Exonic variants associated with development of aspirin exacerbated respiratory diseases

PLoS One. 2014 Nov 5;9(11):e111887. doi: 10.1371/journal.pone.0111887. eCollection 2014.

Abstract

Aspirin-exacerbated respiratory disease (AERD) is one phenotype of asthma, often occurring in the form of a severe and sudden attack. Due to the time-consuming nature and difficulty of oral aspirin challenge (OAC) for AERD diagnosis, non-invasive biomarkers have been sought. The aim of this study was to identify AERD-associated exonic SNPs and examine the diagnostic potential of a combination of these candidate SNPs to predict AERD. DNA from 165 AERD patients, 397 subjects with aspirin-tolerant asthma (ATA), and 398 normal controls were subjected to an Exome BeadChip assay containing 240K SNPs. 1,023 models (210-1) were generated from combinations of the top 10 SNPs, selected by the p-values in association with AERD. The area under the curve (AUC) of the receiver operating characteristic (ROC) curves was calculated for each model. SNP Function Portal and PolyPhen-2 were used to validate the functional significance of candidate SNPs. An exonic SNP, exm537513 in HLA-DPB1, showed the lowest p-value (p = 3.40×10-8) in its association with AERD risk. From the top 10 SNPs, a combination model of 7 SNPs (exm537513, exm83523, exm1884673, exm538564, exm2264237, exm396794, and exm791954) showed the best AUC of 0.75 (asymptotic p-value of 7.94×10-21), with 34% sensitivity and 93% specificity to discriminate AERD from ATA. Amino acid changes due to exm83523 in CHIA were predicted to be "probably damaging" to the structure and function of the protein, with a high score of '1'. A combination model of seven SNPs may provide a useful, non-invasive genetic marker combination for predicting AERD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Asthma, Aspirin-Induced / diagnosis
  • Asthma, Aspirin-Induced / genetics*
  • Disease Progression
  • Exons*
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Genetic Variation*
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • ROC Curve
  • Risk Factors
  • Young Adult

Associated data

  • GEO/GSE61129

Grants and funding

This study was supported by a grant from the Korea Healthcare Technology R& D Project, Ministry for Health, Welfare & Family Affairs, and Republic of Korea (HI13C0319). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.