Interleukin-1 Receptor Antagonist Gene (IL1RN) Variants Modulate the Cytokine Release Syndrome and Mortality of COVID-19

Background We examined effects of single-nucleotide variants (SNVs) of IL1RN, the gene encoding the anti-inflammatory interleukin 1 receptor antagonist (IL-1Ra), on the cytokine release syndrome (CRS) and mortality in patients with acute severe respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.Methods IL1RN CTA haplotypes formed from 3 SNVs (rs419598, rs315952, rs9005) and the individual SNVs were assessed for association with laboratory markers of inflammation and mortality. We studied 2589 patients hospitalized with SARS-CoV-2 between March 2020 and March 2021.Results Mortality was 15.3% and lower in women than men (13.1% vs 17.3%, P = .0003). Carriers of the CTA-1/2 IL1RN haplotypes exhibited decreased inflammatory markers and increased plasma IL-1Ra. Evaluation of the individual SNVs of the IL1RN, carriers of the rs419598 C/C SNV exhibited significantly reduced inflammatory biomarker levels and numerically lower mortality compared to the C/T-T/T genotype (10.0% vs 17.8%, P = .052) in men, with the most pronounced association observed in male patients <= 74 years old, whose mortality was reduced by 80% (3.1% vs 14.0%, P = .030).Conclusions The IL1RN haplotype CTA and C/C variant of rs419598 are associated with attenuation of the CRS and decreased mortality in men with acute SARS-CoV-2 infection. The data suggest that the IL1RN pathway modulates the severity of coronavirus disease 2019 (COVID-19) via endogenous anti-inflammatory mechanisms. We provide genetic evidence that variants of IL1RN modify the severity of SARS-CoV-2 infection. The IL1RN CTA haplotype and rs419598 C/C single-nucleotide variant are associated with lower levels of inflammatory markers and a reduction in the mortality of men. Graphical Abstract This graphical abstract is also available at Tidbit: https://tidbitapp.io/tidbits/interleukin-1-receptor-antagonist-gene-il1rn-variants-modulate-the-cytokine-release-syndrome-and-mortality-of-sars-cov-2?utm_campaign=tidbitlinkshare%26utm_source=ITPr