Table 2 Replicated genes of ICS pharmacogenomic studies

Tantisira et al. [49]

131 SNPs genotyped in 14 candidate genes in the steroid pathway

 ALOX15 (4 SNPs)

 CRH (4 SNPs)

 CRHBP (5 SNPs)

 CRHR1 (17 SNPs)

 FCER2 (15 SNPs)

 GATA3 (9 SNPs)

 HSD11B1 (10 SNPs)

 IL18BP (7 SNPs)

 MAPK8 (4 SNPs)

 NFATC4 (11 SNPs)

 NR3C1 (16 SNPs)

 POMC (6 SNPs)

POMC (6STAT3 (10 SNPs)

POMC (6STAT5A (10 SNPs)

Caucasian children and adults:

 Adult study (Adults, n = 415)

 CAMP (Children, n = 201)

 ACRN (Adults, n = 224)

Three independent 6–8 week clinical trials

rs242941

0.3 (T)

rs1876828 (T)

Flunisolide 1000–2000 μg once daily

Budesonide 200 μg twice daily

Tramcinolone acetonide 400 μg twice daily

Changes in FEV1% from baseline

(CRHR1, NM_004382), was associated with treatment response in all three populations

Individuals homozygous for the variants manifested a doubling to quadrupling of the lung function response to ICS compared with lack of the variants (p values ranging from 0.006 to 0.025 for three asthmatic populations). rs1876828, rs242939, and rs242941, were each associated with ICS treatment response in both the Adult Study and CAMP. rs1876828, was also strongly associated with improved FEV1 over the 6-week triamcinolone treatment in ACRN adult asthmatics

Dijkstra et al. [50]

CRHR1(17q21.31)

 rs1876828

 rs242939

 rs242941

281 adult patients with symptomatic asthma under 45 years of age

Asthma cohort followed for 22 years, clinical trial (Netherland)

rs242941

0.4 (T)

rs1876828

0.2 (T)

749 μg/days (426–1152)

Mean daily dose of ICS was calculated to an equivalent daily dose of beclomethasone.

Immediate effect:

 Changes in FEV1

from baseline within 3–6 months

Long-term effect:Rate of decline in FEV1

 annually during 13.0 (7–19) years

CRHR1 polymorphisms are not associated with immediate or long-term improvement in FEV1 by ICSs or with prevention of accelerated FEV1 decrease in adult asthma

Rogers et al. [51]

CRHR1-rs242941

FCER2-T2206C

311 children (5–12 years)

African-American and Caucasian

Children (CAMP)

CAMP 4-year clinical trial

CRHR1 rs242941

0.26 (T)

FCER2 T2206C

0.26 (G) in Caucasians, 0.44 (G) in African-Americans

Budesonide 200 μg twice daily

Exacerbations:

Emergency Department visits

Hospitalizations

Oral prednisone burst

 Lung function measurements:

  poor responders:change in FEV1 %pred: ≤ 7.5%

Lower bronchodilator response to albuterol and the minor alleles of RS242941 in CRHR1 (OR 1.6, CI 95% 1–2.7, p = 0.05) and T2206C in FCER2 (OR: 2.1, 95%CI 1.2–3.5, p = 0.006) are associated with poor lung function response

The minor allele of rs28364072 in FCER2 was associated with recurrent exacerbations in white subjects (OR: 1.9 for minor allele, p < 0.05) but it did not reach significance in multivariate analysis

Mougey et al. [52]

CRHR1 (17q21.31)

 rs1876828

 rs242941

Caucasian children, adolescence and adults continuing ICS (n = 65)

16 weeks Clinical trial

rs242941

0.34 (T)

rs1876828

0.15 (T)

Fluticasone

100 μg twice daily

Change in FEV1% pred

Asthma symptoms:

Slopes of plots of ACQ scores versus time

Minor allele of rs1876828 was associated with improvements in FEV1% pred (p = 1.89 × 10⁻⁴)

Minor allele of rs242941 was associated with decrement in FEV1% pred (p = 2.07 × 10⁻³)

Keskin et al. [43]

NR3C1(rs41423247)

CRHR1(rs242939, rs242941, rs1876828)

TBX21

(rs2240017)

GLCCl1 (rs37973, rs3099266, rs2305089)

82 children with asthma exacerbation

Single high dose ICS study in children with moderate-severe asthma exacerbation, Clinical trial

NR3C1

rs41423247 0.8 (G)

CRHR1

rs242939 0.08 (G)

rs242941 0.27 (T)

rs1876828 0.87 (G)

TBX21

rs2240017 0.04 (G)

GLCCl1

rs37973 0.47 (G)

rs3099266 0.39 (A)

rs2305089 0.35 (A)

