Association between WDR21A polymorphisms and airway responsiveness to inhaled corticosteroids in asthmatic patients

초록

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 [FEV1 (Delta FEV1)] induced by 4 weeks of inhaled treatment with fluticasone propionate (1000 mu g 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 Delta FEV1. The Delta FEV1 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 G beta(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 G beta(1) proteins for binding to GRs. Pharmacogenetics and Genomics 22:327-335 (C) 2012 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

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