Pharmacogenomics in asthma treatment

Med posamezniki obstajajo velike razlike v učinku protiastmatične terapije, ki so pogojene predvsem z različnim genetskim zapisom. Namen farmakogenomike je poiskati tiste polimorfizme, ki so povezani z vsemi učinki določenega zdravila. Farmakogenomika pri astmi zaenkrat proučuje predvsem vpliv genov, ki kodirajo receptorje za zdravila, komponente postreceptorske signalne transdukcije in transkripcijske dejavnike. Največ raziskav je bilo narejenih na področju farmakogenomike beta2 agonistov. Mutacija Arg/Arg na mestu 16 gena ADRB2, ter mutacije v genih LTC4S, ALOX5 in CRHR1 spremenijo odziv na protiastmatično terapijo. Cilj farmakogenomike astme pa je poiskati čimbolj učinkovito protiastmatično zdravilo z čimmanj stranskimi učinki individualno za vsakega posameznika na podlagi njegovega genotipa.There are substantial differences in the effect of antiasthmatic therapy between individuals which are dependent on the diversity of the genetic code. The purpose of pharmacogenomics is to find out those polymorphisms, which are connected with all effects of certain drug. For now the pharmacogenomics of asthma above all study the influence of the genes which code for drug receptors, signal transduction components and transcription factors. Most studies were done in the field of pharmacogenomics of beta2 agonists. Gene mutations that are known to alter the response to asthma therapy include Arg/Arg at position 16 in ADRB2 gene, mutations of LTC4S and ALOX5 and CRHR1 variants. The goal of pharmacogenomics is to find out most efficient drug without adverse side effects individually suited for each patient on basis of his genotype

Pharmacogenomic associations of adverse drug reactions in asthma:systematic review and research prioritisation

We would like to thank the NIHR Collaboration for Leadership in Applied Health Research and Care North West Coast (CLAHRC) for funding Amanda McKenna’s internship, and Charlotte Kings MPhil, and the members of the PiCA consortia for their help in completing the survey. U. Potočnik, K. Repnik and V. Berce were supported by SysPharmPedia grant, co-financed by Ministry of Education, Science and Sport of the Republic of Slovenia Author information These authors contributed equally: Charlotte King, Amanda McKenna These authors jointly supervised this work: Ian Sinha, Daniel B. HawcuttPeer reviewedPublisher PD

17q21 variant increases the risk of exacerbations in asthmatic children despite inhaled corticosteroids use

_To the Editor,_ Approximately 25% of the asthmatic children suffer from uncontrolled asthma despite regular use of inhaled corticosteroids (ICS). Variation within the 17q21 locus is the strongest genetic determinant for childhood‐onset asthma. Recently, the influence of this locus on treatment outcomes has been shown in several studies. The Pharmacogenomics in Childhood Asthma (PiCA) consortium is a multiethnic consortium that brings together data from ≥14 000 asthmatic children/young adults from 12 different countries to study the pharmacogenomics of uncontrolled asthma despite treatment. In 14 PiCA populations (with over 4000 asthmatic patients), we studied the association between variation in the 17q21 locus, and asthma exacerbations despite ICS use. We specifically focused on rs7216389, a single nucleotide polymorphism (SNP) in the 17q21 locus strongly associated with childhood asthma and initially identified by Moffatt et al. [...

Genome-wide association study of inhaled corticosteroid response in admixed children with asthma

Background Inhaled corticosteroids (ICS) are the most widely prescribed and effective medication to control asthma symptoms and exacerbations. However, many children still have asthma exacerbations despite treatment, particularly in admixed populations, such as Puerto Ricans and African Americans. A few genome‐wide association studies (GWAS) have been performed in European and Asian populations, and they have demonstrated the importance of the genetic component in ICS response. Objective We aimed to identify genetic variants associated with asthma exacerbations in admixed children treated with ICS and to validate previous GWAS findings. Methods A meta‐analysis of two GWAS of asthma exacerbations was performed in 1347 admixed children treated with ICS (Hispanics/Latinos and African Americans), analysing 8.7 million genetic variants. Those with P ≤ 5 × 10−6 were followed up for replication in 1697 asthmatic patients from six European studies. Associations of ICS response described in published GWAS were followed up for replication in the admixed populations. Results A total of 15 independent variants were suggestively associated with asthma exacerbations in admixed populations (P ≤ 5 × 10−6). One of them, located in the intergenic region of APOBEC3B and APOBEC3C, showed evidence of replication in Europeans (rs5995653, P = 7.52 × 10−3) and was also associated with change in lung function after treatment with ICS (P = 4.91 × 10−3). Additionally, the reported association of the L3MBTL4‐ARHGAP28 genomic region was confirmed in admixed populations, although a different variant was identified. Conclusions and clinical relevance This study revealed the novel association of APOBEC3B and APOBEC3C with asthma exacerbations in children treated with ICS and replicated previously identified genomic regions. This contributes to the current knowledge about the multiple genetic markers determining responsiveness to ICS which could lead in the future the clinical identification of those asthma patients who are not able to respond to such treatment

Pharmacogenomic associations of adverse drug reactions in asthma: systematic review and research prioritisation