Single-dose Inhaled 4000 mcg Fluticasone propionate

+Nebulized albuterol solution

Changes in FEV1 at 4th hour

Homozygosity for the G allele at rs41423247 of the NR3C1 gene is associated with a higher improvement in FEV1 at 4 h in children with moderate-to-severe asthma exacerbation treated with high-dose ICS (p = 0.006)

No genotype-related significant difference was observed in SNPs CRHR1 gene rs242939, s242941,and rs1876828, TBX21 rs2240017; GLCCl1 rs37973; and T gene rs3099266 and rs2305089 in FEV1 change

Hosking et al. [53]

GLCCI1 (7p21.3)

Rs37973 (A/G)

Non-Hispanic white adolescents and adults (n = 1916)

Pooled data of seven studies, six studies of 8 week trials and one 12-week clinical trial

0.44 (G)

Various doses of Fluticasone furoate ranged between 25 and 800 μg daily, Fluticasone propionate 100–500 μg twice daily

Changes in FEV1 from baseline after 8 weeks in 6 studies and at week 12 in one study

There was no significant association between changes in FEV1 and rs37973 genotypes

Izuhara et al. [54]

GLCCI1 (7p21.3)

Rs37973 (A/G)

Adult Japanese (n = 224)

Asthma cohort receiving ICS fot at least 4 years

0.44 (G)

ICS maintenance dose varied between patients

Annual decline in FEV1 30 ml/year or more

rs37973 GG was associated with a decline in FEV1 of 30 ml/year or more (estimated effect: 1.10: 0.02 to 2.18, p = 0.047)

There was no association between rs37973 genotypes and the outcome, when decline in FEV1 was analyzed as a continuous variable

Vijverberget al. [55]

GLCCI1 (7p21.3)

Rs37972 (T/C)

North European children and young adults

BREATHE (n = 1037)

PACMAN (n = 431)

PAGES (n = 323)

Meta-analysis of three pediatric asthma cohorts

BREATH:0.45 (T)

PACMAN: 0.44 (T)

PAGES: 0.41(T)

ICS maintenance dose varied between patients

Exacerbations:

 Hospital visits

 OCS use

Poor asthma symptoms:

 ACT scores ≤ 19

 ACQ-scores ≥ 1.5

There was no significant association between increased risk of OCS use, increased risk of asthma exacerbations and rs37972 genotypes

Hu et al. [23]

GLCCI1 (7p21.3)

Rs37972 (T/C)

Rs11976862, (A/G)

Rs37973 (A/G)

Chinese population of 182 asthmatic patients and 180 healthy controls

The association of GLCCI1 variations with ICS response was analyzed in 30 mild-to-moderate asthmatics

Case control: study 24 SNPs of GLCCI1 were genotyped in 182 asthmatic patients and 180 healthy controls. –Treatment trial: 2-week run-in period and maintanance ICS therapy for 12 weeks.

Rs37972 (T/C) Asthmatics:0.67 (T) Control: 0.12 (T)

Rs11976862

Asthmatics: 0.07 (G) Control: 0.37 (G)

Rs37973 Asthmatics: 0.55 (G), Control: 0.37 (G)

Inhaled fluticasone propionate (125 mg, twice a day)

Changes in FEV1

FEV1 change was significantly correlated with rs37972, rs37973 and rs11976862 at 4 weeks ICS (p = 0.021 for rs37972 and rs37973; p = 0.043 for rs11976862), at 8 weeks (p = 0.021, p = 0.025 and p = 0.035, respectively) and at 12 weeks (p = 0.040 for rs37972 and rs37973, p = 0.020 for rs11976862)

Xu et al. [44]

GLCCI1 (7p21.3)

Rs37973 (A/G)

Chinese population of 418 asthmatics

Inhaled fluticasone propionate/salmeterol combination (250/50 mg, twice daily) for the next 24 weeks. Follow-up visits occurred at 4, 12, and 24 weeks, and asthma control tests were reviewed and lung function tests were performed

0.49 (G)

Long term ICS treatment

Changes in FEV1

rs37973 was independently associated with poorer clinical therapeutic response to ICS

Homozygotes for the wild-type allele who had a percent FEV1 change greater than 5% were more common than were homozygotes of the rare allele (rs37973, AA 67.01% vs. GG 49.49%, p < .05)

Rijavec et al. [45]

GLCCI1 (7p21.3)

Rs37973 (A/G)

208 Slovenian adults with atopic and nonatopic, mild-to-moderate persistent asthma

ICS (alone or in combination with a LABA, depending on the degree of asthma control

Follow-up visits with spirometry testing after 3 months (short-term) and after at least 3 years (long-term) of ICS treatment

