Dual-specificity phosphatase 1 as a pharmacogenetic modifier of inhaled steroid response among asthmatic patients

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• 作者：Ying Jin ; Donglei Hu ; Edward L. Peterson ; Celeste Eng ; Albert M. Levin ; Karen Wells ; Kenneth Beckman ; Rajesh Kumar ; Max A. Seibold ; Gloria Karungi ; Am ; a Zoratti ; John Gaggin ; Janis Campbell ; Joshua Ga
• 关键词：Asthma ; inhaled corticosteroids ; dual-specificity phosphatase 1 ; DUSP1 ; corticosteroid responsiveness
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2010
• 出版时间：September 2010
• 年：2010
• 卷：126
• 期：3
• 页码：618-625.e2
• 全文大小：562 K

文摘

Background

Inhaled corticosteroids (ICSs) are considered first-line treatment for persistent asthma, yet there is significant variability in treatment response. Dual-specificity phosphatase 1 (DUSP1) appears to mediate the anti-inflammatory action of corticosteroids.

Objective

We sought to determine whether variants in the DUSP1 gene are associated with clinical response to ICS treatment.

Methods

Study participants with asthma were drawn from the following multiethnic cohorts: the Genetics of Asthma in Latino Americans (GALA) study; the Study of African Americans, Asthma, Genes & Environments (SAGE); and the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE). We screened GALA study participants for genetic variants that modified the relationship between ICS use and bronchodilator response. We then replicated our findings in SAGE and SAPPHIRE participants. In a group of SAPPHIRE participants treated with ICSs for 6 weeks, we examined whether a DUSP1 polymorphism was associated with changes in FEV₁ and self-reported asthma control.

Results

The DUSP1 polymorphisms rs881152 and rs34507926 localized to different haplotype blocks and appeared to significantly modify the relationship between ICS use and bronchodilator response among GALA study participants. This interaction was also seen for rs881152 among SAPPHIRE but not SAGE participants. Among the group of SAPPHIRE participants prospectively treated with ICSs for 6 weeks, rs881152 genotype was significantly associated with changes in self-reported asthma control but not FEV₁.

Conclusion

DUSP1 polymorphisms were associated with clinical response to ICS therapy and therefore might be useful in the future to identify asthmatic patients more likely to respond to this controller treatment.