Skip to main content

Table 1 GWAS analysis of response to ICS

From: Genetic associations of the response to inhaled corticosteroids in asthma: a systematic review

Referernces Genotyping platform and number of SNPs after pruning Discovery phase population Study design and duration Number of asthmatic patients Medication in the discovery phase Replication population Definition of response SNPs chosen for replication (gene, chromosome position) Study outcome
Tantisira et al. [12] Human Hap 550v3 Bead Chip (Illumina) 534 290 SNPs Caucasian children (CAMP) Clinical trial, 16 months 118 child parent trios Budesonide 200 μg twice daily Caucasian patients (n = 935)
Children: (CARE trial, n = 101, fluticasone propionate 100 μg twice daily)
Adults: (Adult study, n = 385, 1000 μg daily (increased up to 2000 μg if necessary)) (LOCCS, n = 185, fluticasone 100 μg twice daily)
(SOCS/SLIC, n = 264, triamcinolone 400 μg twice daily)
Changes in FEV1 from baseline rs37972 (GLCCI1,7p21.3) In two replication populations patients homozygous forthe wild-type allele (C) hadapproximately 12% improvements in FEV1% compared with the 4% increasein TT carriers after 4–8 weeks of treatment with ICS (combined p = 7×10−4)
Tantisira et al. [13] Affymetrix (Santa Clara, CA) using a Human SNP array 6.0
444 088 SNPs
Caucasians children:
(CAMP and CARE trials) (n = 239)
Adults: (ACRN trial) (n = 179)
Clinical trial, 6–8 weeks 418 CAMP: budesonide 200 μg twice daily
CARE: fluticasone propionate 100 μg twice daily
ACRN: Triamcinolone 400 μg twice daily
Adults (n = 407)
Flunisolide 1000 μg once daily (increased to 2000 μg if necessary)
Changes in FEV1% pred from baseline rs3099266, rs1134481 and rs2305089(T gene, 6q27) Patients homozygous for the wild-type allele of all three SNPs had a two to threefold increase in FEV1%pred compared to homozygotes for the mutant allele
Combined p values of study populations for the rs1134481, rs2305089 and rs3099266 were 1.57 × 10−5, 2.3 × 10−4 and 1.1 × 10−4 respectively
Park et al. [14] Human Hap 550v3 Bead Chip or Infinium HD Human610-Quad Bead Chip (Illumina, San Diego, CA) 440 862 SNPs Caucasian children (CAMP) Clinical trial, 8 weeks 124 Budesonide 200 μg twice daily Caucasian Children: (CARE, n = 77, fluticasone propionate 1000 μg daily (increased up to 2000 μg if necessary)) Adults: (LOCCS, n = 110, fluticasone 100 μg twice daily) (ACRN, n = 110, Triamcinolone 400 μg twice daily) Self-reported asthma symptoms based on diary cards. Scores ranged from 0 (absent) to 3 (severe) rs1558726 (RMST,12q21), rs2388639 (LOC728792) and rs10044254 (FBXL7, 5p15.1) The combined p values of rs2388639, rs10044254 and rs1558726 SNPs for the pediatric CAMP and CARE subjects were 8.56 × 10−9, 9.12x10−8 and 1.02x10−5 respectively. Homozygotes for the mutant allele for rs10044254 had significantly poorer responses to treatment compared to the patients homozygous or heterozygous for the wild-type allele (increase of 1.14 (as median score) in homozygotes for the mutant allele versus 0.28 in homozygotes for the reference allele)
Park et al. [15] Illumina Human 660 W BeadChip (Illumina, San Diego, USA) 430 487 SNPs Korean adults with moderate severe asthma Clinical trial, 4 weeks 189 1000 µg of fluticasone propionate daily Same population with the discovery phase Changes in FEV1% 14 SNPs within ALLC (from GWAS) and 11 additional SNPs in ALLC (2q35) rs17017879, rs7558370, rs11123610, rs6754459, rs17445240 and rs13418767 were significantly associated with change in FEV1% (p value < 1.0 × 10−5)
Wang et al. [16] Affymetrix 6.0 arrays 909 622 SNPs
After pruning 266 944 SNPs were involved in the analysis
