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

Abstract

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.

Keywords: BMI = body mass index; COVID-19 = coronavirus disease 2019; CRP = C-reactive protein; IFIH1 = interferon-induced with helicase c domain 1; IFN = interferon; IRF = interferon regulatory factor; NYU = New York University; OR = odds ratio; PRKG1 = protein kinase cGMP-dependent 1; SLE = systemic lupus erythematosus; SNP = single nucleotide polymorphism; STAT4 = signal transducer and activator of transcription 4.

Fig 1.

COVID-19 mortality rate vs age stratified by genetic variants. (A) shows data for the IRF5 TCTA haplotype in European-Americans, in which TCTA indicates the alleles at the rs2004640, rs3807306, rs10488631, and rs2280714 SNPs in that order, (B) shows PRKG1 rs7897633 genotype in European-Americans, (C) shows rs702966 genotype in African-Americans, (D) shows rs4963128 genotype in African-Americans, and (E) shows rs12444486 genotype in African-Americans. Mortality rate shown ranges from 0 to 1, with 0.2 corresponding to 20% mortality for example.

Fig 2.

Correlation plot between type I IFN ratio by genotype and odds ratio for mortality related to acute COVID-19 by the same genotype. The IFN ratios are calculated from our previous published studies in SLE noted in the Methods section, computing a ratio of median circulating IFN values between the genotype groups. Genotype categories used are the same for both the IFN analysis and the COVID-19 mortality analysis. 95% confidence is shown with the blue shading. TCTA indicates carriage of the associated IRF5 COVID-19 risk haplotype.

Fig 3.

Association analysis results for European ancestry cohort, showing odds ratios for mortality from acute COVID-19 in older (≥55 years) and younger (<55 years) subjects and in the presence or absence of biomarkers for severe disease. The genetic risk factors (coded as “Pos” and shown as red bars) are rs7897633 AA homozygosity and TCTA IRF5 haplotype carriers, subjects lacking these 2 genotypes are coded as “Neg” and shown as blue bars. The biomarker risk factors include D-Dimer >510 ng/mL, CRP >110 mg/L, and Troponin >0.015 ng/mL, and each biomarker above these thresholds was weighted as 1 positive biomarker. All odds ratios and hypothesis test P-values were calculated for mortality risk with respect to the lowest risk group (gene negative and biomarker negative). Dashed lines showing the minimum threshold for 95% statistical confidence are shown in red for each age group (row). When there are no deceased subjects in a given category, no OR and P-value are shown.

Fig 4.

Association analysis results for African-American ancestry cohort, showing odds ratios for mortality from acute COVID-19 in the presence or absence of biomarkers for severe disease. The genetic risk factors (coded as “Pos” and shown as red bars) are IRF7 region rs4963128 C allele carriers and rs702966 G allele carriers. Subjects who do not carry any one of these alleles are coded as “Neg” and shown as blue bars. The biomarker risk factors include D-Dimer >560 ng/mL, CRP >115 mg/L, and Troponin >0.01 ng/mL, and each biomarker above these thresholds was weighted as 1 positive biomarker. All odds ratios and hypothesis test P-values were calculated for mortality risk with respect to the lowest risk group (gene negative and biomarker negative). Dashed lines showing the minimum threshold for 95% statistical confidence are shown in red.