0.29 (G)

ICS or ICS + LABA, depending on the degree of asthma control

FEV1% change after ICS treatment (3 months) and at least 3 years

Treatment was defined as successful when FEV1 decreased by < 30 mL/year

After 3 months of ICS treatment, the change in FEV1% was higher in patients with the GG genotype than in patients with the AG + AA genotype (7.5% vs. 4%, p = .049)

Szczepankiewicz et al. [56]

GR polymorphisms

 rs6190

 rs41423247

 rs6195

 rs10052957

113 asthmatic children (6 to 18 years of age) (54 of children were with severe, difficult-to-treat asthma)

123 healthy control

Analysis of a relationship between the GR polymorphisms and poor response to glucocorticoids in asthmatic patients (Polish)

rs6190

0.03 (G)

rs41423247

0.36 (G)

rs10052957

0.39 (T)

rs6195

0.08 (G)

ICS

The dose of ICS needed to achieve asthma control

Worse response was defined as a necessity of taking high doses of

ICS i.e. > 800 mcg of budesonide and > 500 mcg of fluticasone

propionate

No association of GR polymorphisms with the dose of ICS needed to achieve asthma control was reported

Vijverberget al. [57]

50 tag SNPs were selected for 17 genes for screening:

 Ten genes were selected based on their involvement in the glucocorticoid (GC) receptor complex (NR3C1, HSPCA, HSPA4, FKBP4, ST13), GC transport (SERPINA6) or GC-mediated signalling (CREBBP, TBP, NCOA3, SMAD3)

 Seven genes were selected based on a previously reported association with asthma susceptibility, severity or asthma medication response (ARG1, 17q21 locus, IL2RB IL18R1, PDE4D, HLA-DQ, BCL2)

Children and young adults

PACMAN (n = 357)

BREATHE (n = 820) PAGES (n = 391)

Validation cohorts;

CAMP (n = 172)

GALA II (n = 745)

PASS (n = 391)

Meta-analysis of three cohorts

>0.2

Based on BTS guidlinesfortreatment

 step 2:

  SABA + ICS

 step 3:

  SABA + ICS + LABA

 step 4:

  SABA + ICS

+ LABA + LRA

Exacerbations: hospital visits

Oral corticosteroid (OCS) use in the previous year

In a meta–analysis of six studies:

 ST13 rs138335 remained associated with an increased risk of asthma-related hospital visits and OCS use in the previous year,; OR = 1.22 (p = 0.013) and OR = 1.22 (p = 0.0017) but did not passed Bonferronicorrection test

 None of the other genes including NR3C1, were associated at a nominal level with an increased risk of exacerbations in asthmatics using ICS in the three cohorts

Tantisira et al. [49]

TBX21

rs2240017

(H33Q)

701 children aged 5–12 years with mild to moderate asthma enrolled in CAMP

CAMP, 4 year clinical trial

Minor allele frequency of H33Q: 4.5% no minor homozygotes were detected

Budesonide 200 μg twice daily

Bronchial Hyperreactivity (Methacholine) (PC20)

3.5-fold greater mean increase in log-transformed PC20 for methacholine after four years of inhaled budesonide in asthmatic children with glutamine variants when compared with either H33H homozygotes or in dividuals not taking ICS (p = 0.0002)

Ye et al. [46]

ADRB2

(G16R A > G)

ADCY9

(I772 M T > C)

NK2R

(G231E G > A)

TBX21

(H33Q C > G)

53 mild-to-moderate adult asthmatics

Asthmatics adults (Korean)

5–12 weeks ICS treatment, Clinical trial

MAF of four selected polymorphisms were > 5

5–12 weeks of ICS

Asthma control status and FEV1

NK2R G231E G > A and TBX21 H33Q C > G polymorphisms were significantly associated with asthma control status at 5–12 weeks of ICS treatment (p = 0.041, power = 81.419% and p = 0.006, power = 98.564%, respectively)

The NK2R G231E G > A polymorphism also showed significant associations with the mean changes in FEV1% during 12 weeks of ICS treatment (p < 0.05)

Lopert et al. [59]

TBX21 (17q21.32)

rs9910408

208 adult patients with atopic and non-atopic, mild to moderate persistent asthma

3 years clinical trial

rs9910408

0.38 (G)

Treatment with ICS for 3 years (alone or in combination with long-acting beta agonists (LABA),according to achieved asthma control)

According to the response to ICS therapy patients were divided into ‘‘poor’’ and ‘‘good’’ responders

 BHR:Poor response was defined as an increase of PD20 for methacholine that was smaller than one doubling dose compared to the initial PD20

