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

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 influences 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 identified genetic variants. To date, seven genome wide association studies (GWAS) examining ICS response have been published. There is little overlap between identified variants and methodologies 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.

<p>Pharmacogenetics of Pediatric Asthma: Current Perspectives</p>

“…32,36,40,73,74,79 During this period, candidate-gene studies reported the association of genes previously described in pharmacogenetic studies of pediatric asthma with treatment response (ADRB2, GSDMB, FCER2, and VEGFA). 13,[16][17][18] Additionally, other candidate genes have been related for the first time to this phenotype in children (SPATS2L, ASB3, IL1RL1, MMP9, and COL2A1). Although several findings support previous evidence of some of these genes in asthma treatment response, inconsistent results across the literature or even across the studies included in this review have been found.…”

“…2 Corticosteroids contribute to control asthma symptoms due to its anti-inflammatory and immunosuppressive effects as a result of the interaction with the glucocorticoid receptor (GR). 45 Nonetheless, many factors such as an incorrect inhaler technique, 46 a poor adherence, 47 comorbidities, 48 lung microbiome dysbiosis, [49][50][51][52] and genetic variants, 13,17 may contribute to a loss in asthma control and to the development of asthma exacerbations despite ICScontained therapies. The identification of these factors is essential to differentiate children with difficult-to-treat asthma from those that are resistant to pharmacological therapies.…”

“…12 The evidence of the role of genetic variants on asthma treatment response has been summarized in some recent reviews. [13][14][15][16][17][18] Thereby, this review aims to update the current findings described in pharmacogenetic studies of pediatric asthma published from 2018 through 2019.…”

Novel Comprehensive Bioinformatics Approaches to Determine the Molecular Genetic Susceptibility Profile of Moderate and Severe Asthma

“…Erb-B2 tyrosine kinase 2 (ErbB2) was found to be highly correlated with asthma and was suggested to be a novel therapeutic target for asthma [27,28]. Moreover, both NR3C1 and COL1A1 were linked to inflammation in asthmatic airways [29,30]. While, clinical studies have reported that NR3C1 is strongly associated with asthma severity [31].…”

Precision Medicine in Childhood Asthma: Omic Studies of Treatment Response

“…In the last year, the role of different omics in asthma treatment response has been recapitulated in different reviews [16][17][18][19][20][21]. This review aims to provide an update on the latest findings in omic studies of pediatric asthma treatment response.…”