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Copy Number Variation in MUC5AC and Susceptibility to Allergic Rhinitis: A Low-Coverage Whole-Genome Sequencing and Validation Cohort Study.

Background: The contribution of genetic copy number variations (CNVs) to allergic rhinitis (AR) remains unknown. The aim of this study was to identify genetic CNVs related to AR in the Han Chinese population. Methods: A case/parent trio of patients of Han Chinese descent affected with AR was examined using low-coverage whole-genome sequencing. Select CNVs were also explored for AR association in a validation cohort of 696 diagnosed AR patients and 528 matched controls. AccuCopy™, a multiplex fluorescence competitive polymerase chain reaction (PCR) assay, was used for genotyping of the CNV and was further validated with real-time PCR. Results: In the case/parent trio study, 67 CNVs were found in the Database of Genomic Variants and shared by patients within the family; 7 of these CNVs had a frequency higher than 0.05. A duplication at 11P15.5 was found involving three mucin-encoding genes (MUC2, MUC5AC, and MUC5B) previously identified as candidate genes for asthma and other chronic inflammatory upper airway diseases. In the validation cohort, no CNVs for MUC2 or MUC5B were identified. However, in the case group, 36.21% of individuals had a duplication of MUC5AC, and 28.03% of controls had MUC5AC duplication (χ2 = 9.123; p = 0.0025). The association of MUC5AC copy number with AR was significant in a multivariable logistic regression after adjusting for age and sex (Padj = 0.0010; OR = 2.073; 95% CI, 1.625-2.805). Real-time PCR validation confirmed duplication of MUC5AC, and the CNV genotype detected with AccuCopy assay was validated for 58 (96.67%) individuals. Furthermore, individuals with a high MUC5AC copy number showed enhanced total blood eosinophil counts in the total sample group and the case group (Spearman's ρ: 0.162, p < 0.001; Spearman's ρ: 0.240, p < 0.001). Conclusions: MUC5AC copy number is associated with AR susceptibility. Additional validation and functional studies are warranted to elucidate the effect of MUC5AC CNV on gene expression and AR risk.