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

Ying Jin, Donglei Hu, Edward L. Peterson, Celeste Eng, Albert M. Levin, Karen Wells, Kenneth Beckman, Rajesh Kumar, Max A. Seibold, Gloria Karungi, Amanda Zoratti, John Gaggin, Janis Campbell, Joshua Galanter, Rocío Chapela, José R. Rodríguez-Santana, H. Geoffrey Watson, Kelley Meade, Michael Lenoir, William Rodríguez-CintrónPedro C. Avila, David E. Lanfear, Esteban G. Burchard, L. Keoki Williams

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)618-625.e1-e2
JournalJournal of Allergy and Clinical Immunology
Volume126
Issue number3
DOIs
StatePublished - Sep 2010

Bibliographical note

Funding Information:
Supported by grants from the American Asthma Foundation Strategic Program for Asthma Research, the National Institutes of Health ( AI079139, AI061774, HL079055, and DK064695 ), and the Fund for Henry Ford Hospital to L. K. W. and the National Institutes of Health ( HL078885, AI077439, HL088133, U01 GM61390, ES015794 ) and the Flight Attendant Medical Research Institute (FAMRI) to E. G. B.

Funding Information:
Disclosure of potential conflict of interest: E. L. Peterson has received research support from the National Institutes of Health . R. Kumar has received research support from the National Institutes of Health/National Heart, Lung, and Blood Institute . J. R. Rodriguez-Santana has received research support from GlaxoSmithKline . W. Rodríguez-Cintrón has received research support from the University of California at San Francisco and Sociedad de Investigacion Cientifica, Inc , and is a member of the Scientific Committee of the American College of Chest Physicians. P. C. Avila has received research support from Genentech/Roche . D. E. Lanfear has received research support from Episource and the National Institutes of Health .

Keywords

  • Asthma
  • DUSP1
  • corticosteroid responsiveness
  • dual-specificity phosphatase 1
  • inhaled corticosteroids

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