Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Hernandez-Pacheco N

PROVIDER: S-EPMC7054824 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Hernandez-Pacheco Natalia N Farzan Niloufar N Francis Ben B Karimi Leila L Repnik Katja K Vijverberg Susanne J SJ Soares Patricia P Schieck Maximilian M Gorenjak Mario M Forno Erick E Eng Celeste C Oh Sam S SS Pérez-Méndez Lina L Berce Vojko V Tavendale Roger R Samedy Lesly-Anne LA Hunstman Scott S Hu Donglei D Meade Kelley K Farber Harold J HJ Avila Pedro C PC Serebrisky Denise D Thyne Shannon M SM Brigino-Buenaventura Emerita E Rodriguez-Cintron William W Sen Saunak S Kumar Rajesh R Lenoir Michael M Rodriguez-Santana Jose R JR Celedón Juan C JC Mukhopadhyay Somnath S Potočnik Uroš U Pirmohamed Munir M Verhamme Katia M KM Kabesch Michael M Palmer Colin N A CNA Hawcutt Daniel B DB Flores Carlos C Maitland-van der Zee Anke H AH Burchard Esteban G EG Pino-Yanes Maria M

Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 20190215 6

<h4>Background</h4>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.<h4>Object ...[more]

PMID: 30697902

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Project description:ImportanceDaily use of inhaled corticosteroids is a widely recommended treatment for mild persistent asthma in children. There is concern that, similar to systemic corticosteroids, inhaled corticosteroids may have adverse effects on bone health.ObjectiveTo determine whether there is an increased risk of bone fracture associated with inhaled corticosteroid use in children with asthma.Design, setting, and participantsIn this population-based nested case-control study, we used health administrative databases to identify a cohort of children aged 2 to 18 years with a physician diagnosis of asthma between April 1, 2003, and March 31, 2014, who were eligible for public drug coverage through the Ontario Drug Benefit Program (Ontario, Canada). We matched cases of first fracture after asthma diagnosis to fracture-free controls (ratio of 1 to 4) based on date of birth (within 1 year), sex, and age at asthma diagnosis (within 2 years). We used a 1-year lookback period to ascertain history of inhaled corticosteroid use. Multivariable conditional logistic regression was used to obtain an odds ratio (OR) with 95% confidence interval for fracture, comparing no inhaled corticosteroid use vs current, recent, and past use.ExposuresInhaled corticosteroid use during the child's 1-year lookback period, measured as current user if the prescription was filled less than 90 days prior to the index date, recent user (91-180 days), past user (181-365 days), or no use.Main outcomes and measuresFirst emergency department visit for fracture after asthma diagnosis, identified using International Statistical Classification of Diseases and Related Health Problems, 10th Revision codes.ResultsThis study included 19 420 children (61.0% male; largest proportion of children, 31.5%, were aged 6-9 years at their index date). The multivariable regression results did not show a significant association between first fracture after asthma diagnosis and current use (OR, 1.07; 95% CI, 0.97-1.17), recent use (OR, 0.96; 95% CI, 0.86-1.07), or past use (OR, 1.00; 95% CI, 0.91-1.11) of inhaled corticosteroids, compared with no use, while adjusting for sociodemographic factors and other medication use. However, use of systemic corticosteroids in the 1-year lookback period resulted in greater odds of fracture (OR, 1.17; 95% CI, 1.04-1.33).Conclusions and relevanceSystemic corticosteroids, but not inhaled corticosteroids, were significantly associated with increased odds of fracture in the pediatric asthma population.

Dataset Information

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

Publications

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

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