A systematic review of pharmacogenomic studies capturing adverse drug reactions (ADRs) related to asthma medications was undertaken, and a survey of Pharmacogenomics in Childhood Asthma (PiCA) consortia members was conducted. Studies were eligible if genetic polymorphisms were compared with suspected ADR(s) in a patient with asthma, as either a primary or secondary outcome. Five studies met the inclusion criteria. The ADRs and polymorphisms identified were change in lung function tests (rs1042713), adrenal suppression (rs591118), and decreased bone mineral density (rs6461639) and accretion (rs9896933, rs2074439). Two of these polymorphisms were replicated within the paper, but none had external replication. Priorities from PiCA consortia members (representing 15 institution in eight countries) for future studies were tachycardia (SABA/LABA), adrenal suppression/crisis and growth suppression (corticosteroids), sleep/behaviour disturbances (leukotriene receptor antagonists), and nausea and vomiting (theophylline). Future pharmacogenomic studies in asthma should collect relevant ADR data as well as markers of efficacy

Identification of ROBO2 as a potential locus associated with inhaled corticosteroid response in childhood asthma

Inhaled corticosteroids (ICS) are the most common asthma controller medication. An important contribution of genetic factors in ICS response has been evidenced. Here, we aimed to identify novel genetic markers involved in ICS response in asthma. A ge-nome-wide association study (GWAS) of the change in lung function after 6 weeks of ICS treatment was performed in 166 asthma patients from the SLOVENIA study. Patients with an improvement in lung function ≥8% were considered as ICS responders. Suggestively associated variants (p-value≤5x10-6) were evaluated in an independent study (n=175). Validation of the association with asthma exacerbations despite ICS use was attempted in European (n=2,681) and admixed (n=1,347) populations. Variants previously associated with ICS response were also assessed for replication. As a result, the SNP rs1166980 from the ROBO2 gene was suggestively associated with the change in lung function (OR for G allele: 7.01, 95% CI: 3.29 – 14.93, p=4.61x10-7), although this was not validated in CAMP. ROBO2 showed gene-level evidence of replication with asthma exacerbations despite ICS use in Europeans (minimum p-value=1.44x10-5), but not in admixed individuals. The association of PDE10A-T with ICS response de-scribed by a previous study was validated. This study suggests that ROBO2 could be a potential novel locus for ICS response in Europeans

Epigenome-Wide Association Studies of the Fractional Exhaled Nitric Oxide and Bronchodilator Drug Response in Moderate-to-Severe Pediatric Asthma

Asthma is the most prevalent pediatric chronic disease. Bronchodilator drug response (BDR) and fractional exhaled nitric oxide (FeNO) are clinical biomarkers of asthma. Although DNA methylation (DNAm) contributes to asthma pathogenesis, the influence of DNAm on BDR and FeNO is scarcely investigated. This study aims to identify DNAm markers in whole blood associated either with BDR or FeNO in pediatric asthma. We analyzed 121 samples from children with moderate-to-severe asthma. The association of genome-wide DNAm with BDR and FeNO has been assessed using regression models, adjusting for age, sex, ancestry, and tissue heterogeneity. Cross-tissue validation was assessed in 50 nasal samples. Differentially methylated regions (DMRs) and enrichment in traits and biological pathways were assessed. A false discovery rate (FDR) < 0.1 and a genome-wide significance threshold of p < 9 × 10−8 were used to control for false-positive results. The CpG cg12835256 (PLA2G12A) was genome-wide associated with FeNO in blood samples (coefficient= −0.015, p = 2.53 × 10−9) and nominally associated in nasal samples (coefficient = −0.015, p = 0.045). Additionally, three CpGs were suggestively associated with BDR (FDR < 0.1). We identified 12 and four DMRs associated with FeNO and BDR (FDR < 0.05), respectively. An enrichment in allergic and inflammatory processes, smoking, and aging was observed. We reported novel associations of DNAm markers associated with BDR and FeNO enriched in asthma-related processes

Genome-wide association study of asthma exacerbations despite inhaled corticosteroids use

Rationale Substantial variability in response to asthma treatment with inhaled corticosteroids (ICS) has been described among individuals and populations, suggesting the contribution of genetic factors. Nonetheless, only a few genes have been identified to date. We aimed to identify genetic variants associated with asthma exacerbations despite ICS use in European children and young adults and to validate the findings in non-Europeans. Moreover, we explored whether a gene-set enrichment analysis could suggest potential novel asthma therapies. Methods A genome-wide association study (GWAS) of asthma exacerbations was tested in 2681 European-descent children treated with ICS from eight studies. Suggestive association signals were followed up for replication in 538 European asthma patients. Further evaluation was performed in 1773 non-Europeans. Variants revealed by published GWAS were assessed for replication. Additionally, gene-set enrichment analysis focused on drugs was performed. Results Ten independent variants were associated with asthma exacerbations despite ICS treatment in the discovery phase (p≤5×10−6). Of those, one variant at the CACNA2D3-WNT5A locus was nominally replicated in Europeans (rs67026078, p=0.010), but this was not validated in non-European populations. Five other genes associated with ICS response in previous studies were replicated. Additionally, an enrichment of associations in genes regulated by trichostatin A treatment was found. Conclusions The intergenic region of CACNA2D3 and WNT5A was revealed as a novel locus for asthma exacerbations despite ICS treatment in European populations. Genes associated were related to trichostatin A, suggesting that this drug could regulate the molecular mechanisms involved in treatment response