Objective: Genetic polymorphism is partially responsible for the wide variation in the response of moderate-to-severe asthmatic patients to inhaled corticosteroids. The goal of the study was to examine polymorphisms in WDR21A, which encodes a putative glucocorticoid receptor (GR)-interacting protein, for their possible association with corticosteroid responsiveness.
Methods: The change in forced expiratory volume in 1 s [FEV(1) (ΔFEV(1))] induced by 4 weeks of inhaled treatment with fluticasone propionate (1000 µg daily) was measured in 230 asthmatic patients. Fifteen single nucleotide polymorphisms (SNPs) of WDR21A were genotyped using a TaqMan assay, and 11 SNPs were used for further analysis. WDR21A transcripts were analyzed for variant splicing using reverse transcriptase-PCR. The WDR21A protein structure was predicted using a template-based modeling method and docked to a GR using Zdock.
Results: Of the 11 SNPs and three haplotypes of WDR21A analyzed, only the intronic SNP -10073G>C appeared to affect ΔFEV(1). The ΔFEV(1) of the -10073C/C homozygous genotype was twice that of the -10073G/G and -10073C/G genotypes (P(corr)=0.04 in recessive model). No splicing variant of WDR21A was observed, regardless of genotype. The predicted WDR21A protein structure was similar to the Gβ(1) protein structure (template modeling-score=0.93).
Conclusion: The minor allele -10073C of WDR21A may induce a good response to inhaled corticosteroids possibly through competition with the Gβ(1) proteins for binding to GRs.