Keskin et al. Clin Transl Allergy (2019) 9:2 https://doi.org/10.1186/s13601-018-0239-2 Clinical and Translational Allergy

REVIEW Open Access Genetic associations of the response to inhaled corticosteroids in asthma: a systematic review Ozlem Keskin1, Niloufar Farzan2, Esra Birben3, Hayriye Akel4, Cagatay Karaaslan4, Anke H. Maitland‑van der Zee2,5, Michael E. Wechsler6, Susanne J. Vijverberg2 and Omer Kalayci3*

Abstract There is wide variability in the response to inhaled corticosteroids (ICS) in asthma. While some of this heterogeneity of response is due to adherence and environmental causes, genetic variation also infuences response to treatment and genetic markers may help guide treatment. Over the past years, researchers have investigated the relationship between a large number of genetic variations and response to ICS by performing pharmacogenomic studies. In this systematic review we will provide a summary of recent pharmacogenomic studies on ICS and discuss the latest insight into the potential functional role of identifed genetic variants. To date, seven genome wide association stud‑ ies (GWAS) examining ICS response have been published. There is little overlap between identifed variants and meth‑ odologies vary largely. However, in vitro and/or in silico analyses provide additional evidence that genes discovered in these GWAS (e.g. GLCCI1, FBXL7, T gene, ALLC, CMTR1) might play a direct or indirect role in asthma/treatment response pathways. Furthermore, more than 30 candidate-gene studies have been performed, mainly attempting to replicate variants discovered in GWAS or candidate genes likely involved in the corticosteroid drug pathway. Single nucleotide polymorphisms located in GLCCI1, NR3C1 and the 17q21 locus were positively replicated in independent populations. Although none of the genetic markers has currently reached clinical practise, these studies might provide novel insights in the complex pathways underlying corticosteroids response in asthmatic patients. Keywords: Inhaled corticosteroids, Asthma, Genetics, Genomics, GWAS

Introduction noxious environmental exposures, misdiagnosis, and Afecting up to 18% of the world’s population, asthma truly steroid refractory disease, genetic variation might is a chronic airway disease and inhaled corticosteroids also be an important factor infuencing treatment (ICS) are the preferred frst-line treatment for persis- response in patients with asthma [4, 6–8]. Approximately tent asthma [1]. However, there is a wide variability in 70% of the variance in ICS response is suggested to be response to ICS [2–4] such that up to 35–40% of the due to genetic factors [4, 9]. patients receiving ICS for 8–12 weeks do not show signif- Over the past three decades, researchers have investi- icant improvement in lung function [2, 3]. Furthermore, gated the relationship between a large number of genetic 10% of the asthmatic patients on maintenance ICS treat- variations and response to ICS by performing pharma- ment may remain symptomatic or at high risk of asthma cogenomic studies. Te main aim of these studies was to attacks in spite of the regular use of this medication [5]. identify genetic markers that could help physicians opti- In addition to poor adherence to medication, continuing mize asthma treatment. Te high number of publications has enabled systematic literature reviews that summarize *Correspondence: [email protected] the fndings of the studies and evaluate the potential clin- 3 Pediatric Allergy and Asthma Unit, Hacettepe University School ical relevance of the fndings. One of these systematic lit- of Medicine, 06100 Ankara, Turkey erature reviews was published by Farzan et al. [10]. Tis Full list of author information is available at the end of the article

© The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat​iveco​mmons​.org/licen​ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat​iveco​mmons​.org/ publi​cdoma​in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Keskin et al. Clin Transl Allergy (2019) 9:2 Page 2 of 25

study reviewed pharmacogenomics studies of ICS and Tis systematic review is reported according to PRISMA leukotriene modifers that were published between 1999 guidance [11]. and 2015. Furthermore, SNPs that were positively rep- licated at least once in an independent population were Novel pharmacogenomics studies discussed in detail. Despite the large number of pharma- From 2015 to 2018, nine additional studies were iden- cogenomics studies, there is still no genetic marker used tifed through PubMed. Of these studies, three were in clinical practice to optimize asthma treatment with GWAS and six were candidate gene studies. ICS. However, due to the rapid decrease in the costs of genotyping and emergence of advanced genotyping tech- GWAS (Genome‑wide association studies) nologies, eforts are still ongoing to replicate previously GWAS have provided the opportunity to detect novel identifed markers and/or identify new genetic mark- pharmacogenetic variants related to ICS response by ers by performing Genome-wide association studies scanning a high number of genetic variants across the (GWAS). One of the important issues of single nucleo- entire genome. In the systematic review by Farzan et al. tide polymorphisms (SNPs) that are identifed by GWAS [10], the results of the four GWAS that had been con- is that their function and relation to the disease/trait of ducted prior to 2015 have been described in detail. Tese interest is often not clear and therefore might inhibit fur- GWAS had identifed four new loci to be associated with ther progression towards clinical implementation. Tis ICS response. Tese loci harbored the GLCCI1 (gluco- has encouraged researchers to perform in vitro and/or corticoid-induced transcript 1 protein), T, FBXL7 (F-box in silico studies to unravel the potential role of the SNPs/ and leucine-rich repeat protein 7) and ALLC (Allantoi- genes in the asthma-treatment response pathway. Since case) genes [12–15]. SNPs within GLCCI1, T gene, and the feld is rapidly evolving, this follow-up systematic ALLC were associated with changes in the lung function review aims to (1) provide a summary of the pharma- and rs10044254 SNP within FBXL7 was associated with cogenomics studies on ICS published after 2015 and (2) changes in the asthma symptom scores. From the iden- provide the latest insight into the potential functional tifed SNPs within these genes, rs10044254 was the only role of the identifed genes/variants identifed in GWAS, SNP that reached the genome-widesignifcance thresh- in order to provide an overview of the latest promising old. SNPs within the GLCCI1, T gene, and FBXL7, were clinical markers. associated with ICS response in pediatric asthma popu- lations and were conducted by the same research group [12–14]. Tese studies included Caucasians from the Methods Single-Nucleotide Polymorphism Health Association- Articles published from 1995 January through the end of Asthma Resource Project (SHARP). Although the three August 2018 were searched in PubMed using three key- GWAS all studied the SHARP population, the methods words. Conference abstracts, articles assessing adverse of the GWAS difered quite a lot with regard to sample drug efects and articles that had not been published in size, study design, outcome measurements, and genotyp- English were excluded. First, we eliminated articles from ing platforms. the titles, and then by abstracts. Ten the remaining arti- Between 2015 and 2018, three additional GWAS were cles were read in full. We also screened review articles for published [16–18], of which one was conducted by the possible missed publications. SHARP group. Changes in lung function were consid- A search using the keywords “Asthma and/or Lung ered as the primary outcome in two of these GWAS and function, Corticosteroids, Genetics”yielded 1106 studies; asthma exacerbations were considered the primary out- “Asthma and/or Lung function, Corticosteroids, Phar- come in one study. None of the new GWAS could iden- macogenetics” yielded 93 studies; “Asthma and/or Lung tify the previously found genes/SNPs in candidate gene function Corticosteroids Pharmacogenomics” yielded or GWAS. 122 studies. Of these, 46 met the inclusion criteria with In the GWAS by Wang et al. [16], 120 mild-to-moder- 38 being candidate gene studies and 7 being GWAS and ate adult asthmatics were included. In this study, patients 1 being exome sequencing study (Fig. 1). Nine articles received diferent doses of glucocorticoids (125, 250, 500, remained after excluding the studies before 2015 June. 1000 mcg) and the dosage of ICS was increased each From all the publications selected, the following data week. Te hypothesis underlying this approach was that were extracted: ICS type and duration of treatment, genes integration of pharmacodynamic properties of corticos- and SNPs, outcome, study design, ethnic backgrounds of teroids into pharmacogenetic GWASs containing drug patients, sample size, age range and duration of the study. responses to diferent doses may increase the statistical From GWAS, information regarding the in vitro or in sil- power of signifcant association detection [19]. For the ico analysis after the association analysis was extracted. frst time, a mechanistic model was applied to analyse Keskin et al. Clin Transl Allergy (2019) 9:2 Page 3 of 25

Asthma and/or Lung Asthma and/or Lung Asthma and/or Lung funcon Corcosteroids funcon Corcosteroids funcon Corcosteroids Genecs Pharmacogenecs Pharmacogenomics (n=1106) (n=93) (n=122)

A er general key word based search, arcles was selected according to criteria

Asthma and/or Lung Asthma and/or Lung Asthma and/or Lung funcon Corcosteroids funcon Corcosteroids function Corcosteroids Genecs Pharmacogenecs Pharmacogenomics (n=126) (n=66) (n=77)

A er reading the full-text, duplicated and unrelated arcles were excluded and final list was formed Selected arcles for review (n=46)

