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

• Published in: Translational research : the journal of laboratory and clinical medicine Vol. 244; pp. 47 - 55
• Main Authors: Nln, Ilona, FERNANDEZ-RUIZ, RUTH, MUSKARDIN, THERESA L. WAMPLER, PAREDES, JACQUELINE L., BLAZER, ASHIRA D., TUMINELLO, STEPHANIE, ATTUR, MUKUNDAN, ITURRATE, EDUARDO, PETRILLI, CHRISTOPHER M., ABRAMSON, STEVEN B., CHAKRAVARTI, ARAVINDA, NIEWOLD, TIMOTHY B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2022; Published by Elsevier Inc
• Subjects: Aged; Alleles; Antiviral Agents; BMI = body mass index; COVID-19 - genetics; COVID-19 = coronavirus disease 2019; CRP = C-reactive protein; Genetic Predisposition to Disease; Humans; IFIH1 = interferon-induced with helicase c domain 1; IFN = interferon; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - metabolism; Interferon-alpha - genetics; IRF = interferon regulatory factor; Lupus Erythematosus, Systemic - genetics; Middle Aged; NYU = New York University; Original; OR = odds ratio; Polymorphism, Single Nucleotide; PRKG1 = protein kinase cGMP-dependent 1; SLE = systemic lupus erythematosus; SNP = single nucleotide polymorphism; STAT4 = signal transducer and activator of transcription 4; SLE = systemic lupus erythematosus; OR = odds ratio; STAT4 = signal transducer and activator of transcription 4; IRF = interferon regulatory factor; IFN = interferon; COVID-19 = coronavirus disease 2019; PRKG1 = protein kinase cGMP-dependent 1; BMI = body mass index; CRP = C-reactive protein; IFIH1 = interferon-induced with helicase c domain 1; NYU = New York University; SNP = single nucleotide polymorphism
• ISSN: 1931-5244; 1878-1810
• DOI: 10.1016/j.trsl.2022.01.007

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 antiviral immunity.