CARD8 polymorphism rs2043211 protects against noise-induced hearing loss by causing the dysfunction of CARD8 protein.

Inflammation is a complicated process and is considered to be responsible for the development of noise-induced hearing loss (NIHL). CARD8 is an important component of inflammasome that has been implicated in inflammation. To decide the relationship between the polymorphisms of CARD8 gene and NIHL risk and deduce the potential mechanism, three SNPs (rs2043211, rs1062808, and rs12459322) were genotyped in a Chinese population consisting of 610 NIHL cases and 612 normal hearing controls. The possible impacts of SNPs on CARD8 structure and function were assessed using a variety of bioinformatics tools. Plasmids expressing wild-type and/or mutated CARD8 were transfected into HEK293 cells to verify the effect of SNPs on CARD8 protein expression level by western blot. The results revealed that rs2043211 AA genotype and A allele were associated with decreased risk of NIHL. Stratified analysis found that the male, drinking and exposed to noise ≥ 92 dB, subjects harboring rs2043211 A allele had a low risk of NIHL. The haplotype AGG (rs2043211-rs1062808-rs12459322) was significantly associated with a decreased risk of NIHL. SNP rs2043211 was predicted to be deleterious and affects CARD8 protein structure and stability. Furthermore, the functional experiment showed the mutant CARD8 could significantly decrease the CARD8 protein expression level. This study confirms that rs2043211 A allele may reduce NIHL risk by causing the loss of PPI combined with the decreased CARD8 expression level leading to CARD8 functional changes, and it may be one valuable genetic biomarker of NIHL susceptibility for Chinese noise-exposed workers.