Fig. 1 Flowchart for the inclusion of ICS pharmacogenomic studies

the GWAS data with a series of dose-dependent pharma- 30–300% higher % Forced expiratory volume in one sec- cological phenotypic data and detected associations of ond (FEV1) values at an intermediate dose of glucocor- genome-wide signifcance between dose-dependent pul- ticoids compared to the homozygotes for the wild-type monary function response to ICS, and fve loci: rs6924808 alleles and heterozygotes for all of the associated SNPs −7 on chromosome 6 (p = 5.315 × 10 ), rs10481450 on (with the exception of rs6924808). Some of the SNPs were −8 chromosome 8 (p = 2.614 × 10 ), rs1353649 onchromo- sensitive to a small change in low drug doses and some −9 some 11 (p = 3.924 × 10 ), rs12438740 on chromosome showed variation after larger dose changes. Signifcant −8 15 (p = 4.499 × 10 ), and rs2230155 onchromosome 15 associations were also demonstrated in three additional −7 (p = 1.798 × 10 ). Tese loci are mapped to candidate independent replication populations. Two SNPs, chr6 genes related to cellular functions [20, 21]. Asthmat- rs6924808 and chr11 rs1353649, displayed an increased −16 −11 ics who were homozygous for the mutant alleles had signifcance level (p = 6.661 × 10 and 5.670 × 10 ) in Keskin et al. Clin Transl Allergy (2019) 9:2 Page 4 of 25

the pooled analysis of frst GWAS results with these three [12]. Tis study showed that dexamethasone signifcantly replication trials. Tis GWAS underlined the importance increased GLCCI1 expression. Specifcally, in patients of the optimal ICS dose for individualized asthma treat- homozygous for the mutant allele (G), the expression ment based on a patient’s genetic makeup. was signifcantly lower compared to homozygotes for the Te frst GWAS that studied asthma exacerbations as wild-type allele (A) in the presence of dexamethasone. a primary outcome was performed by Dahlin et al. in Increased expression of the GLCCI1 gene was associated 2015. In this study, 806 asthmatic children with Cauca- with a better response to ICS. Furthermore, Hu et al. [23] sian ethnicity were included from two population-based in their mRNA analysis showed an increased expression biobanks [17]. Te results of the GWASs performed in in GLCCI1 after ICS. Taken together, GG carriers appear these two populations were meta-analysed. However, to be less sensitive to corticosteroids at the cellular level. none of the SNPs from the meta-analysis met the thresh- old for genome-wide signifcance. Te most signifcant FBXL7 result was reported for 6 SNPs (rs2395672 and rs279728, FBXL7, located in chromosome 5, is a member of Skp1- rs4271056, rs6467778, rs2691529, and rs9303988) within Cul1-F-box complex which is involved in ubiquitylation three diferent genes CMTR1 (Cap methyltransferase 1), and degradation of proteins in the cells [24, 25]. In-vitro TRIM24 (Tripartite Motif Containing 24) and MAGI2 studies show that FBXL7 induces cell apoptosis and its (Membrane Associated Guanylate Kinase). Among these, cellular abundance is regulated by FBX18, another SCF the rs2395672 SNP within the CMTR1 gene had the protein [26]. Terefore, increased FBXL7 expression can smallest p value from the meta-analysis [joint Odds Ratio induce cell and tissue injury. In fact, studies on lung epi- −6 (OR) = 1.07, 95% CI 1.03–1.11; p = 2.3 × 10 ]. thelial cells show that overexpression of FBXL7 results in Te latest and so far largest GWAS of ICS response has mitochondrial damage [27]. FBXL7 mediates this func- been published by Mosteller et al. [18]. In this study, 2672 tion through a decrease in the amount another protein patients (12 years and older) were included from seven (survivin) involved in cell survival and apoptosis. To date, randomized, double-blind, placebo-controlled, multi- more than 50 F-box proteins have been identifed and center clinical studies that were performed in a total of these proteins appear to play major roles in infammation 26 countries. Changes in FEV1 at week 8 and 12 follow- and immunity by interacting with each other [28, 29]. A ing futicasone furoate (FF) or futicasone propionate study in murine lung epithelial cells showed that F-box (FP) treatment were considered as the study outcome. family members interact with proteins that can induce Te analysis was performed with more than 9.8 mil- cytokine release in immune cells [26]. In the GWAS of lion genetic variants (minor allele frequency ≥ 1%), and asthma symptoms by Park et al. [14], the variant allele none of the SNPs reached the genome-wide signifcance of the rs10044254 SNP was associated with poor symp- threshold. tom control. A further in vitro analysis using immor- An overview of published GWAS is provided in Table 1. talized B cells obtained from the CAMP participants demonstrated that the variant allele was associated with Evidence of functional activity of the previously identifed a decrease in FBXL7 expression in response to dexameth- genes and SNPs in GWAS asone. Although not statistically signifcant, increased GLCCI1 dexamethasone-induced expression of FBXL7 was asso- GLCCI1is a protein-coding gene located within the ciated with poor asthma symptom scores. Despite these chromosome 7p21.3. Te role of GLCCI1 as one of the promising fndings, no further studies have tried to eluci- target genes of glucocorticoids was described by Chap- date the role of these proteins in asthma control. man et al. more than two decades ago. Tey showed an increased expression of this gene in two diferent T gene cell lines upon the administration of dexamethasone T gene, located within the chromosome 6, is a member [22]. Glucocorticoids can induce apoptosis in several of the genes containing the T locus as a common pro- immune-infammatory cells such as eosinophils and tein motif [30]. Te product of the T locus seems to be lymphocytes. Terefore, researchers concluded that involved in the development of all vertebrate organisms. reduced expression of GLCCI1 because of rs37973 could Furthermore, T gene expression has been previously result in reduced apoptosis of these cells. Consequently, shown in healthy adult lung tissue. In the GWAS study reduced apoptosis of these cells could decrease ICS ef- by Tantisira et al., researchers performed a pathway anal- cacy. To validate the functional role of the gene and its ysis in order to unravel the potential infuence of the T SNP in asthma control, an in vitro study was performed gene on response to corticosteroids. To that end, using using lymphoblastoid B cells derived from children in the the program GeneMANIA (http://genem​ania.org/), Childhood Asthma Management Program (CAMP) study they focused on the T gene–NR3C1 (Nuclear Receptor Keskin et al. Clin Transl Allergy (2019) 9:2 Page 5 of 25 ‑ ) , and ‑ respec − 4 − 5 − 4 − 4 × 10 × 10 × 10 = 7 × 10 populations patients homozy ‑ gous forthe wild - type allele (C) hadapproximately 12% improve ments in FEV1% with compared the 4% increasein TT carriers after of 4–8 weeks with treatment ICS (combined p gous for the gous for wild - type allele SNPs of all three had a two to increase threefold in FEV1%pred to compared homozygotes for the mutant allele values of study populations for the rs1134481, rs2305089 and rs3099266 were 1.57 1.1 tively 2.3 In two replication Patients homozy ‑ Patients p Combined Study outcome Study ,7p21.3) ( GLCCI1 rs1134481 and rs2305089( T gene , 6q27) rs37972 rs3099266, SNPs chosen SNPs for replication (gene, chromosome position) FEV1 from FEV1 from baseline FEV1% pred FEV1% pred baseline from Changes in Changes in Defnition of response = 264, = 407) 385, 1000 μg = 935) = 101, futicasone = = 185, futicasone (n n 100 μg propionate twice daily) n daily (increased 2000 μg if up to necessary)) (LOCCS, n 100 μg twice daily) triamcinolone 400 μg twice daily) once daily to (increased 2000 μg if neces ‑ sary) Caucasian patients Caucasian trial, (CARE Children: study, (Adult Adults: (SOCS/SLIC, n Adults (n Adults 1000 μg Flunisolide Replication Replication population ‑ 200 μg twice daily sonide 200 μg twice daily propionate 100 μg twice daily nolone 400 μg twice daily Budesonide CAMP: bude CAMP: CARE: futicasone ‑ Triamci ACRN: Medication Medication in the discovery phase trios 118 child parent parent child 118 418 Number of asthmatic patients 16 months 6–8 weeks Clinical trial, Clinical trial, Clinical trial, Clinical trial, Study design design Study and duration = 179) = 239) dren (CAMP) dren children: CARE trials) (n trial) (n Caucasian chil ‑ Caucasian Caucasians Caucasians and (CAMP (ACRN Adults: Discovery Discovery phase population Bead Chip (Illumina) 534 290 SNPs Clara, CA) using a Human SNP array 6.0 Human Hap 550v3 Afymetrix (Santa 444 088 SNPs Genotyping platform and number of SNPs after pruning GWAS analysis of response to ICS of response analysis GWAS [ 12 ] [ 13 ] al. et al. Tantisira al. et al. Tantisira 1 Table Referernces Keskin et al. Clin Transl Allergy (2019) 9:2 Page 6 of 25 ‑ × , and − 9 − 8 − 5 ) × 10 − 5 ues of rs2388639, rs10044254 and rs1558726 SNPs the pediatric for and CARE CAMP subjects were 8.56 rs7558370, rs11123610, rs6754459, rs17445240 and rs13418767 were signifcantly with associated change in FEV1% (p value < 1.0 ­ 10 9.12x10 1.02x10 respectively. Homozygotes for the mutant allele rs10044254 had for poorer signifcantly treat to responses ment compared the patients to homozygous or heterozygous for the wild - type allele of 1.14 (increase (as median score) in homozygotes the mutant for 0.28 allele versus in homozygotes the reference for allele) The combined p val ‑ The Study outcome Study rs17017879, ( RMST ,12q21), rs2388639 ) ( LOC728792 and rs10044254 ( FBXL7 , 5p15.1) (from (from ALLC and 11 GWAS) additional SNPs (2q35) in ALLC rs1558726 SNPs chosen SNPs for replication (gene, chromosome position) 14 SNPs within 14 SNPs ‑ asthma symp based toms on diary Scores cards. ranged from 0 (absent) to 3 (severe) FEV1% Self - reported Defnition of response Changes in ‑ = 110, = 77, = 110, ‑ Triamci (CARE, n (CARE, futicasone pro 1000 μg pionate daily (increased 2000 μg if up to necessary)) Adults: n (LOCCS, futicasone 100 μg twice daily) (ACRN, n nolone 400 μg twice daily) the discovery phase Caucasian Children: Children: Caucasian Replication Replication population Same population with ‑ 200 μg twice daily futicasone pro daily pionate Budesonide Medication Medication in the discovery phase 1000 µg of 124 Number of asthmatic patients 189 8 weeks 4 weeks Clinical trial, Clinical trial, Study design design Study and duration Clinical trial, Clinical trial, ‑ dren (CAMP) dren with moder severe ate asthma Caucasian chil ‑ Caucasian Discovery Discovery phase population Korean adults Bead Chip or Infn ‑ ium HD Human610 - Quad Bead Chip (Illumina, San Diego, CA) 440 862 SNPs 660 W BeadChip (Illumina, San Diego, USA) 430 487 SNPs Human Hap 550v3 Genotyping platform and number of SNPs after pruning Illumina Human (continued) 14 ] [ et al. Park 1 Table Referernces al. [ 15 ] et al. Park Keskin et al. Clin Transl Allergy (2019) 9:2 Page 7 of 25 ) ), ), ), − 7 − − 9 − 8 − 7 ‑ ‑ wide sig ‑ - = 5.315 × 10 = 3.924 × 10 = 2.614 × 10 = 4.499 × 10 = 1.798 × 10 ), rs1353649 on ‑ nifcancewithphys response iological glucocorticoidto therapy;rs6924808 on chromo some 6 with wild - type allele C andmutant T (p loci produce loci produce associations of genome 8 chromosome chromosome 11 with wild - type allele G and mutant A (p rs10481450 on chromosome - 8 withwild type allele A and mutant T (p rs12438740 on chromosome 15 with wild - type allele C and mutant T (p and rs2230155 onchromo some15 with wild - type allele T C and mutant (p The following following The Study outcome Study chromosome 6 chromosome 8 chromosome chromosome 11 chromosome 15 chromosome 15 rs6924808 on rs10481450 on rs1353649 on rs12438740 on rs2230155 on SNPs chosen SNPs for replication (gene, chromosome position) FEV1% Changes in Defnition of response ‑ ± inhaled day periodday week run - in week 225, mild, persistent persistent 225, mild, adult asthma, open - label budesonide as or prednisone the guided by - based symptom run - The action plan. in and treatment phases both ended with a 14 - combined of intense Salmeterol therapy) of corticoster oids (SOCS) and salmeterol corticosteroids (SLIC) trials include 79 and 106 adult asthma,respectively, at the end of 6 - period on ICS, the milder patients to allocated were SOCS and the more patients moderate SLIC to allocated The IMPACT trial (n: IMPACT The Replication Replication population ‑ diferent doses diferent of glucocorti ‑ coids - budeso nide (125, 250, 500, 1000 mcg), in which, each dose was used and 1 week for the dose was the doubled for subsequent week Inhaled multiple Medication Medication in the discovery phase 120 Number of asthmatic patients each dose of ICS was used 1 week for Clinical trial, Clinical trial, Study design design Study and duration - moderate moderate adult asth ‑ matics 120 Mild - to Discovery Discovery phase population 909 622 SNPs involved were SNPs in the analysis Afymetrix 6.0 arrays pruning 266 944 After Genotyping platform and number of SNPs after pruning (continued) 16 ] [ et al. Wang 1 Table Referernces Keskin et al. Clin Transl Allergy (2019) 9:2 Page 8 of 25 ). ). Two ). Two − 5 − 6 = 1.07, 95% = 2.3X10 associated with associated risk of diferential asthma exacerba ‑ tions (p < 10 SNPs (rs2395672 SNPs and rs279728) associated were with increased risk of exacerba ‑ SNPs four tions, (rs4271056 ), ( CMTR1 rs6467778 ( TRIM24 ), rs2691529, and ) rs9303988 MAGI2 associated were risk with decreased ‑ met the prespeci for fed threshold ‑ statistical signif cance Rs2395672 in , was CMTR1 with an associated risk of increased exacerbations in both populations (OR CI 1.03–1.11; joint p Six novel SNPs SNPs Six novel Study outcome Study No genetic variant rs4271056 rs279728 rs6467778, rs9303988 rs2395672 CMTR1 TRIM24 rs2691529, MAGI2 SNPs chosen SNPs for replication (gene, chromosome position) ‑ bations week 8 and week ‑ 12 follow ing FF - or FP treatment Asthmaexacer Defnition of response FEV1change at ‑ neResearch Project Project neResearch at the (PMRP) MarshfeldClinic in Wisconsin ‑ PersonalizedMedici Replication Replication population sone, budeson ‑ sone, ciclesonide, ide, funisolide, mometasone, ortriamci ‑ nolone) futicasone (FF) - or furoate futicasone (FP) propionate treatment ICS (beclometha ‑ Medication Medication in the discovery phase Inhaled = 369 = 437 years) asthmatic patients ( ≥ 12 806 Caucasian 806 Caucasian BioVU N N PMRP Number of asthmatic patients 2672 asthma

