Realizing Personalized Medicine in Asthmatic Children Requires Large-Scale Collaboration

Vijverberg, Susanne; Turner, Steve; Palmer, Colin N. A.; Tantisira, Kelan G.; Maitl, Anke Hilse; Zee, van der A Aant

doi:10.4172/2161-0665.1000e127

Cited by 3 publications

(2 citation statements)

References 20 publications

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“…Various authors endorse the major genetic contribution to predisposition to asthma, with estimates of up to 74% in adults and 90% in children [ 42 , 43 , 44 , 45 , 46 , 47 ]. There have also been studies on the role of pharmacogenetics in response to treatment with inhaled SABAs [ 48 ] and ICS [ 49 , 50 , 51 ]. However, no studies report genetic biomarkers associated with the response to BTs, such as omalizumab, in asthmatic patients.…”

Section: Discussionmentioning

confidence: 99%

Influence of Genetics on the Response to Omalizumab in Patients with Severe Uncontrolled Asthma with an Allergic Phenotype

Rojo-Tolosa

Sánchez-Martínez

Pineda-Lancheros

et al. 2023

IJMS

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Omalizumab is a monoclonal antibody indicated for the treatment of severe uncontrolled asthma with an allergic phenotype. Its effectiveness could be influenced by clinical variables and single nucleotide polymorphisms (SNPs) in one or more of the genes involved in the mechanism of action and process of response to omalizumab, and these could be used as predictive biomarkers of response. We conducted an observational retrospective cohort study that included patients with severe uncontrolled allergic asthma treated with omalizumab in a tertiary hospital. Satisfactory response after 12 months of treatment was defined as (1) Reduction ≥ 50% of exacerbations or no exacerbations, (2) Improvement of lung function ≥ 10% FEV1, and (3) Reduction ≥ 50% of OCS courses or no OCS. Polymorphisms in the FCER1A (rs2251746, rs2427837), FCER1B (rs1441586, rs573790, rs1054485, rs569108), C3 (rs2230199), FCGR2A (rs1801274), FCGR2B (rs3219018, rs1050501), FCGR3A (rs10127939, rs396991), IL1RL1 (rs1420101, rs17026974, rs1921622), and GATA2 (rs4857855) genes were analyzed by real-time polymerase chain reaction (PCR) using TaqMan probes. A total of 110 patients under treatment with omalizumab were recruited. After 12 months of treatment, the variables associated with a reduction in exacerbations were the absence of polyposis (odds ratio [OR] = 4.22; 95% confidence interval [CI] = 0.95–19.63), IL1RL1 rs17026974-AG (OR = 19.07; 95% CI = 1.27–547), and IL1RL1 rs17026974-GG (OR = 16.76; 95% CI = 1.22–438.76). Reduction in oral corticosteroids (OCS) was associated with age of starting omalizumab treatment (OR = 0.95; 95% CI = 0.91–0.99) and blood eosinophil levels > 300 cells/µL (OR = 2.93; 95% CI = 1.01–9.29). Improved lung function showed a relationship to the absence of chronic obstructive pulmonary disease (COPD) (OR = 12.16; 95% CI = 2.45–79.49), FCGR2B rs3219018-C (OR = 8.6; 95% CI = 1.12–117.15), GATA2 rs4857855-T (OR = 15.98; 95% CI = 1.52–519.57) and FCGR2A rs1801274-G (OR = 13.75; 95% CI = 2.14–142.68; AG vs. AA and OR = 7.46; 95% CI = 0.94–89.12; GG vs. AA). Meeting one response criterion was related to FCER1A rs2251746-TT (OR = 24; 95% CI = 0.77–804.57), meeting two to age of asthma diagnosis (OR = 0.93; 95% CI = 0.88–0.99), and meeting all three to body mass index (BMI) < 25 (OR = 14.23; 95% CI = 3.31–100.77) and C3 rs2230199-C (OR = 3; 95% CI = 1.01–9.92). The results of this study show the possible influence of the polymorphisms studied on the response to omalizumab and the clinical benefit that could be obtained by defining predictive biomarkers of treatment response.

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Section: Discussionmentioning

confidence: 99%

Influence of Genetics on the Response to Omalizumab in Patients with Severe Uncontrolled Asthma with an Allergic Phenotype

Rojo-Tolosa

Sánchez-Martínez

Pineda-Lancheros

et al. 2023

IJMS

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“…International and nation‐wide collaborations have been established to perform large‐scale GWAS to identify asthma susceptibility genes . To assess the clinical value of genetic markers for asthma management, international collaboration, and large‐scale meta‐analyses with well‐phenotyped asthmatic children are needed . Hopefully, the recent PiCA consortium that combines existing studies to obtain larger sample sizes will deliver new opportunities to study the clinical importance of pharmacogenetics associations in large observational studies …”

Section: Introductionmentioning

confidence: 99%

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

Farzan

Vijverberg

Kabesch

et al. 2018

Pediatric Pulmonology

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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.

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Genomic Predictors of Asthma Phenotypes and Treatment Response

2019

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Asthma is a complex respiratory disease considered as the most common chronic condition in children. A large genetic contribution to asthma susceptibility is predicted by the clustering of asthma and allergy symptoms among relatives and the large disease heritability estimated from twin studies, ranging from 55 to 90%. Genetic basis of asthma has been extensively investigated in the past 40 years using linkage analysis and candidate-gene association studies. However, the development of dense arrays for polymorphism genotyping has enabled the transition toward genome-wide association studies (GWAS), which have led the discovery of several unanticipated asthma genes in the last 11 years. Despite this, currently known risk variants identified using many thousand samples from distinct ethnicities only explain a small proportion of asthma heritability. This review examines the main findings of the last 2 years in genomic studies of asthma using GWAS and admixture mapping studies, as well as the direction of studies fostering integrative perspectives involving omics data. Additionally, we discuss the need for assessing the whole spectrum of genetic variation in association studies of asthma susceptibility, severity, and treatment response in order to further improve our knowledge of asthma genes and predictive biomarkers. Leveraging the individual's genetic information will allow a better understanding of asthma pathogenesis and will facilitate the transition toward a more precise diagnosis and treatment.

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Realizing Personalized Medicine in Asthmatic Children Requires Large-Scale Collaboration

Cited by 3 publications

References 20 publications

Influence of Genetics on the Response to Omalizumab in Patients with Severe Uncontrolled Asthma with an Allergic Phenotype

Influence of Genetics on the Response to Omalizumab in Patients with Severe Uncontrolled Asthma with an Allergic Phenotype

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

Genomic Predictors of Asthma Phenotypes and Treatment Response

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