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Exonic variants associated with development of aspirin exacerbated respiratory diseases.

Shin SW, Park BL, Chang H, Park JS, Bae DJ, Song HJ, Choi IS, Kim MK, Park HS, Kim LH, Namgoong S, Kim JO, Shin HD, Park CS - PLoS ONE (2014)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Genome Research Center for Allergy and Respiratory Diseases, Division of Allergy and Respiratory Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Republic of Korea.

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.

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QQ-plot analysis of 54,555 SNPs between for 165 AERD vs. 397 ATA.
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pone-0111887-g001: QQ-plot analysis of 54,555 SNPs between for 165 AERD vs. 397 ATA.

Mentions: Firstly, we defined the cut-off value of call rate as 97%. Then genotype clusters for 500 variants showing call rate nearby 97% (500 above 97%) were plotted using GenomeStudio (Illumina, Inc., San Diego, CA, USA) software optimized for Korean population. In this study, among 242,985 SNPs displayed on the chip, 1,132 SNPs with call rate <97% and with poor cluster quality were removed. Among the remaining 241,853 SNPs, we checked MAF and removed additional 187,298 SNPs which were monomorphic in our study subjects. Finally, a total 54,555 autosomal SNPs were used for further statistical analysis. The overall call rate for all SNPs was 99.91% and only 6,878 SNPs among the 545,555 SNPs (12.6%) were found to have a MAF<1%. The result of the MDS (multidimensional scaling) plot analysis showed there was no the population substructure (Figure S1). These SNPs were then used for association analysis with AERD under the additive mode using logistic regression and because age, smoking and BMI were significantly different between the two groups in the present and other studies [36], [40], [41], and because female are predominant [42], [43] and Atopy is lower in AERD than general asthma [44]. All these parameters were used as covariate. The comparison between the observed and the expected association p-values in the quantile-quantile (Q-Q) plot revealed that λ value was 1.0013 (Fig. 1). The data discussed has been deposited in NCBI’s Gene Expression Omnibus [45] and is accessible through GEO Series accession number GSE61129 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE61129).


Exonic variants associated with development of aspirin exacerbated respiratory diseases.

Shin SW, Park BL, Chang H, Park JS, Bae DJ, Song HJ, Choi IS, Kim MK, Park HS, Kim LH, Namgoong S, Kim JO, Shin HD, Park CS - PLoS ONE (2014)

QQ-plot analysis of 54,555 SNPs between for 165 AERD vs. 397 ATA.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4221198&req=5

pone-0111887-g001: QQ-plot analysis of 54,555 SNPs between for 165 AERD vs. 397 ATA.
Mentions: Firstly, we defined the cut-off value of call rate as 97%. Then genotype clusters for 500 variants showing call rate nearby 97% (500 above 97%) were plotted using GenomeStudio (Illumina, Inc., San Diego, CA, USA) software optimized for Korean population. In this study, among 242,985 SNPs displayed on the chip, 1,132 SNPs with call rate <97% and with poor cluster quality were removed. Among the remaining 241,853 SNPs, we checked MAF and removed additional 187,298 SNPs which were monomorphic in our study subjects. Finally, a total 54,555 autosomal SNPs were used for further statistical analysis. The overall call rate for all SNPs was 99.91% and only 6,878 SNPs among the 545,555 SNPs (12.6%) were found to have a MAF<1%. The result of the MDS (multidimensional scaling) plot analysis showed there was no the population substructure (Figure S1). These SNPs were then used for association analysis with AERD under the additive mode using logistic regression and because age, smoking and BMI were significantly different between the two groups in the present and other studies [36], [40], [41], and because female are predominant [42], [43] and Atopy is lower in AERD than general asthma [44]. All these parameters were used as covariate. The comparison between the observed and the expected association p-values in the quantile-quantile (Q-Q) plot revealed that λ value was 1.0013 (Fig. 1). The data discussed has been deposited in NCBI’s Gene Expression Omnibus [45] and is accessible through GEO Series accession number GSE61129 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE61129).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Genome Research Center for Allergy and Respiratory Diseases, Division of Allergy and Respiratory Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Republic of Korea.

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.

Show MeSH
Related in: MedlinePlus