‑ - blind initiated ICS initiated prior treatment the exacer to bation event randomized randomized double placebo controlled parallel group multicenter clinical trial Patients had Patients Study design design Study and duration week” “8–12 week” - blind, - blind, years) ‑ VanderbiltU niversityMedi ‑ in cal Center Tennessee patients ( ≥ 12 7 from randomized, double placebo controlled, parallel multi - group, clinical center studies in 26 countries BioVU at Discovery Discovery phase population 2672 asthma ‑ ‑ ‑ ‑ 9.8 million ‑ mergedandpruned 740,924 toobtain commonautoso In fnal malSNPs. dataset 237,726 common, inde pendentSNPswere included Exome BeadChip Exome (Illumina, Inc., San CA) BioVU Diego, (731,390 SNPs) (662,256 PMRP frst were SNPs) common genetic variants the 1000 Genomes > Project Illumina’sOmni2.5 Illumina’sOmni2.5 Genotyping platform and number of SNPs after pruning 2184 haplotypes from 2184 haplotypes from (continued) [ 18 ] al. [ 17 ] Dahlin et al. 1 Table Referernces al. Mosteller et al. Keskin et al. Clin Transl Allergy (2019) 9:2 Page 9 of 25 ‑ ‑ 5), ‑ − = 0.006) = 3.75x10 = 0.00095) and ciation for ciation for rs72821893 in with FEV1%KRT25 (p region was found was found region with associated and FEV1%pred AHR, and ICS treat ment response Mch PD20 (p MchPD20 - based out treatment come (p Study outcome Study Strongest asso Strongest The 17q12 - 21 The SNPs chosen SNPs for replication (gene, chromosome position) (Mch PD20) and ICS response outcomes by measured the increase or decrease of FEV1% and AHR FEV1%, AHR Defnition of response Replication Replication population casone casone Fluticasone and 100 - μg salmeterol Fluticasone and 100 - μg salmeterol Fluticasone and 100 - μg salmeterol - 4 500 μg ‑ L1 - 100 μg Fluti ‑ L2 - 200 μg Fluti L3 - 200 μg L L5 - 1000 μg Medication Medication in the discovery phase with asthma 110 children 110 children Number of asthmatic patients ‑ ‑ ‑ ‑ year rand ‑ year omized clinical omized trialmulticenter ‑ fol pants were up for lowed with the 2 years, - symptom in the days free befo 2 weeks visit, reeach FEV1%, airway ‑ hyperrespon (AHR) siveness methacho to line (MchPD20) every three Treat months. ment dosage was adjusted to according the algorithm of the study 2 - ‑ Partici Study design design Study and duration with children asthma that was not con ‑ well despite trolled ICS CATO study 110 CATO Discovery Discovery phase population ≥ 1%, Exome chip (IlluExome ‑ CA, mina, San Diego, 1.1, USA), version which contains 242 902 variants analysis: MAF 36,519 SNPs < 1%. MAF 24,944 SNPs Infnium Human common SNP For SNP analysis: rare For Genotyping platform and number of SNPs after pruning (continued) ] (Exome [ 67 ] (Exome array) al. et al. Leusink 1 Table Referernces [ 10 ] et al. Farzan from adapted Table Keskin et al. Clin Transl Allergy (2019) 9:2 Page 10 of 25

