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Nat Genet ; 54(8): 1103-1116, 2022 08.
Article in English | MEDLINE | ID: covidwho-1931425


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.

COVID-19 , 2',5'-Oligoadenylate Synthetase/genetics , 2',5'-Oligoadenylate Synthetase/metabolism , Alleles , COVID-19/genetics , Hospitalization , Humans , SARS-CoV-2/genetics
Blood Rev ; 51: 100888, 2022 01.
Article in English | MEDLINE | ID: covidwho-1385128


Hairy cell leukemia (HCL) is an indolent B-cell malignancy, usually driven by the BRAF V600E mutation. For 30 years, untreated and relapsed HCL was successfully treated with purine analogs, but minimal residual disease (MRD) remained in most patients, eventually causing relapse. Repeated purine analogs achieve decreasing efficacy and increasing toxicity, particularly to normal T-cells. MRD-free complete remissions (CRs) are more common using rituximab with purine analogs in both 1st-line and relapsed settings. BRAF inhibitors and Ibrutinib can achieve remission, but due to persistence of MRD, must be used chronically to prevent relapse. BRAF inhibition combined with Rituximab can achieve high MRD-free CR rates. Anti-CD22 recombinant immunotoxin moxetumomab pasudotox is FDA-approved in the relapsed setting and is unique in achieving high MRD-free CR rates as a single-agent. Avoiding chemotherapy and rituximab may be important in ensuring both recovery from COVID-19 and successful COVID-19 vaccination, an area of continued investigation.

COVID-19 , Leukemia, Hairy Cell/diagnosis , Leukemia, Hairy Cell/therapy , Pandemics , Antineoplastic Agents/therapeutic use , COVID-19/epidemiology , Humans , Leukemia, Hairy Cell/epidemiology , Neoplasm, Residual/diagnosis , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Purines/therapeutic use , Recurrence , Rituximab/therapeutic use