A Low-Producing Haplotype of Interleukin-6 Disrupting CTCF Binding Is Protective against Severe COVID-19

Interleukin6 (IL-6) is a key driver of hyperinflammation in COVID-19, and its level strongly correlates with disease progression. To investigate whether variability in COVID-19 severity partially results from differential expression, functional single-nucleotide polymorphisms (SNPs) of were determined in Chinese COVID-19 patients with mild or severe illness. An Asian-common haplotype defined by promoter SNP rs1800796 and intronic SNPs rs1524107 and rs2066992 correlated with COVID-19 severity. Homozygote carriers of variant haplotype were at lower risk of developing severe symptoms (odds ratio, 0.256; 95% confidence interval, 0.088 to 0.739; = 0.007). This protective haplotype was associated with lower levels of and its antisense long noncoding RNA by -expression quantitative trait loci analysis. The differences in expression resulted from the disturbance of stimulus-dependent bidirectional transcription of the / locus by the polymorphisms. The protective rs2066992- allele disrupted a conserved CTCF-binding locus at the enhancer elements of , which transcribed antisense to and induces expression in inflammatory responses. As a result, carriers of the protective allele had significantly reduced expression and attenuated induction in response to acute inflammatory stimuli and viral infection. Intriguingly, this low-producing variant that is endemic to present-day Asia was found in early humans who had inhabited mainland Asia since ∼40,000 years ago but not in other ancient humans, such as Neanderthals and Denisovans. The present study suggests that an individual's genotype underlies COVID-19 outcome and may be used to guide IL-6 blockade therapy in Asian patients. Overproduction of cytokine interleukin-6 (IL-6) is a hallmark of severe COVID-19 and is believed to play a critical role in exacerbating the excessive inflammatory response. Polymorphisms in account for the variability of IL-6 expression and disparities in infectious diseases, but its contribution to the clinical presentation of COVID-19 has not been reported. Here, we investigated polymorphisms in severe and mild cases of COVID-19 in a Chinese population. The variant haplotype , represented by rs1800796, rs1524107, and rs2066992 at the locus, was reduced in patients with severe illness; in contrast, carriers of the wild-type haplotype - - had higher risk of severe illness. Mechanistically, the protective variant haplotype lost CTCF binding at the intron and responded poorly to inflammatory stimuli