Interleukin-1 receptor antagonist gene (IL1RN) variants modulate the cytokine release syndrome and mortality of SARS-CoV-2

Abstract

ABSTRACTObjectiveTo explore the regulation of the inflammatory response in acute SARS-CoV-2 infection, we examined effects of single nucleotide variants (SNVs) ofIL1RN, the gene encoding the anti-inflammatory IL-1 receptor antagonist (IL-1Ra), on the cytokine release syndrome and mortality.MethodsWe studied 2589 patients hospitalized with SARS-CoV-2 between March 2020 and March 2021 at NYU Langone’s Tisch Hospital. CTA and TTG haplotypes formed from three SNVs (rs419598, rs315952, rs9005) and the individual SNVs of theIL1RNgene were assessed for association with laboratory markers of the cytokine release syndrome (CRS) and mortality.ResultsMortality in the population was 15.3%, and was lower in women than men (13.1% vs.17.3%, p<0.0003). Carriers of the CTA-1/2IL1RNhaplotypes exhibiteddecreasedinflammatory markers andincreasedplasma IL-1Ra relative to TTG carriers. Decreased mortality among CTA-1/2 carriers was observed in male patients between the ages of 55-74 [9.2% vs. 17.9%, p=0.001]. Evaluation of individual SNVs of theIL1RNgene (rs419598, rs315952, rs9005) indicated that carriers of theIL1RNrs419598 CC SNV exhibited lower inflammatory biomarker levels, and was associated with reduced mortality compared to the CT/TT genotype in men (OR 0.49 (0.23 – 1.00); 0.052), with the most pronounced effect observed between the ages of 55-74 [5.5% vs. 18.4%, p<0.001].ConclusionTheIL1RNhaplotype CTA, and sequence variant of rs419598 are associated with attenuation of the cytokine release syndrome and decreased mortality in males with acute SARS-CoV2 infection. The data suggest thatIL1RNmodulates the COVID-19 cytokine release syndrome via endogenous “ anti-inflammatory” mechanisms.Significance statementWe provide evidence that variants ofIL1RNmodulate the severity of SARS-CoV-2 infection. TheIL1RN CTA haplotype andrs419598 CC single nucleotide variant are associated with decreased plasma levels of inflammatory markers, interleukin-1 beta (IL-1β), interleukin-6 (IL-6), interleukin-2 (IL-2), C-reactive protein (CRP), D-dimer, ferritin, and procalcitonin, in association with higher levels of IL-1Ra and IL-10, anti-inflammatory proteins. Both haplotype CTA and rs419598 CC genotype are associated with a significant reduction in the mortality of men. These data provide genetic evidence that inflammasome activation and the IL-1 pathway plays an important role in the mortality and morbidity associated with severe SARS-CoV-2 infection, and that genetic regulation of inflammatory pathways by variants ofIL1RNmerits further evaluation in severe SARS-CoV-2 infection.