Open AccessA Low-Producing Haplotype of Interleukin-6 Disrupting CTCF Binding Is Protective against Severe COVID-19
Author(s) -
Tao Chen,
Yuxin Lin,
Yan Zha,
Ying Sun,
Jinxiu Tian,
Zhiping Yang,
Shanwen Lin,
Fuxun Yu,
ZiSheng Chen,
Bo-Hua Kuang,
Jin-Ju Lei,
Yingjie Nie,
Yonghao Xu,
Dan Tian,
Yingzi Li,
Bin Yang,
Qiang Xu,
Yang Li,
Nanshan Zhong,
Meizhen Zheng,
Yimin Li,
Jincun Zhao,
Xiangyan Zhang,
Lin Feng
Publication year - 2021
Publication title -
mbio
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.562
H-Index - 121
eISSN - 2161-2129
pISSN - 2150-7511
DOI - 10.1128/mbio.01372-21
Subject(s) - haplotype , ctcf , single nucleotide polymorphism , allele , biology , locus (genetics) , snp , genetics , expression quantitative trait loci , immunology , enhancer , transcription factor , genotype , gene
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.