Life Sci"},{"issue":"4","key":"pone.0345137.ref015","first-page":"100323","article-title":"Stratified analyses refine association between TLR7 rare variants and severe COVID-19","volume":"5","author":"J Boos","year":"2024","journal-title":"HGG Adv"},{"key":"pone.0345137.ref016","doi-asserted-by":"crossref","first-page":"1801","DOI":"10.1093\/gerona\/glaa169","article-title":"ApoE e4e4 genotype and mortality with COVID-19 in UK Biobank","volume":"75","author":"CL Kuo","year":"2020","journal-title":"Journals of Gerontology - Series A Biological Sciences and Medical Sciences"},{"key":"pone.0345137.ref017","unstructured":"World Health Organization. COVID-19 Therapeutic Trial Synopsis. 2020."},{"key":"pone.0345137.ref018","doi-asserted-by":"crossref","first-page":"440","DOI":"10.3389\/fimmu.2020.00440","article-title":"Haplotype-Based Analysis of KIR-Gene Profiles in a South European Population-Distribution of Standard and Variant Haplotypes, and Identification of Novel Recombinant Structures","volume":"11","author":"E Cisneros","year":"2020","journal-title":"Front Immunol"},{"key":"pone.0345137.ref019","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1056\/NEJMoa2020283","article-title":"Genomewide Association Study of Severe Covid-19 with Respiratory Failure","volume":"383","author":"D Ellinghaus","year":"2020","journal-title":"New England Journal of Medicine"},{"issue":"4","key":"pone.0345137.ref020","doi-asserted-by":"crossref","first-page":"679","DOI":"10.3906\/sag-2005-395","article-title":"The effects of blood group types on the risk of COVID-19 infection and its clinical outcome","volume":"50","author":"H G\u00f6ker","year":"2020","journal-title":"Turk J Med Sci"},{"key":"pone.0345137.ref021","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkq537","article-title":"The GeneMANIA prediction server: biological network integration for gene prioritization and predicting gene function","volume":"38","author":"D Warde-Farley","year":"2010","journal-title":"Nucleic Acids Res"},{"key":"pone.0345137.ref022","doi-asserted-by":"crossref","first-page":"146790","DOI":"10.1016\/j.gene.2022.146790","article-title":"Systematic review and meta-analysis of human genetic variants contributing to COVID-19 susceptibility and severity","volume":"844","author":"K Gupta","year":"2022","journal-title":"Gene"},{"key":"pone.0345137.ref023","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1038\/s41591-022-02156-9","article-title":"Comorbidities, multimorbidity and COVID-19","volume":"29","author":"CD Russell","year":"2023","journal-title":"Nat Med"},{"key":"pone.0345137.ref024","unstructured":"Turkish Red Crescent Association. https:\/\/www.kanver.org\/"},{"key":"pone.0345137.ref025","doi-asserted-by":"crossref","first-page":"108911","DOI":"10.1016\/j.clim.2021.108911","article-title":"Association of KIR gene polymorphisms with COVID-19 disease","volume":"234","author":"A Hajeer","year":"2022","journal-title":"Clin Immunol"},{"key":"pone.0345137.ref026","unstructured":"Turkish Genome Project. https:\/\/tgd.tuseb.gov.tr\/en\/"}],"container-title":["PLOS One"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0345137","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T17:25:36Z","timestamp":1779902736000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0345137"}},"subtitle":[],"editor":[{"given":"Mohsan","family":"Ullah","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,5,27]]},"references-count":26,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5,27]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0345137","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,27]]}}}