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

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 FEV(1) 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 FEV(1).

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.

Figure 1. Chromosomal and DUSP1 position of single nucleotide polymorphisms assessed

Polymorphism positions are indicated with the blue triangles. Exons are shown in yellow, untranslated (UTL) regions in gray, and introns as the connecting lines. The 3’ UTL is denoted by the pointed end. DUSP1 denotes dual specificity phosphatase-1.

Figure 2. Relationship between DUSP1 genotype rs881152 and bronchodilator responsiveness among individuals in the SAPPHIRE cohort, stratified by inhaled corticosteroid (ICS) use

Bronchodilator responsiveness was measured as the percentage change in pre- and post-bronchodilator FEV₁ at the initial screening visit for individuals in the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE). Concurrent ICS use at the time of this screening was determined from patient report and from pharmacy claims. The number of individuals with the rs881152 genotypes GG, AG, and AA were 239, 125, and 21, respectively among those without concurrent ICS use, and 26, 17, and 2, respectively among those currently using ICS medication.

Figure 3. Relationship between DUSP1 genotype rs881152 and inhaled corticosteroid (ICS) responsiveness among the subgroup of individuals treated as part of SAPPHIRE

Inhaled corticosteroid responsiveness was measured both as the percentage change in pre-bronchodilator FEV₁ (A) and the change in asthma control (B) between the initial screening visit and following 6 weeks of ICS treatment. The change in asthma control was measured as the absolute difference in Asthma Control Test (ACT) score at these two time points. The number of individuals with rs881152 genotypes GG, AG, and AA were 88, 63, and 10, respectively, for the analysis looking at percentage change in pre-bronchodilator FEV₁. The number of individuals with rs881152 genotypes GG, AG, and AA were 86, 63, and 10, respectively, for the analysis looking at the change in ACT score. As shown in Table 4, the P-values for the association between rs881152 genotype (i.e., coded GG=0, AG=1, and AA=2) and both FEV₁ change (A) and ACT score change (B) were 0.981 and 0.011, respectively. DUSP1 denotes dual specificity phosphatase-1.