Niloufar Farzan

Rationale and design of the multiethnic Pharmacogenomics in Childhood Asthma consortium

AIM International collaboration is needed to enable large-scale pharmacogenomics studies in childhood asthma. Here, we describe the design of the Pharmacogenomics in Childhood Asthma (PiCA) consortium. MATERIALS & METHODS Investigators of each study participating in PiCA provided data on the study characteristics by answering an online questionnaire. RESULTS A total of 21 studies, including 14,227 children/young persons (58% male), from 12 different countries are currently enrolled in the PiCA consortium. Fifty six percent of the patients are Caucasians. In total, 7619 were inhaled corticosteroid users. Among patients from 13 studies with available data on asthma exacerbations, a third reported exacerbations despite inhaled corticosteroid use. In the future pharmacogenomics studies within the consortium, the pharmacogenomics analyses will be performed separately in each center and the results will be meta-analyzed. CONCLUSION PiCA is a valuable platform to perform pharmacogenetics studies within a multiethnic pediatric asthma population.

Pharmacogenomics of inhaled corticosteroids and leukotriene modifiers : a systematic review

Pharmacogenetics studies of anti‐inflammatory medication of asthma have expanded rapidly in recent decades, but the clinical value of their findings remains limited.

Treatment response heterogeneity in asthma: the role of genetic variation

ABSTRACT Introduction: Asthmatic patients show a large heterogeneity in response to asthma medication. Rapidly evolving genotyping technologies have led to the identification of various genetic variants associated with treatment outcomes. Areas covered: This review focuses on the current knowledge of genetic variants influencing treatment response to the most commonly used asthma medicines: short- and long-acting beta-2 agonists (SABA/LABA), inhaled corticosteroids (ICS) and leukotriene modifiers. This review shows that various genetic variants have been identified, but none are currently used to guide asthma treatment. One of the most promising genetic variants is the Arg16 variant in the ADRB2 gene to guide LABA treatment in asthmatic children. Expert commentary: Poor replication of initially promising results and the low fraction of variability accounted for by single genetic variants inhibit pharmacogenetic findings to reach the asthma clinic. Nevertheless, the identification of genetic variation influencing treatment response does provide more insights in the complex processes underlying response and might identify novel targets for treatment. There is a need to report measures of clinical validity, to perform precision-medicine guided trials, as well as to understand how genetic variation interacts with environmental factors. In addition, systems biology approaches might be able to show a more complete picture of these complex interactions.

The use of pharmacogenomics, epigenomics, and transcriptomics to improve childhood asthma management: Where do we stand?

Asthma is a complex multifactorial disease and it is the most common chronic disease in children. There is a high variability in response to asthma treatment, even in patients with good adherence to maintenance treatment, and a correct inhalation technique. Distinct underlying disease mechanisms in childhood asthma might be the reason of this heterogeneity. A deeper knowledge of the underlying molecular mechanisms of asthma has led to the recent development of advanced and mechanism‐based treatments such as biologicals. However, biologicals are recommended only for patients with specific asthma phenotypes who remain uncontrolled despite high dosages of conventional asthma treatment. One of the main unmet needs in their application is lack of clinically available biomarkers to individualize pediatric asthma management and guide treatment. Pharmacogenomics, epigenomics, and transcriptomics are three omics fields that are rapidly advancing and can provide tools to identify novel asthma mechanisms and biomarkers to guide treatment. Pharmacogenomics focuses on variants in the DNA, epigenomics studies heritable changes that do not involve changes in the DNA sequence but lead to alteration of gene expression, and transcriptomics investigates gene expression by studying the complete set of mRNA transcripts in a cell or a population of cells. Advances in high‐throughput technologies and statistical tools together with well‐phenotyped patient inclusion and collaborations between different centers will expand our knowledge of underlying molecular mechanisms involved in disease onset and progress. Furthermore, it could help to select and stratify appropriate therapeutic strategies for subgroups of patients and hopefully bring precision medicine to daily practice.

Pharmacogenetics of inhaled long-acting beta2-agonists in asthma: A systematic review

Long‐acting beta2‐agonists (LABA) are recommended in asthma therapy; however, not all asthma patients respond well to LABA. We performed a systematic review on genetic variants associated with LABA response in patients with asthma.

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

Approximately 25% of the asthmatic children suffer from uncontrolled asthma despite regular use of inhaled corticosteroids (ICS).1 Variation within the 17q21 locus is the strongest genetic determinant for childhood‐onset asthma.2 Recently, the influence of this locus on treatment outcomes has been shown in several studies.3, 4 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.5 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.2 Ten PiCA studies included patients with non‐Hispanic European origins, two included Hispanic patients, one African American, and one included East Asian patients. Additional details of the study populations can be found in the Data S1. Two outcomes were assessed: (i) asthma‐related hospitalizations/emergency department visit (ED) visits and (ii) short courses of oral corticosteroid (OCS) use reported by the parent/child at the study visit or based on completed study questionnaires. Age, gender, genotype data, and exacerbation data were available for 4529 steroid‐treated children and young adults (Table 1). Logistic regression analysis was used to assess the risk of exacerbations when carrying rs7216389. Due to potential heterogeneity between cohorts, the odds ratios (ORs) were meta‐analyzed with the inverse variance weighting method assuming random effects. See Data S1 for more detail.