120 Mild-to-moderate adult asthmatics Clinical trial, each dose of ICS was used for 1 week 120 Inhaled multiple different doses of glucocorticoids-budesonide (125, 250, 500, 1000 mcg), in which, each dose was used for 1 week and the dose was doubled for the subsequent week The IMPACT trial (n: 225, mild, persistent adult asthma, open-label budesonide or prednisone as guided by the symptom-based action plan. The run-in and treatment phases both ended with a 14-day period of intense combined therapy) Salmeterol off corticosteroids (SOCS) and salmeterol ± inhaled corticosteroids (SLIC) trials include 79 and 106 adult asthma,respectively, at the end of the 6-week run-in period on ICS, the milder patients were allocated to SOCS and the more moderate patients allocated to SLIC Changes in FEV1% rs6924808 on chromosome 6
rs10481450 on chromosome 8
rs1353649 on chromosome 11
rs12438740 on chromosome 15
rs2230155 on chromosome 15
The following loci produce associations of genome-wide significancewith physiological response to glucocorticoid therapy;rs6924808 on chromosome 6 with wild-type allele C andmutant T (p = 5.315 × 10−7), rs10481450 on chromosome 8 withwild-type allele A and mutant T (p = 2.614 × 10− 8), rs1353649 on chromosome 11 with wild-type allele G and mutant A (p = 3.924 × 10−9), rs12438740 on chromosome 15 with wild-type allele C and mutant T (p = 4.499 × 10−8), and rs2230155 onchromosome15 with wild-type allele C and mutant T (p = 1.798 × 10− 7)
Dahlin et al. [17] Illumina’sOmni2.5 Exome BeadChip (Illumina, Inc., San Diego, CA) BioVU (731,390 SNPs) PMRP (662,256 SNPs) were firstmergedandprunedtoobtain 740,924 commonautosomalSNPs. In final dataset 237,726 common, independentSNPswereincluded BioVU at VanderbiltUniversityMedical Center in Tennessee Patients had initiated ICS treatment prior to the exacerbation event 806 Caucasian asthmatic
BioVU N = 369
PMRP N = 437
ICS (beclomethasone, budesonide, ciclesonide, flunisolide, mometasone, ortriamcinolone) PersonalizedMedicineResearch Project (PMRP) at theMarshfieldClinic in Wisconsin Asthmaexacerbations CMTR1 rs2395672 rs4271056 rs279728
TRIM24 rs6467778,
MAGI2 rs2691529, rs9303988
Six novel SNPs associated with differential risk of asthma exacerbations (p < 10−5). Rs2395672 in CMTR1, was associated with an increased risk of exacerbations in both populations (OR = 1.07, 95% CI 1.03–1.11; joint p = 2.3X10−6). Two SNPs (rs2395672 and rs279728) were associated with increased risk of exacerbations, four SNPs (rs4271056 (CMTR1), rs6467778 (TRIM24), rs2691529, and rs9303988 MAGI2) were associated with decreased risk
Mosteller et al. [18] 2184 haplotypes from the 1000 Genomes Project > 9.8 million common genetic variants 2672 asthma patients (≥ 12 years)from 7 randomized, double-blind, placebo-controlled, parallel group, multi-center clinical studies in 26 countries “8–12 week” randomized double-blind placebo controlled parallel group multicenter clinical trial 2672 asthma patients (≥ 12 years) Inhaled fluticasone furoate (FF)- or fluticasone propionate (FP) treatment   FEV1change at week 8 and 12 following FF- or FP treatment   No genetic variant met the prespecified threshold for statistical significance
Leusink et al. [67] (Exome array) Infinium Human Exome chip (Illumina, San Diego, CA, USA), version 1.1, which contains 242 902 variants
For common SNP analysis: MAF ≥ 1%, 36,519 SNPs
For rare SNP analysis: MAF < 1%. 24,944 SNPs
CATO study 110 children with asthma that was not well controlled despite ICS 2-year randomized clinical multicenter trial
Participants were followed up for 2 years, with the symptom-free days in the 2 weeks beforeeach visit, FEV1%, airway hyperresponsiveness (AHR) to methacholine (MchPD20) every threemonths. Treatment dosage was adjusted according to the algorithm of the study
110 children with asthma L1-100-μg Fluticasone
L2-200-μg Fluticasone
L3-200-μg Fluticasone and 100-μg salmeterol
L-4 500-μg Fluticasone and 100-μg salmeterol
L5-1000-μg Fluticasone and 100-μg salmeterol
  FEV1%, AHR (Mch PD20) and ICS response outcomes measured by the increase or decrease of FEV1% and AHR   Strongest association for rs72821893 in KRT25 with FEV1% (p = 3.75x105), Mch PD20 (p = 0.00095) and MchPD20-based treatment outcome (p = 0.006)
The 17q12-21 region was found associated with FEV1%pred and AHR, and ICS treatment response
  1. Table adapted from Farzan et al. [10]