Genome-wide association study in minority children with asthma implicates DNAH5 in bronchodilator responsiveness
Year: 2022
Type: article
Study design: Observational Study
Abstract: Variability in response to short-acting β2-agonists (e.g., albuterol) among patients with asthma from diverse racial/ethnic groups may contribute to asthma disparities. We sought to identify genetic variants associated with bronchodilator response (BDR) to identify potential mechanisms of drug response and risk factors for worse asthma outcomes. Genome-wide association studies of bronchodilator response (BDR) were performed using TOPMed Whole Genome Sequencing data of the Asthma Translational Genomic Collaboration (ATGC), which corresponded to 1136 Puerto Rican, 656 Mexican and 4337 African American patients with asthma. With the population-specific GWAS results, a trans-ethnic meta-analysis was performed to identify BDR-associated variants shared across the three populations. Replication analysis was carried out in three pediatric asthma cohorts, including CAMP (Childhood Asthma Management Program; n = 560), GACRS (Genetics of Asthma in Costa Rica Study; n = 967) and HPR (Hartford-Puerto Rico; n = 417). A genome-wide significant locus (rs35661809; P = 3.61 × 10–8) in LINC02220, a non-coding RNA gene, was identified in Puerto Ricans. While this region was devoid of protein-coding genes, capture Hi-C data showed a distal interaction with the promoter of the DNAH5 gene in lung tissue. In replication analysis, the GACRS cohort yielded a nominal association (1-tailed P < 0.05). No genetic variant was associated with BDR at the genome-wide significant threshold in Mexicans and African Americans. Our findings help inform genetic underpinnings of BDR for understudied minority patients with asthma, but the limited availability of genetic data for racial/ethnic minority children with asthma remains a paramount challenge.
Source: Scientific Reports
Authors: Jaehyun Joo, Angel C. Y. Mak, Shujie Xiao, Patrick M. Sleiman, Donglei Hu, Scott Huntsman, Celeste Eng, Mengyuan Kan, Avantika R. Diwakar, Jessica A. Lasky-Su, Scott T. Weiss, Joanne E. Sordillo, Ann C. Wu, Michelle Cloutier, Glorisa Canino, Erick Forno, Juan C. Celedón, Max A. Seibold, Hakon Hakonarson, L. Keoki Williams, Esteban G. Burchard, Blanca E. Himes
Institutions: University of Pennsylvania, University of California, San Francisco, Henry Ford Health, Henry Ford Hospital, Children's Hospital of Philadelphia, Brigham and Women's Hospital, Harvard University, Harvard Pilgrim Health Care, University of Connecticut, UConn Health, University of Puerto Rico System, University of Pittsburgh, Children's Hospital of Pittsburgh, National Jewish Health
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,190
Funders: Robert Wood Johnson Foundation, Tobacco-Related Disease Research Program, Children's Hospital of Philadelphia, University of Washington, American Asthma Foundation, New York Genome Center, National Institutes of Health, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Eye Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Environmental Health Sciences, National Institute on Minority Health and Health Disparities
Awards: G1052645489, G1268573537, G1278681517, CEBPD-Mediated Mechanisms of Glucocorticoid Insensitivity in Severe Asthma, G141679577, G1678129981, G1846019065, G2034299771, G2096685756, Integrative Analyses to Uncover Biological Mechanisms Mediating Gene Associations with Asthma Drug Response Among Minority Children, Rare variants and NHLBI traits in deeply phenotyped cohorts, G2189466114, Addressing disparities in chronic disease with a teen and young adult focus, G2305281594, G232264632, G2600070839, G2802321639, G2816736420, G2976884267, G3078883119, G3194560040, G3256118428, G3498535170, G3520747131, G3586134318, G4086346382, G4091723164, G4183848059, G4432600228, G457392980, G4650774565, G4765065348, G4949958486, G50080621, G5163278296, Genetic Control of Airway Epithelium Gene Expression in Childhood Asthmatics, PHARMACOGENOMICS OF INHALED CORTICOSTEROID RESPONSIVENESS IN PATIENTS WITH ASTHMA, G5631728042, G631129105, G6460128660, G6546735057, Combined Transcriptomics and Genomics to Find Asthma Genes in Admixed Populations, G6615318374, G7307112236, Genes, air pollution, and asthma severity in minority children, G7519571385, G7865763634, Studies of Rare Genetic Variation in the Isolated Population of Sardinia, G842692683, G8532757437, NHGRI Genome Sequencing Program Coordinating Center, G9000112574, Center of Excellence in Environmental Toxicology
OpenAlex ID: W4286470549