Interferon pathway lupus risk alleles modulate risk of death from acute COVID-19.

Autor:	Nln I; Colton Center for Autoimmunity, NYU Grossman School of Medicine, New York, NY., Fernandez-Ruiz R; Colton Center for Autoimmunity, NYU Grossman School of Medicine, New York, NY., Wampler Muskardin TL; Colton Center for Autoimmunity, NYU Grossman School of Medicine, New York, NY., Paredes JL; Colton Center for Autoimmunity, NYU Grossman School of Medicine, New York, NY., Blazer AD; Colton Center for Autoimmunity, NYU Grossman School of Medicine, New York, NY., Tuminello S; Center for Human Genetics and Genomics, NYU Grossman School of Medicine, New York, NY., Attur M; Divison of Rheumatology, Department of Medicine, NYU Grossman School of Medicine, New York, NY., Iturrate E; Department of Medicine, NYU Grossman School of Medicine, New York, NY., Petrilli CM; Department of Medicine, NYU Grossman School of Medicine, New York, NY., Abramson SB; Department of Medicine, NYU Grossman School of Medicine, New York, NY., Chakravarti A; Center for Human Genetics and Genomics, NYU Grossman School of Medicine, New York, NY., Niewold TB; Colton Center for Autoimmunity, NYU Grossman School of Medicine, New York, NY.
Jazyk:	angličtina
Zdroj:	MedRxiv : the preprint server for health sciences [medRxiv] 2021 Nov 02. Date of Electronic Publication: 2021 Nov 02.
DOI:	10.1101/2021.11.01.21265766
Abstrakt:	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. Background: We 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 Significance: We 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:	MEDLINE
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