Table 1.
GWAS analysis of response to ICS
| 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 = 3.75x10−5), 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 |
Table adapted from Farzan et al. [10]