Pharmacogenetics of asthma controller treatment

Abstract

The interpatient variability in response to asthma controllers is significant and associates with pharmacogenomic variability. The goal of the present study was to identify novel variants that associate with response to common asthma controllers: fluticasone, combination of fluticasone + salmeterol and montelukast with single nucleotide polymorphisms (SNPs) in β2-adrenergic receptor, corticosteroid and leukotriene pathway candidate genes. Participants in a large clinical trial of step-down strategies volunteered for this pharmacogenetic study. 169 SNPs in 26 candidate genes were genotyped in 189 Caucasian participants with asthma who took either fluticasone (100 μg bid), fluticasone (100 μg) + salmeterol (50 μg) (FP/Salm) or montelukast (5 or 10 mg) each night for 16 weeks. Primary outcomes were the slopes of plots of Asthma Control Questionnaire (ACQ) scores vs. time following randomization; and the percent change in percent predicted FEV1 (ΔFEV1%pred) from enrollment to the end of the study. Associations between SNPs and outcomes were analyzed using general linear models. False Discovery Rate and Bonferroni corrections were used to correct for multiple comparisons. In all, 16 SNPs in seven genes were significantly associated with outcomes. For FP/Salm, 3 SNPs in CHRM2 associated with ACQ slope (p=2.8×10−5), and rs1461496 in HSPA8 associated with ΔFEV1%pred. For fluticasone, 5 SNPs in CRHR1 (p=1.9×10−4), and 3 SNPs in COL2A1 associated with ACQ slope and ΔFEV1%pred, respectively. For montelukast, 4 SNPs in CHRM2 associated with ΔFEV1%pred and predicted an opposite effect compared to fluticasone (p=9×10−3). The present study indentified several novels SNPs that associate with response to common asthma controllers and support further pharmacogenomic study and the use of genetic variants to personalize asthma treatment.

Treatment response heterogeneity in asthma: the role of genetic variation

“…Nevertheless, smaller studies by Mougey et al (n = 65 patients) [46] and Kotani et al (n=21 patients) [61] did not find any pharmacogenetics effect of this variant in studies with montelukast.…”

“…It has been hypothesized that variation in this gene influences the level of endogenous corticosteroid secretion and thereby alters the response to ICS. Several SNPs in this gene have been studied and two variants have been replicated at least once [30,46,47] in independent populations of children and adults with asthma; however, results have been inconsistent [48].…”

Frequency of polymorphic variants in CRHR1, GLCCI1 and FCER2 genes in healthy and asthmatic Tamilian population

“…Five markers in CRHR1 (rs 242941, rs 739645, rs 1876831, rs 1876829 and rs 1876828) showed significant association with change in % predicted of Forced Expiratory Volume in 1second (∆FEV1%pred), wherein rs242941 was associated with decreased FEV1%pred. 12 Moreover, rs 242941 was also studied as a biomarker for susceptibility to major depressive disorder (MDD) and fluoxetine response variation among Americans, Mexican-Americans and Chinese. [13][14][15][16][17] GLCCI1 gene (Glucocorticoid induced 1; Chromosomal locus: 7p21.3; NCBI Gene ID: 113263) with eight exons encodes a protein of unknown function which has induced expression by glucocorticoids.…”

“…7 Reported MAF of rs 242941 ('T') among Caucasian, Greece, Korean and North Indian populations were 0.34, 0.28, 0.08 and 0.26, respectively. 11,12,27 From above stated studies on genetic association with ICS response rate, it can be assumed that, carriers of rs 37972 ('T'), rs 28364072 ('G') and rs 242941 ('T') are associated with either decrement or no improvement in lung function in spite of treatment, thus poorly responding to ICS. From the present study findings we conclude that, minor allele frequencies of rs 242941, rs 28364072 and rs37972 were 0.51, 0.33 and 0.38, respectively in Tamilian population which were significantly different from various global populations.…”

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

“…11,12 Traditional measures (eg, self-reported symptoms) are important to diagnose and monitor response to asthma treatment. 2,3,15,16 However, there have been few pharmacogenomic studies focusing on self-reported asthma symptoms, 17,18 although self-reported asthma symptoms account for a substantial proportion of the clinical measures of treatment response. 19,20 Therefore we performed a genome-wide association study (GWAS) with the hypothesis that we could identify novel genetic markers predicting symptomatic response to ICSs in asthmatic patients.…”