Subfamily 3 Group C Member 1) interactions [13]. Te gene (hMTr1) is involved in defense mechanisms against results showed that the T gene is co-expressed with the viral infections. Increased CMTR1 expression has been NRIP1, FOXA2, and TTPA genes. Te same analysis found to be associated with T cell mediated immune showed that these genes directly interact or are predicted response mechanisms in human peripheral blood mon- to interact with NR3C1. onuclear cells [41]. Using independent microarrays, Considering the important role of corticosteroids in Dahlin et al. [17], evaluated the expression level of the lung development, it has been suggested that alterations top genes identifed in their GWAS. Tey collected nasal in corticosteroid-responsive genes during development lavage samples from children during and 1–2 weeks after mighthave an infuence on bothasthma susceptibilityand asthma exacerbations. Te expression level of CMTR1, treatment response. Previous studies have shown that a but not TRIM24 or MAGI2,was signifcantly reduced decrease in T gene expression inhibits chondrogenesis, 1–2 weeks after exacerbations. Since viral infections are the process of cartilage development, mediated by BMP2 the main causes of asthma exacerbations in children and and FGFR3 [31]. Tese two proteins have been shown expression of CMTR1 has been shown to be upregulated to be associated with corticosteroids resistance [32, 33]. in children during asthma exacerbations [42], this gene As suggested by Tantisira et al. [13], these fndings might and its product might be promising new therapeutic tar- provide a mechanistic basis for the T gene in response to gets that treat viral infections. ICS. However, despite these fndings no further studies have tried to explore the functional role of this gene in Candidate gene studies ICS response. In total 29 candidate gene studies were included in the systematic review by Farzan et al. [10]. In summary, ALLC SNPs within the CRHR1 (Corticotropin Releasing Hor- Te study by Park et al. [15], was the frst study ever to mone Receptor 1), GLCCI1, FCER2 [Fc fragment of IgE, report an association between the ALLC gene and a low-afnity II, receptor for (CD23)], NR3C1, STIP1, disease or treatment response. By performing in silico and TBX21(T-box 21) were studied the most. However, analysis, Park et al. reported correlations between the despite the large number of studied SNPs (> 500) within ALLC function and three SNPs (rs13418767, rs6754459, 120 genes, the most consistent results were reported and rs13409104) in high LD with the most signifcant only for one SNP, rs28364072, within the FCER2 gene. SNP (rs11123610) from the GWAS. Furthermore, using rs28364072 was signifcantly associated with all three the TFSEARCH program, they showed that rs13418767 outcomes (lung function, symptoms, and exacerbations) is a binding site for Sp1, a member of the Skp1-Cul1-F- in pediatric asthma populations. box complex. A recent study that investigated the asso- Between 2015 and 2018, six additional candidate gene ciation between occupational exposure to pesticides and studies were published. Tese studies attempted to rep- genome-wide DNA methylation sites found diferential licate the previously studied markers within the GLCCI1 DNA methylation in the ALLC gene [34]. In patients [23, 43–45]; ADRB2 (Adrenoceptor Beta 2) [46, 47], with airway obstruction who were exposed to high doses NR3C1 [43], CRHR1 [43], 17q21 locus [48] and TBX21 of pesticides, two diferent CpG sites of the ALLC gene [43]. SNPs located in the GLCCI1, NR3C1,and 17q21 were signifcantly hypo-methylated. ALLC is an enzyme were positively replicated in independent populations. that has lost its uricolytic activity during vertebrae evolu- An overview of replicated candidate gene studies is pro- tion. However, animal studies suggest rather than a non- vided in Table 2 [23, 43–61]. functionality, there seems to be low expression level and low substrate afnity of this gene in animals [35]. Tere Replicated genes and SNPs is limited knowledge regarding the role of this gene and GLCCI1 (glucocorticoid induced 1) its variations on asthma and treatment response. While By 2015, three candidate gene studies had studied ALLC located within chromosome 2 seems to have a lost GLCCI1 in order to replicate the fndings of a GWAS function in humans, this chromosome harbors several published by Tantisira et al. [12]. In short, the GLCCI1 genes that have been found to be associated with FEV1 rs37973 was positively replicated only in one of the three [36, 37] and IgE levels [38]. candidate gene studies. Te positive replication study included 224 adult asthmatic patients of Japanese ethnic- CMTR1 ity. Te SNP was signifcantly associated with an annual CMTR1, located within the chromosome 6p21, is decline in FEV1 of 30 ml/year or greater [54]. After 2015, involved in mRNA capping [39]. Capping of mRNA four additional studies, including one study by our own stimulates the stability of mRNA and increases efcient research group, have assessed the association between mRNA translation [40]. Furthermore, the product of this rs37973 SNP and ICS response [23, 43–45]. Keskin et al. Clin Transl Allergy (2019) 9:2 Page 11 of 25 ‑ ‑ week week are not associated not associated are or with immediate long - term improve ment in FEV1 ICSs by or with prevention FEV1of accelerated in adult decrease asthma was associated with was associated in response treatment populations all three the variants gous for a doubling manifested quadrupling of to the lung function ICS to response with lack of compared the variants (p values 0.006 to from ranging asth ‑ three 0.025 for matic populations). rs1876828, rs242939, and rs242941, were each associated with ICS treatment in both response Study and the Adult rs1876828, was CAMP. associ ‑ also strongly with improved ated the 6 - FEV1 over triamcinolone treat adult ment in ACRN asthmatics CRHR1 polymorphisms ( CRHR1 , NM_004382), Individuals homozy ‑ Study outcome Study 3–6 months of decline in FEV1 (7–19) years from baseline from Immediate efect: Changes in FEV1 baseline within from - term efect:Rate Long annually during 13.0 Changes in FEV1% Defnation Defnation of response ‑ (426–1152) to was calculated an equivalent daily dose of beclometha ‑ sone. nide 400 μg twice daily 2000 μg once daily twice daily μg/days 749 μg/days Mean daily dose of ICS Flunisolide 1000– Flunisolide Budesonide 200 μg aceto Tramcinolone Medication rs242941 0.4 (T) rs1876828 0.2 (T) rs242941 0.3 (T) rs1876828 (T) MAF years, 22 years, for lowed clinical trial (Neth ‑ erland) week clinical 6–8 week trials Asthma cohortAsthma ‑ fol Three independent Three Design = 224) = 415) = 201) symptomatic asthma symptomatic of under 45 years age adults: n n 281 adult patients with Caucasian children and children Caucasian study (Adults, Adult (Children, CAMP n (Adults, ACRN Study population Study in 14 candidate in 14 candidate genes in the steroid pathway SNPs) SNPs) CRHR1 (17q21.31) rs1876828 rs242939 rs242941 131 SNPs genotyped 131 SNPs (4 SNPs) ALOX15 CRH (4 SNPs) CRHBP (5 SNPs) CRHR1 (17 SNPs) FCER2 (15 SNPs) (9 SNPs) GATA3 HSD11B1 (10 SNPs) IL18BP (7 SNPs) (4 SNPs) MAPK8 (11 SNPs) NFATC4 NR3C1 (16 SNPs) POMC (6 SNPs) (10 POMC (6STAT3 (10 POMC (6STAT5A SNPs Replicated genes of ICS pharmacogenomic studies genes of ICS pharmacogenomic Replicated al. [ 50 ] Dijkstra et al. al. [ 49 ] et al. Tantisira 2 Table References Keskin et al. Clin Transl Allergy (2019) 9:2 Page 12 of 25 ) − 3 ‑ ­ 10 ) × − 4 ­ 10 0.05) but it × = 0.05) and < = 2.07 0.006) are associ ‑ 0.006) are = 1.89 = rs1876828 was associ ‑ with improve ated ments in FEV1% pred (p ated with poor lung ated function response rs28364072 in FCER 2 with was associated exacerba ‑ recurrent subjectstions in white minor 1.9 for (OR: p allele, response to albuterol albuterol to response and the minor alleles of RS242941 in CRHR1 1.6, CI 95% (OR 1–2.7, p T2206C in FCER2 (OR: 2.1, 95%CI 1.2–3.5, p ‑ signif did not reach cance in multivariate analysis was associated with was associated in FEV1% decrement (p pred Minor allele of The minor allele of The Lower bronchodilator bronchodilator Lower Study outcome Study Minor allele of rs242941 ‑ ≤ 7.5% scores versus time versus scores ment visits urements: responders:change in FEV1 %pred: Change in FEV1% pred symptoms: Asthma Slopes of plots ACQ Exacerbations: Emergency Depart Hospitalizations burst Oral prednisone function meas ‑ Lung poor Defnation Defnation of response twice daily Fluticasone 100 μg twice daily Budesonide 200 μg Medication 0.44 (G) in African - 0.44 (G) Americans rs242941 0.34 (T) rs1876828 0.15 (T) CRHR1 rs242941 0.26 (T) FCER2 T2206C in Caucasians, 0.26 (G) MAF year clinical year trial weeks Clinical trial 16 weeks CAMP 4 - CAMP Design = 65) adolescence and adults continuing ICS (n (5–12 years) Caucasian Caucasian children, children, Caucasian 311 children 311 children African - American and (CAMP) Children Study population Study T2206C CRHR1 (17q21.31) rs1876828 rs242941 CRHR1 - rs242941 FCER2 - SNPs (continued) Mougey [ 52 ] et al. al. [ 51 ] Rogers et al. 2 Table References Keskin et al. Clin Transl Allergy (2019) 9:2 Page 13 of 25 - ‑ related - related dose ICS = 0.047) = 0.006) severe asthma - severe ated with a decline ated in FEV1 of 30 ml/year (estimated or more 1.10: 0.02 to efect: 2.18, p tion between rs37973 genotypes and the when outcome, decline in FEV1 was as a continu ‑ analyzed ous variable association between changes in FEV1 and rs37973 genotypes G allele at rs41423247 of the NR3C1 gene with a is associated higher improvement in FEV1 at 4 h in chil ‑ with moderate dren to exacerbation treated with high - (p difer signifcant ence was observed CRHR1 gene in SNPs rs242939, s242941,and rs1876828, TBX21 rs2240017; GLCCl1 rs37973; and T gene rs3099266 and rs2305089 in FEV1 change rs37973 GG was associ ‑ was no associa ‑ There There was no signifcant was no signifcant There Homozygosity the for No genotype Study outcome Study FEV1 or 30 ml/year more from baseline after from in 6 studies 8 weeks 12 in and at week one study 4th hour Annual decline in Changes in FEV1 Changes in FEV1 at Defnation Defnation of response dose Inhaled - varied between patients Fluticasone furoate furoate Fluticasone ranged between 25 and 800 μg daily, ‑ propion Fluticasone 100–500 μg ate twice daily ‑ 4000 mcg Flutica sone propionate solution ICS maintenance dose ICS maintenance Various doses of Various Single albuterol + Nebulized Medication 0.44 (G) 0.44 (G) 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) MAF - week clinical trial week ing ICS fot at least ing ICS fot 4 years studies, six studies of studies, trials and one 8 week 12 - study in children study in children with moderate asthma severe exacerbation, Clinical trial Asthma cohortAsthma ‑ receiv Pooled data of seven data of seven Pooled Single high dose ICS Design = 1916) = 224) (n adolescents and adults (n asthma exacerbation Adult Japanese Adult Non - Hispanic white 82 children with 82 children Study population Study rs242941, rs1876828) rs3099266, rs2305089) (7p21.3) GLCCI1 Rs37973 (A/G) ( 7p21.3 ) GLCCI1 Rs37973 (A/G) NR3C1 (rs41423247) CRHR1 (rs242939, TBX21 (rs2240017) (rs37973, GLCCl1 SNPs (continued) Izuhara [ 54 ] et al. Hosking [ 53 ] et al. Keskin [ 43 ] et al. 2 Table References Keskin et al. Clin Transl Allergy (2019) 9:2 Page 14 of 25 = 0.020 = 0.021 = 0.021, = 0.043 0.040 for rs37972 0.040 for = = 0.025 and = 0.035, ‑ respec dently associated dently associated clinical with poorer therapeutic response ICS to the wild - type allele who had a percent FEV1 change greater more than 5% were common than were homozygotes of the allele (rs37973, AA rare GG 49.49%, 67.01% vs. p < .05) signifcantly correlated correlated signifcantly with rs37972, rs37973 and rs11976862 at ICS (p 4 weeks rs37972 and for rs37973; p rs11976862), at for (p 8 weeks p p and at 12 weeks tively) (p and rs37973, p rs11976862) for association between risk of OCS increased risk increased use, of asthma exacerba ‑ tions and rs37972 genotypes rs37973 was indepen ‑ Homozygotes for FEV1 change was There was no signifcant was no signifcant There Study outcome Study ‑ ≥ 1.5 ≤ 19 - scores toms: Changes in FEV1 Changes in FEV1 Exacerbations: Hospital visits OCS use asthma symp Poor ACT scores ACQ Defnation Defnation of response ‑ ment mg, (125 mg, propionate twice a day) varied between patients Long term ICS treat Long Inhaled futicasone ICS maintenance dose ICS maintenance Medication Asthmatics:0.67 (T)Asthmatics:0.67 0.12 (T)Control: 0.37 (G) Control: Control: 0.55 (G), 0.37 (G) 0.49 (G) Rs37972 (T/C) Rs11976862 0.07 (G) Asthmatics: Rs37973 Asthmatics: BREATH:0.45 (T)BREATH:0.45 0.44 (T)PACMAN: 0.41(T)PAGES: MAF ‑ ‑ week run - in week propionate/salme combination terol twice (250/50 mg, the next daily) for - up Follow 24 weeks. at 4, visits occurred 12, and 24 weeks, and asthma control reviewed were tests and lung function per were tests formed SNPs of GLCCI1 were were of GLCCI1 SNPs genotyped in 182 asthmatic patients and 180 healthy –Treatment controls. trial: 2 - period and maintan ‑ for ance ICS therapy 12 weeks. pediatric asthma cohorts Inhaled futicasone Case control: study 24 control: Case analysis of three Meta - analysis of three Design = 1037) = 431) moderate - moderate = 323) 418 asthmatics of 182 asthmatic patients and 180 controls healthy variations GLCCI1 with ICS response in 30 was analyzed mild - to asthmatics children and young and young children adults Chinese population of Chinese population association of The North European (n BREATHE (n PACMAN PAGES (n PAGES Study population Study (7p21.3) GLCCI1 Rs37973 (A/G) (7p21.3) GLCCI1 Rs37972 (T/C) Rs11976862, (A/G) Rs37973 (A/G) (7p21.3) GLCCI1 Rs37972 (T/C) SNPs (continued) al. [ 44 ] et al. Xu al. [ 23 ] Hu et al. Vijverberget al. [ 55 ] al. Vijverberget 2 Table References Keskin et al. Clin Transl Allergy (2019) 9:2 Page 15 of 25 = .049) ‑ + AA genotype

