Interferon pathway lupus risk alleles modulate risk of death from acute COVID-19
| Autor: | M. Attur, C. M. Petrilli, Ruth Fernandez-Ruiz, S. B. Abramson, Timothy B. Niewold, Jacqueline L. Paredes, Ashira D Blazer, A. Chakravarti, E. Iturrate, T. L. Wampler Muskardin, S. Tuminello, I. Nln |
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| Rok vydání: | 2021 |
| Předmět: |
PRKG1
protein kinase cGMP-dependent 1 NYU New York University BMI body mass index STAT4 signal transducer and activator of transcription 4 Antiviral Agents Polymorphism Single Nucleotide Article SLE systemic lupus erythematosus Physiology (medical) Genotype Humans Lupus Erythematosus Systemic Medicine IFN interferon Genetic Predisposition to Disease Allele Alleles COVID-19 coronavirus disease 2019 Aged Systemic lupus erythematosus business.industry Biochemistry (medical) Haplotype Public Health Environmental and Occupational Health COVID-19 Interferon-alpha General Medicine SNP single nucleotide polymorphism Middle Aged medicine.disease OR odds ratio Interferon Regulatory Factors Immunology CRP C-reactive protein Biomarker (medicine) IRF7 business IFIH1 interferon-induced with helicase c domain 1 IRF5 IRF interferon regulatory factor Interferon regulatory factors |
| Zdroj: | medRxiv article-version (status) pre article-version (number) 1 Translational Research |
| Popis: | Type I interferon (IFN) is critical in our defense against viral infections. Increased type I IFN pathway activation is a genetic risk factor for systemic lupus erythematosus (SLE), and a number of common risk alleles contribute to the high IFN trait. We hypothesized that these common gain-of-function IFN pathway alleles may be associated with protection from mortality in acute COVID-19. We studied patients admitted with acute COVID-19 (756 European-American and 398 African-American ancestry). Ancestral backgrounds were analyzed separately, and mortality after acute COVID-19 was the primary outcome. In European-American ancestry, we found that a haplotype of interferon regulatory factor 5 (IRF5) and alleles of protein kinase cGMP-dependent 1 (PRKG1) were associated with mortality from COVID-19. Interestingly, these were much stronger risk factors in younger patients (OR=29.2 for PRKG1 in ages 45-54). Variants in the IRF7 and IRF8 genes were associated with mortality from COVID-19 in African-American subjects, and these genetic effects were more pronounced in older subjects. Combining genetic information with blood biomarker data such as C-reactive protein, troponin, and D-dimer resulted in significantly improved predictive capacity, and in both ancestral backgrounds the risk genotypes were most relevant in those with positive biomarkers (OR for death between 14 and 111 in high risk genetic/biomarker groups). This study confirms the critical role of the IFN pathway in defense against COVID-19 and viral infections, and supports the idea that some common SLE risk alleles exert protective effects in anti-viral immunity.BackgroundWe find that a number of IFN pathway lupus risk alleles significantly impact mortality following COVID-19 infection. These data support the idea that type I IFN pathway risk alleles for autoimmune disease may persist in high frequency in modern human populations due to a benefit in our defense against viral infections.Translational SignificanceWe develop multivariate prediction models which combine genetics and known biomarkers of severity to result in greatly improved prediction of mortality in acute COVID-19. The specific associated alleles provide some clues about key points in our defense against COVID-19. |
| Databáze: | OpenAIRE |
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