The chr12q24.13 locus encoding OAS1–OAS3 antiviral proteins has been associated with coronavirus disease 2019 (COVID-19) susceptibility. Here, we report genetic, functional and clinical insights into this locus in relation to COVID-19 severity. In our analysis of patients of European (n = 2,249) and African (n = 835) ancestries with hospitalized versus nonhospitalized COVID-19, the risk of hospitalized disease was associated with a common OAS1 haplotype, which was also associated with reduced severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clearance in a clinical trial with pegIFN-λ1. Bioinformatic analyses and in vitro studies reveal the functional contribution of two associated OAS1 exonic variants comprising the risk haplotype. Derived human-specific alleles rs10774671-A and rs1131454-A decrease OAS1 protein abundance through allele-specific regulation of splicing and nonsense-mediated decay (NMD). We conclude that decreased OAS1 expression due to a common haplotype contributes to COVID-19 severity. Our results provide insight into molecular mechanisms through which early treatment with interferons could accelerate SARS-CoV-2 clearance and mitigate against severe COVID-19.

Gelatin degradation assay, invadopodia characterization, and microscopy Cells were plated on Oregon Green 488-conjugated gelatin (G13186; Invitrogen) coated coverslips (29). In cases of inhibitor treatment, cells were allowed to attach for 1 hour, then incubated Markwell et al.

Genomic regions have been associated with COVID-19 susceptibility and outcomes, including the chr12q24.13 locus encoding antiviral proteins OAS1-3. Here, we report genetic, functional, and clinical insights into genetic associations within this locus. In Europeans, the risk of hospitalized vs. non-hospitalized COVID-19 was associated with a single 19Kb-haplotype comprised of 76 OAS1 variants included in a 95% credible set within a large genomic fragment introgressed from Neandertals. The risk haplotype was also associated with impaired spontaneous but not treatment-induced SARS-CoV-2 clearance in a clinical trial with pegIFN-λ1. We demonstrate that two exonic variants, rs10774671 and rs1131454, affect splicing and nonsense-mediated decay of OAS1. We suggest that genetically-regulated loss of OAS1 expression contributes to impaired spontaneous clearance of SARS-CoV-2 and elevated risk of hospitalization for COVID-19. Our results provide the rationale for further clinical studies using interferons to compensate for impaired spontaneous SARS-CoV-2 clearance, particularly in carriers of the OAS1 risk haplotypes.

the United States Appalachian region harbors a higher cancer burden than the rest of the nation, with disparate incidence of head and neck squamous cell carcinomas (HnScc), including oral cavity and pharynx (oc/p) cancers. Whether elevated HnScc incidence generates survival disparities within Appalachia is unknown. To address this, HNSCC survival data for 259,737 tumors from the North American Association for Central Cancer Registries 2007-2013 cohort were evaluated, with ageadjusted relative survival (RS) calculated based on staging, race, sex, and Appalachian residence. tobacco use, a primary HnScc risk factor, was evaluated through the Behavioral Risk factor Surveillance System from Appalachian states. Decreased oc/p RS was found in stage iV Appalachian white males within a subset of states. The survival disparity was confined to human papillomavirus (HPV)-associated oropharyngeal cancers, specifically the oropharynx subsite. This correlated with significantly higher smoking and male smokeless tobacco use in most Appalachian disparity states. Lower survival of Appalachian males with advanced-stage HpV-associated oropharyngeal cancers suggests pervasive tobacco consumption likely generates more aggressive tumors at HpV-associated oropharynx subsites than national averages. comprehensive tobacco and HpV status should therefore be evaluated prior to considering treatment de-intensification regimens for HPV-associated oropharyngeal cancers in populations with high tobacco consumption. HNSCC involves the epithelium of the oral cavity, pharynx and larynx. OC/P cancers are a major HNSCC subset, with nearly 11,000 deaths predicted in the US in 2020 1. Risk factors include tobacco and alcohol use, and highrisk human papillomavirus (HPV) infection 2,3. OC/P cancers are subdivided into HPV-associated oropharynx (HPV-associated) and non-HPV-associated oral cavity, hypopharynx, and nasopharynx (non-HPV-associated) cancers 4. These designations are supported by studies indicating that non-HPV-associated cancers are primarily tobacco/alcohol induced, whereas HPV-associated cancers are predominantly caused by HPV infection 5. Furthermore, HPV-negative or non-HPV-associated cancers consistently have poorer outcomes than HPV-positive or HPV-associated cancers, segregating these cancers as distinct diseases with differential clinical management 6,7. While national incidence of non-HPV-associated cancers is decreasing due to tobacco cessation, HPV-associated cancers are increasing due to rising infection rates 8. Regarding race, blacks with HNSCC present with more advanced disease, are older and have worse survival than whites, denoting a racial disparity 9-11. Increased screening for HPV coupled with subsite analysis indicates that blacks with HNSCC have less HPV-positive cancer than whites, explaining differences in survival 12,13. Consistent with this, HPV-associated cancers continue to increase in white males and in rural areas 4,14,15. The Appalachian region encompasses 205,000 square miles across 420 counties in 13 contiguo...

Long noncoding RNAs (lncRNA) have been implicated in many diseases, including cancer. Although these disease-associated effects have been mostly attributed to the ability of lncRNAs to function as regulatory noncoding transcripts, there is growing evidence that lncRNAs may also encode functional micropeptides. In the current issue of Cancer Research, Wu and colleagues report a micropeptide encoded by a Y chromosome–linked lncRNA that may explain the higher incidence of esophageal cancer in male smokers. Furthermore, this report provides broader insights related to the molecular epidemiology of male-dominant and smoking-driven cancers and may also help explain some cancer-related associations with mosaic Y chromosome loss. See related article by Wu et al., p. 2790