GR polymor phisms with the dose of ICS needed to asthma con ‑ achieve was reported trol treatment, the change treatment, in FEV1% was higher in patients with the GG genotype than in patients with the AG 4%, p (7.5% vs. No association of After 3 months of ICS After Study outcome Study mL/year needed to achieve achieve needed to asthma control defned as a neces ‑ sity of taking high doses of of budesonide and > 500 mcg of futicasone ICS treatment ICS treatment (3 months) and at least 3 years defned as suc ‑ cessful when FEV1 decreased < 30 by The dose of ICS The was response Worse ICS > 800 i.e. mcg propionate FEV1% change after was Treatment Defnation Defnation of response + LABA, depending on the of asthma degree control ICS ICS or Medication rs6190 0.03 (G) rs41423247 0.36 (G) rs10052957 0.39 (T) rs6195 0.08 (G) 0.29 (G) MAF - term) and ship between the GR polymorphisms and poor response glucocorticoidsto in asthmatic patients (Polish) nation with a LABA, depending on the of asthma degree control spirometry testing after 3 months (short after at least 3 years (long - term) of ICS treatment ‑ Analysis of a relation ICS (alone or in combi ‑ - up visits with Follow Design - - asthma) - treat years of age) 18 years (6 to were (54 of children difcult with severe, to with atopic and with atopic mild - to nonatopic, moderate persistent persistent moderate asthma 113 asthmatic children 113 asthmatic children control 123 healthy 208 Slovenian adults 208 Slovenian Study population Study GR polymorphisms rs6190 rs41423247 rs6195 rs10052957 (7p21.3) GLCCI1 Rs37973 (A/G) SNPs (continued) [ 56 ] al. Szczepankiewicz et al. 45 ] [ et al. Rijavec 2 Table References Keskin et al. Clin Transl Allergy (2019) 9:2 Page 16 of 25 = 1.22 = 0.0002) = 1.22 (p = 0.0017) = 0.013) and increase in log - increase PC20 transformed methacholine for of years after four inhaled budesonide in asthmatic children with glutamine vari ‑ ants when compared with either H33H homozygotes or in dividuals not taking ICS (p studies: associated remained risk with an increased of asthma - related hospital visits and ‑ OCS use in the previ OR ous year,; (p OR but did not passed Bonferronicorrection test genes including associ ‑ NR3C1 , were at a nominal level ated risk with an increased of exacerbations in asthmatics using ICS cohortsin the three fold greater mean greater 3.5 - fold In a meta–analysis of six ST13 rs138335 None of the other Study outcome Study tivity (Methacholine) (PC20) tal visits use in the (OCS) year previous Bronchial Hyperreac ‑ Bronchial Exacerbations: hospi ‑ Oral corticosteroid Defnation Defnation of response + LRA + ICS + ICS LABA + ICS twice daily linesfortreatment Budesonide 200 μg Based on BTS guid ‑ Based on BTS 2: step SABA 3: step SABA 4: step SABA + LABA Medication of H33Q: 4.5% no minor homozygotes detected were Minor allele frequency >0.2 MAF trial cohorts year clinical 4 year CAMP, analysis of three Meta - analysis of three Design = 820) = 357) = 391) = 745) = 172) = 391) years with mild 5–12 years asthma moderate to in CAMP enrolled adults PAGES (n PAGES 701 children aged 701 children Children and young and young Children (n PACMAN BREATHE (n BREATHE PASS (n PASS Validation cohorts; Validation (n CAMP GALA II (n Study population Study selected for 17 genes selected for screening: for selected based on their involvement in the glucocorti ‑ coid (GC) receptor complex ( NR3C1 , , FKBP4 HSPCA , HSPA4 ST13 ), GC transport ( SERPINA6 ) or GC - signalling mediated , ( CREBBP , TBP NCOA3 SMAD3 ) selected based on a reportedpreviously association with asthma susceptibility, severity or asthma medication response ( ARG1 , 17q21 locus, IL2RB IL18R1 , PDE4D HLA - DQ , BCL2 ) Ten genes were genes were Ten TBX21 rs2240017 (H33Q) 50 tag SNPs were were 50 tag SNPs Seven genes were SNPs (continued) al. [ 49 ] et al. Tantisira Vijverberget al. [ 57 ] al. Vijverberget 2 Table References Keskin et al. Clin Transl Allergy (2019) 9:2 Page 17 of 25 ‑ A and = 0.041, > = 81.419% = 98.564%, = 0.006, TBX21 H33Q C > G polymorphisms were associ ‑ signifcantly with asthma ated status at control of ICS 5–12 weeks (p treatment power and p power respectively) polymorphism also signifcant showed associations with the mean changes in FEV1% during of ICS treat 12 weeks ment (p < 0.05) The NK2R The G231E > A G NK2R G231E G Study outcome Study and FEV1 Asthma control status control Asthma Defnation Defnation of response weeks of ICS 5–12 weeks Medication polymorphisms > 5 were MAF of four selected of four MAF MAF ‑ ment, Clinical trial (Korean) Asthmatics adults Asthmatics ICS treat 5–12 weeks Design moderate - moderate adult asthmatics 53 mild - to Study population Study M T > C) ADRB2 (G16R A > G) ADCY9 (I772 NK2R (G231E G > A) TBX21 (H33Q C > G) SNPs (continued) al. [ 46 ] et al. Ye 2 Table References Keskin et al. Clin Transl Allergy (2019) 9:2 Page 18 of 25 ‑ = 0.049) = 0.008) = 0.009) 0.013) and in = = 0.048) genotype‑ was signif cantly higher in good (p responders was even response evident in the more of non - subgroups smokers (p and in non - atopic patients (p among represented sac ‑ good responder changes in to cording FEV1 in the subgroups of non - smokers (p patients non - atopic (p The frequencyThe of AA genotypeThis related AA genotype was over Study outcome Study - point response to ICS to response patients therapy divided into were and ‘‘good’’ ‘‘poor’’ responders was defned as an of PD20 for increase methacholine that was smaller than one doubling dose the to compared initial PD20 decrease response in FEV1 more by than 30 ml/year was response Poor defned as less than a three in the ACTincrease after at least score of treatment 3 years Poor quality of life: was response defned as less than a 16 - point increase the initial AQLQ from score According to the to According response BHR:Poor function: Poor Lung control: Asthma - related Asthma Defnation Defnation of response years (alone 3 years for or in combina ‑ tion with long - acting beta agonists (LABA),according asthma achieved to control) Treatment with ICS Treatment Medication rs9910408 0.38 (G) MAF years clinical trial 3 years Design with atopic and with atopic mild to non - atopic, persistent moderate asthma 208 adult patients Study population Study TBX21 (17q21.32) rs9910408 SNPs (continued) al. [ 59 ] Lopert et al. 2 Table References Keskin et al. Clin Transl Allergy (2019) 9:2 Page 19 of 25 = 0.0004) variant was associ ‑ with increased ated risk of asthma - related hospital visits in the meta - analysis (OR 2.38, 95% CI 1.47–3.85, p with increased ated risk of uncontrolled by asthma measured 2.64, (OR scores ACQ 95% CI 1.00–6.98) and with was associated daily steroid increased 2.46, 95% CI dose (OR 1.38–4.39) as hazard ratios, for for ratios, as hazard exacerbations in those homozygous the for T2206C mutant allele were and (3.08;95% CI likely 1.00–9.47).more exac ‑ a severe have to erbation compared T2206C all other to genotypes in children The rs28364072 The variantThe was associ ‑ Relative risk,Relative expressed (3.95; 95% CI 1.64–9.51); and both white African - American Study outcome Study ‑ ‑ ‑ ‑ - scores ment visits disturbances limitations in Daily activities medication use dur ing the preceding 12 month bation risk Exacerbations: Emergency depart Hospitalization control: Asthma ACQ Respiratory symptoms sleep - related Asthma related - related Asthma (airway)Additional Severe asthma exacer Severe Defnation Defnation of response MAN: varied between patients twice daily ‑ and PAC BREATHE For dose ICS maintenance CAMP: Budesonide 200 µg Budesonide 200 μg twice daily Medication PACMAN 0.27 (G) BREATHE 0.26 (G) T2206C in 0.26 (G) in - 0.44 (G) Caucasians, African - Americans MAF year Clinical year year clinical trial year trial PACMAN& BREATHE: PACMAN& cohorts Asthma CAMP: 4 - CAMP 4 - CAMP Design = 939) = 386) = 311) African - American and Caucasian children Caucasianchildren (n PACMAN (n BREATHE CAMP (n CAMP 311 children (CAMP) (CAMP) 311 children Study population Study FCER2 (19p13.3) rs28364072 (A/G) FCER2 (19p13.3) rs889182 rs2287867 rs12980031 rs8110128 rs4804773 rs7249320 rs2277989 rs1042428 T2206C rs4996974 SNPs (continued) al. [ 61 ] Koster et al. al. [ 60 ] et al. Tantisira 2 Table References Keskin et al. Clin Transl Allergy (2019) 9:2 Page 20 of 25 ‑ = .01, ± 13.8% ± 10.7% in ± 9.6% in = 0.0150) ± 16.0% = 0.0463) = 22.8%) 13 studies, rs7216389 13 studies, ‑ was statistically signif with cantly associated ED asthma ‐ related visits/hospitalizations, (summary OR per in risk allele: increase 1.32, 95% CI 1.17–1.49, p < .0001, I2 = 3.9%) of the nine studies, the rs7216389 ‐ T was ‑ statistically signif with cantly associated risk of an increased OCS use/high ‐ dose ICS (summary OR per in variant increase allele: 1.19, 95% CI 1.04 ‐ 1.36, p I2 genotype AA had an 11.1 in mean increase FEV1 after 4–6 weeks of ICS, compared with 4.6 GG homozygotes (p had a 8.5 in mean increase FEV1 after ICS treat ment, which was higher signifcantly than 5.5 asthmatics with G allele (p In the meta ‐ analysis of In the meta ‐ analysis Asthmatics with Asthmatics Carriers of A allele Study outcome Study ‑ pitalizations/emer gency department visit (ED) oral corticosteroid use reported(OCS) the parent/child by at the study visit or based on completed study questionnaires related hos ‑ ‐ related Asthma (ii) short courses of Changes in FEV1 Defnation Defnation of response years years years of 12 years > of age: 200 mcg of futicasone dry daily powder age: 400 mcg futi ‑ casone dry powder daily < 12 Children ICS weeks of ICS: 4–6 weeks Children Medication 0.54–0.81 (T) 0.39 (A) MAF ‑ between variation in and the 17q21 locus, asthma exacerba ‑ ICS use tions despite of exacerbations in the observational cohort studies population CAMP were regularly regularly were with ICSs, treated spirometry was after repeated of treat 4–6 weeks ment. Bronchial hyperreactivity was assessed with a methacholine chal ‑ lenge test the association reporting retrospective study in Prospective In asthmatics who Design cogenomics in Childhood Asthma) populations (4529 treated steroid and young children adults) included patients with non ‐ Hispanic origins, European two included His ‑ one panic patients, African American, one East Asian patients were regularly regularly were with ICSs treated ‑ (Pharma 14 PiCA studies PiCA Ten - 213 asthmatics who Study population Study 17q21 locus rs7216389 (C/T) ORMDL3 (17q21) rs2872507 (G/A) SNPs (continued) al. [ 10 ] et al. Farzan al. [ 68 ] et al. Berce 2 Table References [ 10 ] et al. Farzan from adapted Table Keskin et al. Clin Transl Allergy (2019) 9:2 Page 21 of 25

