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, which may protect the carriers from hyperinflammation in response to acute SARS-CoV-2 infection. These results point out the possibility that genotypes underlie the differential viral virulence during the outbreak of COVID-19. The risk loci we identified may serve as a genetic marker to screen high-risk COVID-19 patients.