{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T15:58:13Z","timestamp":1753891093327,"version":"3.41.2"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T00:00:00Z","timestamp":1748995200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Genome-wide associative studies can potentially uncover novel pathways which modulate anti-viral immune responses against SARS-CoV-2 or identify drivers of severe disease. To date, these studies have yielded loci mostly in non-functional domains of unknown biological significance and invariably require large sample sizes, potentially missing lower frequency variants, especially in under-represented or minority populations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To identify unique genetic traits predisposing to severe COVID-19 in Asians, we employed an alternative strategy using whole exome sequencing of representative cohort of severe versus mild COVID-19 patients. Candidate gene variants were identified by performing logistic regression against top genetic principal components, prioritised for missense variants with likely causal impact.\u00a0Then, functional sequelae of variants were replicated <jats:italic>in-vitro<\/jats:italic> and\u00a0re-validated\u00a0in\u00a0patients ex vivo to demonstrate causality between genotype and clinical phenotype.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Of 136 COVID-19 patients in Singapore (of whom 25% had severe disease), a single nucleotide polymorphism rs2980619 (p.L252F substitution) belonging to NudC-Domain-Containing-1 (NUDCD1) was highly-placed. Homozygous bearers of variant p.L252F had higher (3.97x) odds of severe disease. Age &amp;gt;50 years and male sex were significant covariates which increased the odds of severe disease by 3.38x and 3.16x, respectively. We showed <jats:italic>in-vitro<\/jats:italic> that variant p.L252F reduced NUDCD1 activity, leading to reduced antiviral signalling through RNA helicase DHX15 and antiviral signalling adaptor MAVS, reduced activation of NF\u03baB components RelB and p65, and resultant 1-log higher SARS-CoV-2 viral load compared to wild type (L252) cells. Patients bearing p.L252F had lower NUDCD1, MAVS, and RelB expressions, affirming the above findings.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>A gene variant of NUDCD1 influences COVID-19 severity in Asians through interacting with DHX15 and MAVS, affecting effective response against SARS-CoV-2.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1581293","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T05:39:51Z","timestamp":1749015591000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel NUDCD1 gene variant predisposes to severe COVID-19 disease in Asians through modulation of antiviral DHX15- and MAVS-mediated signalling"],"prefix":"10.3389","volume":"16","author":[{"given":"Aseervatham","family":"Anusha Amali","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Douglas Jie Wen","family":"Tay","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiqi","family":"Seow","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marie","family":"Loh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharada","family":"Ravikumar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jocelyn Jin","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shaun Seh Ern","family":"Loong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siew Wai","family":"Fong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chang Jie Mick","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan Jordon Cailu","family":"Lim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Louis Hanqiang","family":"Gan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Winston Lian Chye","family":"Koh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ying","family":"Ding","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi Hui","family":"Sam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhaohong","family":"Tan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel Ying Min","family":"Tan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chong Boon","family":"Lua","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Justin Jang Hann","family":"Chu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amit","family":"Singhal","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shyam","family":"Prabhakar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wee Joo","family":"Chng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laurent","family":"Renia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David Chien Boon","family":"Lye","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa F. 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