Association of ZNF608 Polymorphisms With House Dust Mite-Induced Allergic Rhinitis

Abstract

Background: Genetic factors contribute essentially to the pathophysiology of house dust mite (HDM)-induced allergic rhinitis. Previous studies mainly focused on the biological pathogenesis, but the heritability remains poorly explained.

Methods: A genome-wide gene association analysis (GWGAS) integrating joint-genetic variant effects at the gene level was initially conducted on allergic rhinitis, validated by differential gene expression analysis. A weighted polygenic risk score (wPRS) was used to proxy the cumulative effect of candidate genetic variants in key genes. Gene-set analysis and eQTL analysis were performed to explore the immunologic pathway and genetic regulation of the key gene.

Results: ZNF608 was identified as the key gene involving HDM-induced allergic rhinitis risk (p = 1.23 × 10^-6), which was highly expressed in nasal epithelium cells of allergic rhinitis patients (p = 0.041). Furthermore, a wPRS of five significant variants, rs6862252, rs10067299, rs10042766, rs6866116, and rs79679768 in the ZNF608, showed the cumulative effect was associated with the increased HDM-induced allergic rhinitis risk (odds ratio [OR] = 1.40, 95% confidence interval [CI] = 1.18-1.65, p = 1.18 × 10^-4), with varied effects under diverse conditions of nasal symptoms. Additionally, both rs6862252 G allele and rs10042766 T allele elevated the expression of ZNF608 involving in state and perturbation of immune cells, such as B cell, T cell, and dendritic cell, contributing to HDM-induced allergic rhinitis.

Conclusion: This study highlights the key gene ZNF608 of HDM-induced allergic rhinitis, which may lay the groundwork for risk assessment and early diagnosis of allergic rhinitis.

Keywords: ZNF608; allergic rhinitis; genetic variants; immune cell; polygenic risk score.

FIGURE 1

Flow chart of the study. The left pink part represents the identification of the key gene ZNF608 associated with HDM‐induced allergic rhinitis risk by a genome‐wide gene association analysis. Then, we explored the expression pattern of ZNF608 between patients with allergic rhinitis and controls. To further investigate the genetic predisposition to allergic rhinitis, we performed genetic association studies to identify candidate SNPs. The eQTL analysis and functional annotation were applied to characterize the potential biological properties. A weighted polygenic risk score was calculated to assess the joint effect. Moreover, pathway enrichment analysis was conducted based on immunological signature gene sets harboring ZNF608.

FIGURE 2

ZNF608 is associated with risk of HDM‐induced allergic rhinitis. (A) Circle Manhattan plot depicts the results of genome‐wide gene association analysis by MAGMA. The black dotted line represents genome‐level significant level (p = 3.05 × 10⁻⁶) and the gray one represents significant level (p = 0.05). (B) The expression pattern of ZNF608 in nasal epithelium cells between five patients diagnosed with allergic rhinitis and six controls from GSE44037. Individual data points are overlaid to show sample distribution.

FIGURE 3

Identification of genetic variants in ZNF608 and their cumulative effects to HDM‐induced allergic rhinitis susceptibility. (A) Selection of variants in ZNF608 involved in HDM‐induced allergic rhinitis. After excluding SNPs showed high linkage disequilibrium (r ² > 0.8), 237 SNPs were retained for further logistic analysis. Five SNPs in ZNF608 were significantly associated with allergic rhinitis. LD, linkage disequilibrium. FDR, false discovery rate. (B) Forest plot illustrates the cumulative effects and stratification analysis of the association between wPRS constructed by five associated SNPs in ZNF608 and the susceptibility to HDM‐induced allergic rhinitis. p, p value adjusted for age, sex and the first three PCs. TNSS, total nasal symptom score. There is missing information on sneezing, rhinorrhea, nasal itching, and nasal obstruction for some patients.

FIGURE 4

The biological function and eQTL effects of SNPs in ZNF608. (A) Functional annotation of five SNPs based on HaploReg (upon filled in green) and RegulomeDB (bottom filled in white). (B–C) Circos plots of chromatin loops, states and 3D interaction of rs10067299 and rs79679768 in ZNF608 using 3DSNP. (D–E) MFE structure plots of rs6862252 and rs10042766 colored by base‐pair probabilities based on SNP‐fold website. (F) Gene‐set analysis of immune signature gene‐set harboring ZNF608 and HDM‐induced allergic rhinitis. The size of point represents the genes involved in the pathway. The range of color represents the significance. (G) The expression level of ZNF608 in 28 immune cell types from ImmuNexUT. (H) Box plots depict the eQTL effects between rs6862252 and rs10042766 genotypes and ZNF608 expression of 423 donors from ImmuNexUT. The number of samples for each genotype is shown below X‐axis.