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.
Highlights
Aspirin - hypersensitivity refers to development of aspirin-exacerbated respiratory diseases (AERD), and ocular and skin manifestations following ingestion of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) [1]
We performed a genome-wide association studies (GWAS) using the HumanExome BeadChip v1.1 (Illumina Inc.) to identify new genetic variants and, in particular, exonic variants associated with the risk of AERD, and we evaluated the diagnostic potential of these candidate SNPs to predict AERD in Korean patients with asthma
All patients had a history of dyspnea and wheezing in the previous 12 months, plus one of the following: (1) .15% increase in forced expiratory volume in 1 s (FEV1) or .12% increase plus 200 mL following inhalation of a short-acting bronchodilator, (2),10 mg/ mL PC20 methacholine and (3) .20% increase in FEV1 following 2 weeks of treatment with inhaled or systemic corticosteroids and they met the criteria for asthma according to the Global Initiative for Asthma (GINA) guidelines [35]
Summary
Aspirin (acetylsalicylic acid, ASA) - hypersensitivity refers to development of aspirin-exacerbated respiratory diseases (AERD), and ocular and skin manifestations following ingestion of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) [1]. The prevalence of aspirin hypersensitivity in adult asthmatics varies widely depending on whether it is identified by clinical history alone or after challenge with ASA [2]. Based on patients’ histories alone, the incidence of AERD in adults is 38%, but this percentage increases three-fold after ASA challenge via the oral or bronchial route [3]. Identification of aspirin hypersensitivity, especially in hidden cases, is essential to avoid serious bronchospasm attacks in asthmatics. Diagnosis of AERD can be established with certainty only by provocation tests such as Oral aspirin challenge (OAC). OAC is a time-consuming procedure, and in some cases, serious complications can occur. The development of non-invasive diagnostic methods is necessary to prevent the unexpected complications of aspirin use in susceptible patients
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