Exonic variants associated with development of aspirin exacerbated respiratory diseases.
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.
Genome Research Center for Allergy and Respiratory Diseases, Division of Allergy and Respiratory Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Republic of Korea.
Seung-Woo
SW
Shin
Department of Genetic Epidemiology, SNP Genetics Inc., Seoul, Republic of Korea.
Byung Lae
BL
Park
Genome Research Center for Allergy and Respiratory Diseases, Division of Allergy and Respiratory Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Republic of Korea; Department of Interdisciplinary Program in Biomedical Science Major Graduate School of Soonchunhyang University, Asan, Republic of Korea.
HunSoo
H
Chang
Genome Research Center for Allergy and Respiratory Diseases, Division of Allergy and Respiratory Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Republic of Korea.
Jong Sook
JS
Park
Department of Interdisciplinary Program in Biomedical Science Major Graduate School of Soonchunhyang University, Asan, Republic of Korea.
Da-Jeong
DJ
Bae
Department of Interdisciplinary Program in Biomedical Science Major Graduate School of Soonchunhyang University, Asan, Republic of Korea.
Hyun-Ji
HJ
Song
Department of Allergy, Chonnam National University Medical School and Research Institute of Medical Sciences, Gwangju, Republic of Korea.
Inseon S
IS
Choi
Division of Allergy, Department of Internal Medicine, Chungbuk National University, Cheongju, Republic of Korea.
Mi-Kyeong
MK
Kim
Department of Allergy & Clinical Immunology, Ajou University Hospital, Suwoon, Republic of Korea.
Hea-Sim
HS
Park
Department of Genetic Epidemiology, SNP Genetics Inc., Seoul, Republic of Korea; Department of Life Science, Sogang University, Seoul, Republic of Korea.
Lyoung Hyo
LH
Kim
Department of Genetic Epidemiology, SNP Genetics Inc., Seoul, Republic of Korea; Department of Life Science, Sogang University, Seoul, Republic of Korea.
Suhg
S
Namgoong
Department of Genetic Epidemiology, SNP Genetics Inc., Seoul, Republic of Korea; Department of Life Science, Sogang University, Seoul, Republic of Korea.
Ji On
JO
Kim
Department of Genetic Epidemiology, SNP Genetics Inc., Seoul, Republic of Korea; Department of Life Science, Sogang University, Seoul, Republic of Korea.
Hyoung Doo
HD
Shin
Genome Research Center for Allergy and Respiratory Diseases, Division of Allergy and Respiratory Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Republic of Korea.
Choon-Sik
CS
Park
D000293:Adolescent; D000328:Adult; D000368:Aged; D055963:Asthma, Aspirin-Induced / Q000175:diagnosis / Q000235:genetics*; D018450:Disease Progression; D005091:Exons; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012372:ROC Curve; D012307:Risk Factors; D055815:Young Adult