In a Chinese population of 418 adult asthmatics receiv- studies [63, 64]. By 2015, two studies had investigated ing 24 weeks of ICS treatment, rs37973 was indepen- the role of SNPs in the NR3C1 in glucocorticoid sensi- dently associated with lower ICS response measured with tivity and response. However, only one study in adults FEV1 changes [44]. Percentages of homozygotes for the hadfound an association between anSNP within this wild-type allele who had > 5% FEV1 change were more gene (rs41423247) and response (defned by changes in common than homozygotes of the rare allele (AA 67.01% FEV1 predicted) to prednisolone but not ICS. In-vitro vs. GG 49.49%, p < .05) [44]. and in vivo models have shown that the G allele of the In another Chinese study, Hu et al. evaluated the asso- rs41423247 locus at the NR3C1 gene was associated with ciation of 24 SNPs within the GLCCI1 gene with ICS hypersensitivity to glucocorticoids [65, 66]. response. Tey included 180 healthy individuals and 182 Recently, our group reported a signifcant association adult asthmatic patients from Chinese Han population. between rs41423247 and improvements in FEV1 after 4 h In line with the previous fndings, patients homozygous upon a single high-dose of ICS (4000 µg FP) in 82 Turk- for the G allele had signifcantly poorer improvements ish children with moderate-to-severe asthma exacerba- in their lung function compared to the heterozygotes tions [43]. Children with the GG genotype at rs41423247 and homozygotes for the A allele after 12 weeks of treat- had a higher improvement in FEV1 [24.2% (11.5–36.3)] ment with ICS [23]. Contrasting fndings were shown in a compared to those with CG + CC, [7.9% (6.1–24.6) study in 208 Slovenian adults with atopic and nonatopic (p = 0.006)]. asthma. FEV1% predicted was higher in patients with GG genotype than patients with the AG or AA geno- 17q21locus type; after 3 months treatment FEV1% predicted change: 17q21 is the most consistently identifed locus associated 7.5% in patients homozygous for the G allele versus 4% with asthma onset in children and severe asthma, and it (patients with AG/AA genotype), p value: 0.049. After has also been linked to ICS response. By 2015, two stud- 3 years of treatment, similar efects were observed; FEV1 ies examined the association between SNPs within the %pred 7% (GG) versus 3.5% (AG/AA), p-value: 0.041) 17q21 locus and response to ICS [67, 68], though dif- [45]. ferent variants were studied. A Slovenian study showed However, in a study we performed in 82 Turkish chil- that asthmatic children treated with ICS showed a bet- dren with moderate-severe asthma exacerbation, we were ter improvement in FEV1% when they were homozygous unable to show any association between FEV1 increase for the AA genotype at rs2872507 at 17q21 compared to after 4 h of single-high-dose ICS and variation at GLCCI1 patients with AG or GG genotypes (13.3% vs. 7.0% vs. rs37973, rs3099266, rs2305089 genotypes [43]. 4.9% respectively). In addition, a post hoc exome array Terefore, seven candidate gene studies have tried analysis of Dutch children who participated in the Chil- to replicate the results of the original GWAS. Interest- dren Asthma Terapy Optimal (CATO) trial, showed that ingly, three studies that included East Asian popula- several variants in the 17q12-21 locus were found nomi- tions (Japanese and Chinese) could positively replicate nally associated with treatment response to ICS (based the results of the GWAS. Although the exact defnition on FEV1% improvement or BHR during ICS treatment). of the outcomes was diferent (annual decline in FEV1 Te strongest association in this region was found for and improvements in FEV1), all three showed that the G rs72821893 in KRT25. allele was associated with poor lung function outcomes. In 2018, one of the largest pharmacogenomics studies Interestingly, the minor allele frequency of rs37973 in [48] so far was performed by the international Pharma- East Asian patients was comparable to patients of Cauca- cogenomics in Childhood Asthma (PiCA) consortium sian ethnicity. However, in contrast to the non-Hispanic [69]. In this study, more than 4000 children were included white subjects in the GWAS, where LD was almost per- from 13 diferent studies. Genetic variation at position fect between rs37972 and rs37973, in the study by Hu rs7216389 in the17q21 locus was found to be associated et al. this LD was far from perfect. with an increased risk of OCS use and asthma-related hospitalizations/ER visits despite ICS use. NR3C1 Glucocorticoids bind to their receptors in the cytosol Discussion and after the transfer of glucocorticoid receptor com- In the past 3 years, nine additional pharmacogenom- plex to the nucleus, they regulate expression of the ics studies on ICS have been published, of which three genes involved in the infammatory pathways [62, 63]. GWAS. Although there is few overlap between identifed Terefore, due to its central role in glucocorticoid sign- variants and applied methodologies vary largely, in vitro aling pathway, NR3C1, the gene encoding GR, has been and/or in silico analyses provide additional evidence that the center of attention in numerous pharmacogenomics genes discovered in GWAS (e.g. GLCCI1, FBXL7, T gene, Keskin et al. Clin Transl Allergy (2019) 9:2 Page 22 of 25

