A genetic variant in IL-6 lowering its expression is protective for critical patients with COVID-19
Bo Gong, Lulin Huang, Yongquan He, Wen Xie, Yi Yin, Yi Shi, Jialing Xiao, Ling Zhong, Yi Zhang, Zhilin Jiang, Hao Fang, Yu Zhou, Huan Li, Li Jiang, Xingxiang Yang, Xiangrong Song, Yan Kang, Lin Tuo, Yi Huang, Ping Shuai, Yuping Liu, Fang Zheng, Zhenglin Yang
Abstract
Abstract Critical coronavirus disease 2019 (COVID-19) is associated with high mortality and potential genetic factors have been reported to be involved in the development of critical COVID-19. We performed a genome-wide association study to identify the genetic factors responsible for developing critical COVID-19. 632 critical patients with COVID-19 and 3021 healthy controls from the Chinese population were recruited. First, we identified a genome-wide significant difference of IL-6 rs2069837 ( p = 9.73 × 10 −15 , OR = 0.41) between 437 critical patients with COVID-19 and 2551 normal controls in the discovery cohort. When replicated these findings in a set of 195 patients with critical COVID-19 and 470 healthy controls, we detected significant association of rs2069837 with COVID-19 ( p = 8.89 × 10 −3 , OR = 0.67). This variant surpassed the formal threshold for genome-wide significance (combined p = 4.64 × 10 −16 , OR = 0.49). Further analysis revealed that there was a significantly stronger expression of IL-6 in the serum from patients with critical COVID-19 than in that from patients with asymptomatic COVID-19. An in vitro assay showed that the A to G allele changes in rs2069837 within IL-6 obviously decreased the luciferase expression activity. When analyzing the effect of this variant on the IL-6 in the serum based on the rs2069837 genotype, we found that the A to G variation in rs2069837 decreased the expression of IL-6, especially in the male. Overall, we identified a genetic variant in IL-6 that protects against critical conditions with COVID-19 though decreasing IL-6 expression in the serum.