A genome-wide association study of bronchodilator response in asthmatics

Q L Duan, J Lasky-Su, B E Himes, W Qiu, A A Litonjua, A Damask, R Lazarus, B Klanderman, C G Irvin, S P Peters, J P Hanrahan, J J Lima, F D Martinez, D Mauger, V M Chinchilli, M Soto-Quiros, L Avila, J C Celedón, C Lange, S T Weiss, K G Tantisira, Q L Duan, J Lasky-Su, B E Himes, W Qiu, A A Litonjua, A Damask, R Lazarus, B Klanderman, C G Irvin, S P Peters, J P Hanrahan, J J Lima, F D Martinez, D Mauger, V M Chinchilli, M Soto-Quiros, L Avila, J C Celedón, C Lange, S T Weiss, K G Tantisira

Abstract

Reversibility of airway obstruction in response to β2-agonists is highly variable among asthmatics, which is partially attributed to genetic factors. In a genome-wide association study of acute bronchodilator response (BDR) to inhaled albuterol, 534 290 single-nucleotide polymorphisms (SNPs) were tested in 403 white trios from the Childhood Asthma Management Program using five statistical models to determine the most robust genetic associations. The primary replication phase included 1397 polymorphisms in three asthma trials (pooled n=764). The second replication phase tested 13 SNPs in three additional asthma populations (n=241, n=215 and n=592). An intergenic SNP on chromosome 10, rs11252394, proximal to several excellent biological candidates, significantly replicated (P=1.98 × 10(-7)) in the primary replication trials. An intronic SNP (rs6988229) in the collagen (COL22A1) locus also provided strong replication signals (P=8.51 × 10(-6)). This study applied a robust approach for testing the genetic basis of BDR and identified novel loci associated with this drug response in asthmatics.

Conflict of interest statement

Conflict of Interest

None declared.

Figures

Figure 1
Figure 1
An overview of the genome-wide analyses methods and replication strategies used. The initial GWAS in CAMP applied five statistical models (linear regression of BDR at randomization in 403 asthmatics using additive and recessive models, longitudinal mixed models of 11 repeated BDR measures in 171 probands using additive and recessive models, and a family-based association test of BDR at randomization in 403 trios). A total of 1536 SNPs providing p-values

Figure 2

The distribution of BDR at…

Figure 2

The distribution of BDR at randomization across all asthma trial populations. BDR is…

Figure 2
The distribution of BDR at randomization across all asthma trial populations. BDR is defined as a percent change in lung function (FEV1) in response to inhaled albuterol across all asthma trial populations.

Figure 3

Manhattan plot of –Log 10…

Figure 3

Manhattan plot of –Log 10 (p-value) for the FBAT analysis of BDR using…

Figure 3
Manhattan plot of –Log10(p-value) for the FBAT analysis of BDR using 403 parent-offspring trios with 534,290 SNPs. Similar plots were generated for the other four statistical models. The analysis was adjusted for age, gender, height, and baseline preFEV1.
Figure 2
Figure 2
The distribution of BDR at randomization across all asthma trial populations. BDR is defined as a percent change in lung function (FEV1) in response to inhaled albuterol across all asthma trial populations.
Figure 3
Figure 3
Manhattan plot of –Log10(p-value) for the FBAT analysis of BDR using 403 parent-offspring trios with 534,290 SNPs. Similar plots were generated for the other four statistical models. The analysis was adjusted for age, gender, height, and baseline preFEV1.

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