ALLC, CMTR1) might play a direct or indirect role in studies have emphasized the importance of defning asthma/treatment response pathways. the correct phenotype in successful asthma treatment. Candidate gene analysis, on the other hand identi- A good characterization of patients as well has a stand- fed fve SNPs within four genes (CRHR1: rs242941, ardized defnition of treatment response is therefore rs1876828; GLCCI1: rs37973; FCεR2: rs28364072 and extremely important. Since most pharmacogenetic stud- TBX21: rs2240017) that were positively replicated at ies are underpowered, collaboration is inevitable. Novel least once. In line with the previous systematic review by consortia, such as the Pharmacogenomics in Childhood Farzan et al., most consistent results were obtained for Asthma (PiCA) consortium, are emerging [69, 72] and FCεR2 (rs28364072) and TBX21(rs2240017) [46, 51, 58, are able to conduct large-scale GWAS meta-analyses, 60, 61]. Te only gene that showed a positive association while performing sensitivity analyses for specifc sub- in both GWAS and candidate gene analyses was GLCCI1 groups. Tis might lead to novel insights on the general- [12, 23, 44, 45, 54]. However, it should be noted that this izability of fndings between diferent populations, as well may be partly due to the fact the candidate gene stud- as more power to identify novel genetic variants. ies were undertaken after identifcation of GLCCI1 in a In order to increase the utility of the pahramacog- GWAS analysis. enomic studies in asthma the data that have emerged Consistent signifcant associations were replicated from GWAS, candidate gene, and mechanistic candi- between FCεR2 rs28364072 and poor ICS response meas- dates should be evaluated together. Tis approach will ured by exacerbations in two long follow up childhood allow the discovery not only of pharmacologic agents that studies [60, 61], asthma symptoms measured by ACQ in directly target the disease asthma but also other path- one long follow up childhood study [61], and lung func- ways and biomarkers that are indirectly associated with tion in one study [51] in asthmatic children. Moreover, or increase the risk of the disease such as atopy, eosino- supporting clinical fndings, functional data related with phils, bronchial hyperreactivity, pulmonary functions, FCER2 provided a mechanistic basis for the observed and NO [73]. associations with severe exacerbations. Tis variation in Pharmacogenomics may produce very important infor- FCER2, T2206C, was associated with decreased FCER2 mation for the practicing clinician. Predicting the drug expression and can adversely afect normal negative response based on genetic testing has implications with feedback in the control of IgE synthesis and action [60]. respect to not only providing the best treatment but Moreover, it has been shown that the highest IgE levels also preventing the adverse events that may be associ- were found in subjects both homozygous for the T2206C ated especially with higher doses and systemic CS [74, variant and taking ICSs, demonstrating a signifcant ster- 75]. On a larger scale it may have tremendous efect on oid-genotype interaction. Tis may actually be connected pharmacoeconomics by decreasing unnecessary medica- with the observation that higher IgE levels are associated tion use as well as by having a positive impact on the cost with increased frequency of exacerbations [70], and hos- of the disease, as has been shown in other disease areas pitalizations [71, 72] in children with asthma. [76]. Even though ongoing international attempts such Both studies investigating TBX21 H33Q and ICS as “Ubiquitous Pharmacogenomics (U-PGx)” project response showed signifcant association measured by two “An Horizon2020 Program to Drive Pharmacogenom- diferent outcomes: improvement in BHR in one child- ics into Clinical Practice” that is going on in seven Euro- hood study of 4 years duration [58], and asthma control pean countries [77] holds promise, we are far from using status in a 5–12 weeks adult study [46]. Since BHR and pharmacogenomics data in clinical asthma practice. In asthma control level are related to the quality of life in contrast to long-acting beta-2 agonists [78], response asthma patients and prognosis of asthma, genetic varia- to corticosteroids might be too complex to be mainly tion in TBX21 may be important for asthma phenotypes. driven by a few genetic variants. Nevertheless, pharma- Tis fnding was further supported by a functional study cogenomics studies still might provide useful insights that showed that the TBX21 variant increases T helper 1 in underlying pathways or identify novel drug targets, and decreases T helper 2 cytokine expression compared especially when combined with other-omics layers (e.g. to wild type [58]. However, we were not able show any epigenomics, transcriptomics, microbiomics, breathom- association between TBX21 H33Q and FEV1 4 h after ics) or assessing the interaction with the environmental single-high-dose ICS in children with moderate-severe factors using genome-wide interaction studies in well asthma exacerbation [43]. Tis diference may be due to characterized patient populations [79]. Especially with diferent outcome parameter or diferent study design or the emergence of novel expensive biologics for patients diferent doses and duration of ICS. with a poor response to ICS, it is of great importance to Asthma is a very heterogeneous disease with various assess at an early stage which patients have an intrinsic phenotypes and underlying disease pathways. Recent poor response to ICS and will be eligible candidates for Keskin et al. Clin Transl Allergy (2019) 9:2 Page 23 of 25

