ABSTRACT 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 IL-6 expression, functional single-nucleotide polymorphisms (SNPs) of IL-6 were determined in Chinese COVID-19 patients with mild or severe illness. An Asian-common IL-6 haplotype defined by promoter SNP rs1800796 and intronic SNPs rs1524107 and rs2066992 correlated with COVID-19 severity. Homozygote carriers of C-T-T variant haplotype were at lower risk of developing severe symptoms (odds ratio, 0.256; 95% confidence interval, 0.088 to 0.739; P = 0.007). This protective haplotype was associated with lower levels of IL-6 and its antisense long noncoding RNA IL-6-AS1 by cis -expression quantitative trait loci analysis. The differences in expression resulted from the disturbance of stimulus-dependent bidirectional transcription of the IL-6 / IL-6-AS1 locus by the polymorphisms. The protective rs2066992- T allele disrupted a conserved CTCF-binding locus at the enhancer elements of IL-6-AS1 , which transcribed antisense to IL-6 and induces IL-6 expression in inflammatory responses. As a result, carriers of the protective allele had significantly reduced IL-6-AS1 expression and attenuated IL-6 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 IL-6 genotype underlies COVID-19 outcome and may be used to guide IL-6 blockade therapy in Asian patients.
【저자키워드】 COVID-19, interleukin-6, CTCF, genetic polymorphisms, 【초록키워드】 viral infection, therapy, Inflammatory responses, IL-6, severity, Human, SNPs, variant, polymorphism, COVID-19 severity, outcome, Polymorphisms, Asia, Disease progression, Viral, humans, hyperinflammation, Genotype, Single-nucleotide polymorphisms, Mild, SNP, expression, Quantitative, patients, Protective, Haplotype, Endemic, Analysis, Odds ratio, COVID-19 patient, antisense, IL-6 blockade, Asian, long noncoding RNA, locus, 95% confidence interval, carriers, Variability, severe symptoms, Chinese, lower risk, allele, loci, disturbance, IL-6 expression, Neanderthal, element, promoter, enhancer, carrier, T allele, intronic SNPs, inflammatory stimuli, defined, conserved, significantly, reduced, functional, correlated, induce, transcribed, severe symptom, bidirectional transcription, intronic SNP, single-nucleotide, with COVID-19, 【제목키워드】 interleukin-6,