Genetic predictors associated with improvement of asthma symptoms in response to inhaled corticosteroids

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• 作者：Heung-Woo Park ; MD ; PhD^a ; ^b ; Amber Dahlin ; PhD ; MMSc^a ; Szeman Tse ; MDCM ; MPH^a ; Qing Ling Duan ; PhD^a ; Brooke Schuemann ; BS^a ; Fernando D. Martinez ; MD^c ; Stephen P. Peters ; MD ; PhD^d ; Stanley J. Szefler ; MD^e ; John J. Lima ; PharmD^f ; Michiaki Kubo ; MD ; PhD^g ; Mayumi Tamari ; MD ; PhD^g ; Kelan G. Tantisira ; MD ; MPH^a ; ^h ; ^{kelan.tantisira@channing.harvard.edu" class="auth_mail}
• 关键词：Asthma ; child ; glucocorticoid ; pharmacogenomics ; polymorphism
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：March, 2014
• 年：2014
• 卷：133
• 期：3
• 页码：664-669.e5
• 全文大小：841 K

文摘

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Background

To date, genome-wide association studies (GWASs) of inhaled corticosteroid (ICS) response in asthmatic patients have focused primarily on lung function and exacerbations.

Objective

We hypothesized that GWAS analysis could identify novel genetic markers predicting a symptomatic response to ICSs.

Methods

We analyzed differences in asthma symptoms in response to ICSs in 124 white children from the Childhood Asthma Management Program (CAMP) trial using scores from diary cards. Of the 440,862 single nucleotide polymorphisms (SNPs) analyzed, the top 100 ranked SNPs were pursued for replication initially in subjects from the pediatric Childhood Asthma Research and Education trials (77 white children) and then in subjects from the adult Asthma Clinical Research Network (110 white adults) and Leukotriene Modifier or Corticosteroid or Corticosteroid-Salmeterol trials (110 white adults).

Results

The lowest P value for GWAS analysis in the CAMP trial was 8.94 脳 10^鈭? (rs2388639). Of the 60 SNPs available in the Childhood Asthma Research and Education Network trials, rs1558726 (combined P聽= 1.02 脳 10^鈭?), rs2388639 (combined P聽= 8.56 脳 10^鈭?), and rs10044254 (combined P聽= 9.16 脳 10^鈭?) independently replicated. However, these 3 SNPs were not additionally replicated in the adult asthmatic patients of the remaining trials. rs10044254 lies in the intronic region of F-box and leucine-rich repeat protein 7 (FBXL7) and is associated with decreased expression in immortalized B cells derived from CAMP participants.

Conclusions

We have identified a novel SNP, rs10044254, associated with both decreased expression of FBXL7 and improved symptomatic response to ICSs in 2 independent pediatric cohorts. Our results suggest that there might be a specific genetic mechanism regulating symptomatic response to ICSs in children that does not carry over to adults.