these novel targeted treatments. Genomics might, at 3. Malmstrom K, Rodriguez-GomezG G, Guerra J, et al. Oral montelukast, inhaled beclomethasone, and placebo for chronic asthma: a randomized, least partly, help to answer this question. controlled trial. Montelukast/Beclomethasone Study Group. Ann Intern Med. 1999;130:487–95. 4. Drazen JM, Silverman EK, Lee TH. Heterogeneity of therapeutic responses Abbreviations in asthma. Br Med Bull. 2000;56:1054–70. ICS: inhaled corticosteroid; SNP: single nucleotide polymorphism; GWAS: 5. Chung KF, Godard P, Adelroth E, et al. Difcult/therapy-resistant asthma: genome wide association studies; SHARP: Single-Nucleotide Polymorphism the need for an integrated approach to defne clinical phenotypes, evalu‑ Health Association-Asthma Resource Project; FEV1: forced expiratory volume ate risk factors, understand pathophysiology and fnd novel therapies. in one second; FP: futicasone propionate; FF: futicasone furoate; CAMP: ERS Task Force on Difcult/Therapy-Resistant Asthma. European Respira‑ Childhood Asthma Management Program; GLCCI1: glucocorticoid-induced tory Society. Eur Respir J. 1999;13:1198–208. transcript 1 protein; FBXL7: F-box and leucine-rich repeat protein 7; ALLC: 6. Haughney J, Price D, Kaplan A, et al. Achieving asthma control in allantoicase gene; CMTR1: cap methyltransferase 1; TRIM24: tripartite motif practice: understanding the reasons for poor control. Respir Med. containing 24; MAGI2: Membrane Associated Guanylate Kinase; NR3C1: 2008;102:1681–93. nuclear receptor subfamily 3 group C member 1; CRHR1: corticotropin releas‑ 7. McGhan SL, MacDonald C, James DE, et al. Factors associated with ing hormone receptor 1; FCER2: Fc fragment of IgE, low-afnity II, receptor for poor asthma control in children aged fve to 13 years. Can Respir J. (CD23); ADRB2: Adrenoceptor beta 2; TBX21: T-box 21. 2006;13:23–9. 8. Lima JJ, Blake KV, Tantisira KG, Weiss ST. Pharmacogenetics of asthma. Authors’ contributions Curr Opin Pulm Med. 2009;15:57–62. OZK, OMK, EB, CK, HA: made substantial contributions to conception and 9. Palmer LJ, Silverman ES, Weiss ST, Drazen JM. Pharmacogenetics of design, acquisition of data, analysis and interpretation of data. OZK, OMK, EB, asthma. Am J Respir Crit Care Med. 2002;165:861–6. CK, HA: been involved in drafting the manuscript. OZK, OMK, NF, AHMvdZ, 10. Farzan N, Vijverberg SJ, Arets HG, Raaijmakers JA, Maitland-van der Zee MEW, SJV been involved in revising the manuscript critically for important AH. Pharmacogenomics of inhaled corticosteroids and leukotriene modi‑ intellectual content and given fnal approval of the version to be published. fers: a systematic review. Clin Exp Allergy. 2017;47:271–93. Each author have participated sufciently in the work to take public respon‑ 11. Moher D, Liberati A, Tetzlaf J, Altman DG, PRISMA Group. Preferred sibility for appropriate portions of the content; and agreed to be accountable reporting items for systematic reviews and meta-analyses: the PRISMA for all aspects of the work in ensuring that questions related to the accuracy or statement. J Clin Epidemiol. 2009;62:1006–12. integrity of any part of the work are appropriately investigated and resolved. 12. Tantisira KG, Lasky-Su J, Harada M, et al. Genomewide association All authors read and approved the fnal manscript. between GLCCI1 and response to glucocorticoid therapy in asthma. N Engl J Med. 2011;365:1173–83. Author details 13. Tantisira KG, Damask A, Szefer SJ, et al. Genome-wide association identi‑ 1 Paediatric Allergy and Immunology Department, School of Medicine, fes the T gene as a novel asthma pharmacogenetic locus. Am J Respir 2 Gaziantep University, Gaziantep, Turkey. Department of Respiratory Medicine, Crit Care Med. 2012;185:1286–91. University of Amsterdam, Amsterdam UMC, Meibergdreef 9, Amsterdam, 14. Park H-W, Dahlin A, Tse S, et al. Genetic predictors associated with 3 Netherlands. Pediatric Allergy and Asthma Unit, Hacettepe University School improvement of asthma symptoms in response to inhaled corticoster‑ 4 of Medicine, 06100 Ankara, Turkey. Department of Molecular Biology, Faculty oids. J Allergy Clin Immunol. 2014;133(664–9):e5. 5 of Sciences, Hacettepe University, Ankara, Turkey. Department of Pediatric 15. Park T-J, Park J-S, Cheong HS, et al. Genome-wide association study identi‑ Respiratory Medicine and Allergy, University of Amsterdam, Amsterdam UMC, fes ALLC polymorphisms correlated with FEV1 change by corticosteroid. 6 Meibergdreef 9, Amsterdam, Netherlands. Department of Medicine, National Clin Chim Acta. 2014;436:20–6. Jewish Health, Denver, CO, USA. 16. Wang Y, Tong C, Wang Z, Wang Z, Mauger D, Tantisira KG, Israel E, Szefer SJ, Chinchilli VM, Boushey HA, Lazarus SC, Lemanske RF, Wu R. Pharma‑ Competing interests codynamic genome-wide association study identifes new responsive The authors declare that they have no competing interests. loci for glucocorticoid intervention in asthma. Pharmacogenomics J. 2015;15:422–9. Consent for publication 17. Dahlin A, Denny J, Roden DM, et al. CMTR1 is associated with increased Not applicable. asthma exacerbations in patients taking inhaled corticosteroids. Immun Infamm Dis. 2015;3:350–9. Ethics approval and consent to participate 18. Mosteller M, Hosking L, Murphy K, et al. No evidence of large genetic Not applicable. efects on steroid response in asthma patients. J Allergy Clin Immunol. 2017;139(797–803):e7. Funding 19. Wu RL, Tong CF, Mauger D, Mauger D, Tantisira K, Szefer SJ, et al. A There is no funding. conceptual framework for pharmacodynamic genome-wide association studies in pharmacogenomics. Drug Discov Today. 2011;16:804–90. Publisher’s Note 20. Yeh TY, Sbodio JI, Nguyen MT, Meyer TN, Lee RM, Chi NW. Tankyrase-1 over expression reduces genotoxin-induced cell death by inhibiting Springer Nature remains neutral with regard to jurisdictional claims in pub‑ PARP1. Mol Cell Biochem. 2005;276:183–92. lished maps and institutional afliations. 21. Kuschel L, Hansel A, Schonherr R, Weissbach H, Brot N, Hoshi T, et al. 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