Exonic Variants Associated with Development of Aspirin Exacerbated Respiratory Diseases

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.

The Genetics of Drug Hypersensitivity Reactions

“…In this sense, a recent genome-wide methylation study on nasal polyps found a differential pattern in patients with NSAID-induced DHRs [133], and a set of 2 gene markers has been proposed to discriminate NERD from aspirin-tolerant asthma [134]. Exome sequencing has also been used to identify variants associated with hypersensitivity to NSAIDs [135].…”

Genetic and Epigenetic Components of Aspirin-Exacerbated Respiratory Disease

“…Three additional exonic SNPs on HLA-DPB1 (exm537513, exm537522 and exm537523) were also present among the top 20 SNPs. A prior GWAS 77 had identified exm537522 (also annotated as rs1042151 in that study) as having the strongest association with AERD susceptibility; therefore, the authors replicated one of their top associations from a previous study 76 . To develop a predictive model for AERD risk, the authors selected the best combination of the top 10 SNPs that could discriminate between AERD and ATA, using multiple logistic regression, and calculated ROC curves and AUC values for each combination model 76 .…”

“…Shin et al recently used an exome-wide profiling approach using the HumanExome BeadChip v1.1 (Illumina Inc.) to identify novel, rare and exonic SNPs associated with AERD status in 165 AERD patients, 397 patients with ATA, and 398 normal controls of Korean ancestry 76 . After filtering and quality control of genotype data, over 54,000 SNPs remained and were evaluated for association with AERD risk 76 . A SNP in HLA-DPB1 , exm537513, achieved genome-wide significance and was associated with increased risk of AERD (OR: 3.28, p -value of 3.4×10 −8 ) 76 .…”

“…After filtering and quality control of genotype data, over 54,000 SNPs remained and were evaluated for association with AERD risk 76 . A SNP in HLA-DPB1 , exm537513, achieved genome-wide significance and was associated with increased risk of AERD (OR: 3.28, p -value of 3.4×10 −8 ) 76 . From the top 100 SNP associations, the p -values of remaining top 10 SNPs ranged from 3.4×10 −8 to 2.4×10 −4 with ORs from 0.13 to 13.61 76 .…”

“…A SNP in HLA-DPB1 , exm537513, achieved genome-wide significance and was associated with increased risk of AERD (OR: 3.28, p -value of 3.4×10 −8 ) 76 . From the top 100 SNP associations, the p -values of remaining top 10 SNPs ranged from 3.4×10 −8 to 2.4×10 −4 with ORs from 0.13 to 13.61 76 . Three additional exonic SNPs on HLA-DPB1 (exm537513, exm537522 and exm537523) were also present among the top 20 SNPs.…”