 Lung function: Poor response decrease in FEV1 by more than 30 ml/year

 Asthma control: Poor response was defined as less than a three-point increase in the ACT score after at least 3 years of treatment

 Asthma-related quality of life: Poor response was defined as less than a 16-point increase from the initial AQLQ score

The frequency of AA genotype was significantly higher in good responders (p = 0.049)

This genotype related response was even more evident in the subgroups of non-smokers (p = 0.008) and in non-atopic patients (p = 0.009)

AA genotype was overrepresented among good responder saccording to changes in FEV1 in the subgroups of non-smokers (p = 0.013) and in non-atopic patients (p = 0.048)

Tantisira et al. [60]

FCER2(19p13.3)

 rs889182

 rs2287867

 rs12980031

 rs8110128

 rs4804773

 rs7249320

 rs2277989

 rs1042428

 T2206C

 rs4996974

311 children (CAMP) African-American and Caucasian children

CAMP 4-year Clinical trial

T2206C

0.26 (G) in

Caucasians,-0.44 (G) in

African-Americans

Budesonide 200 μg

twice daily

Severe asthma exacerbation risk

Relative risk, expressed as hazard ratios, for exacerbations in those homozygous for the T2206C mutant allele were

(3.95; 95% CI 1.64–9.51); and (3.08;95% CI 1.00–9.47).more likely to have a severe exacerbation compared to all other T2206C genotypes in

both white and

African-American children

Koster et al. [61]

FCER2 (19p13.3)

rs28364072 (A/G)

Caucasianchildren

 PACMAN (n = 386)

 BREATHE (n = 939)

 CAMP (n = 311)

PACMAN& BREATHE:

 Asthma cohorts

CAMP:

 4-year clinical trial

PACMAN

 0.27 (G)

BREATHE

 0.26 (G)

For BREATHE and PACMAN:

ICS maintenance dose varied between patients

CAMP:

Budesonide 200 µg twice daily

Exacerbations:

Emergency department visits

Hospitalization

Asthma control:

ACQ- scores

Respiratory symptoms

Asthma-related sleepdisturbances

Asthma-related limitations in Daily activities

Additional (airway) medication use during the preceding 12 month

The rs28364072 variant was associated with increased risk of asthma-related hospital visits in the meta-analysis (OR 2.38, 95% CI 1.47–3.85, p = 0.0004)

The variant was associated with increased risk of uncontrolled asthma measured by ACQ scores (OR 2.64, 95% CI 1.00–6.98) and was associated with increased daily steroid dose (OR 2.46, 95% CI 1.38–4.39)

Berce et al. [68]

ORMDL3 (17q21)

rs2872507 (G/A)

-213 asthmatics who were regularly treated with ICSs

In asthmatics who were regularly treated with ICSs, spirometry was repeated after 4–6 weeks of treatment. Bronchial hyperreactivity was assessed with a methacholine challenge test

0.39 (A)

4–6 weeks of ICS:

 Children < 12 years of age: 200 mcg of fluticasone dry powder daily

 Children > 12 years of age: 400 mcg fluticasone dry powder daily

Changes in FEV1

Asthmatics with genotype AA had an 11.1 ± 16.0% mean increase in FEV1 after 4–6 weeks of ICS, compared with 4.6 ± 9.6% in GG homozygotes (p = 0.0463)

Carriers of A allele had a 8.5 ± 13.8% mean increase in FEV1 after ICS treatment, which was significantly higher than 5.5 ± 10.7% in asthmatics with G allele (p = 0.0150)

Farzan et al. [10]

17q21 locus

rs7216389 (C/T)

14 PiCA (Pharmacogenomics in Childhood Asthma) populations (4529 steroid treated children and young adults)

Ten PiCA studies included patients with non‐Hispanic European origins, two included Hispanic patients, one African American, one East Asian patients

the association between variation in the 17q21 locus, and asthma exacerbations despite ICS use

retrospective reporting of exacerbations in the observational cohort studies

Prospective study in CAMP population

0.54–0.81 (T)

ICS

Asthma‐related hospitalizations/emergency department visit (ED)

(ii) short courses of oral corticosteroid (OCS) use reported by the parent/child at the study visit or based on completed study questionnaires

In the meta‐analysis of 13 studies, rs7216389 was statistically significantly associated with asthma‐related ED visits/hospitalizations, (summary OR per increase in risk allele: 1.32, 95% CI 1.17–1.49, p < .0001, I2 = 3.9%)

In the meta‐analysis of the nine studies, the rs7216389‐T was statistically significantly associated with an increased risk of OCS use/high‐dose ICS (summary OR per increase in variant allele: 1.19, 95% CI 1.04‐1.36, p = .01, I2 = 22.8%)