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Both diseases share symptoms and clinical risk factors<jats:sup>1<\/jats:sup>, but the extent to which these conditions have a common genetic etiology is unknown. This is partly because host genetic risk factors are well characterized for COVID-19 but not for influenza, with the largest published genome-wide association studies for these conditions including &gt;2 million individuals<jats:sup>2<\/jats:sup> and about 1,000 individuals<jats:sup>3\u20136<\/jats:sup>, respectively. Shared genetic risk factors could point to targets to prevent or treat both infections. Through a genetic study of 18,334 cases with a positive test for influenza and 276,295 controls, we show that published COVID-19 risk variants are not associated with influenza. Furthermore, we discovered and replicated an association between influenza infection and noncoding variants in <jats:italic>B3GALT5<\/jats:italic> and <jats:italic>ST6GAL1<\/jats:italic>, neither of which was associated with COVID-19. In vitro small interfering RNA knockdown of ST6GAL1\u2014an enzyme that adds sialic acid to the cell surface, which is used for viral entry\u2014reduced influenza infectivity by 57%. These results mirror the observation that variants that downregulate <jats:italic>ACE2<\/jats:italic>, the SARS-CoV-2 receptor, protect against COVID-19 (ref. <jats:sup>7<\/jats:sup>). Collectively, these findings highlight downregulation of key cell surface receptors used for viral entry as treatment opportunities to prevent COVID-19 and influenza.<\/jats:p>","DOI":"10.1038\/s41588-024-01844-1","type":"journal-article","created":{"date-parts":[[2024,8,5]],"date-time":"2024-08-05T10:04:42Z","timestamp":1722852282000},"page":"1592-1596","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Genetic risk factors for COVID-19 and influenza are largely distinct"],"prefix":"10.1038","volume":"56","author":[{"given":"Jack A.","family":"Kosmicki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Marcketta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepika","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvio Alessandro","family":"Di Gioia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samantha","family":"Batista","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Man","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gannie","family":"Tzoneva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hector","family":"Martinez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Sidore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael D.","family":"Kessler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie E.","family":"Horowitz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Genevieve H. 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