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A genome-wide association study of asthma hospitalizations in adults

Authors :
Esther Herrera-Luis
Edna Acosta-Pérez
Donglei Hu
Maria Pino-Yanes
Erick Forno
Glorisa Canino
Michelle M. Cloutier
Esteban G. Burchard
Jose R. Rodriguez-Santana
Sam S. Oh
Wei Chen
Qi Yan
Scott Huntsman
Celeste Eng
Ge Yang
Juan C. Celedón
Source :
J Allergy Clin Immunol
Publication Year :
2021
Publisher :
Elsevier BV, 2021.

Abstract

Background Little is known about the genetic determinants of severe asthma exacerbations. Objectives We aimed to identify genetic variants associated with asthma hospitalizations. Methods We conducted a genome-wide association study of asthma hospitalizations in 34,167 white British adults with asthma, 1,658 of whom had at least 1 asthma-related hospitalization. This analysis was conducted by using logistic regression under an additive genetic model with adjustment for age, sex, body mass index, smoking status, and the first 5 principal components derived from genotypic data. We then analyzed data from 2 cohorts of Latino children and adolescents for replication and conducted quantitative trait locus and functional annotation analyses. Results At the chromosome 6p21.3 locus, the single-nucleotide polymorphism (SNP) rs56151658 (8 kb from the promoter of HLA-DQB1) was most significantly associated with asthma hospitalizations (for test allele A, odds ratio = 1.36 [95% CI = 1.22-1.52]; P = 3.11 × 10–8); 21 additional SNPs in this locus were associated with asthma hospitalizations at a P value less than 1 × 10–6. In the replication cohorts, multiple SNPs in strong linkage disequilibrium with rs56151658 were associated with severe asthma exacerbations at a P value of .01 or less in the same direction of association as in the discovery cohort. Three HLA genes (HLA-DQA2, HLA-DRB6, and HLA-DOB) were also shown to mediate the estimated effects of the SNPs associated with asthma hospitalizations through effects on gene expression in lung tissue. Conclusions We identified strong candidate genes for asthma hospitalizations in adults in the region for class II HLA genes through genomic, quantitative trait locus, and summary data–based mendelian randomization analyses.

Details

ISSN :
00916749
Volume :
147
Database :
OpenAIRE
Journal :
Journal of Allergy and Clinical Immunology
Accession number :
edsair.doi.dedup.....c9593ad7e0e875fd544f67b93505f93f
Full Text :
https://doi.org/10.1016/j.jaci.2020.08.020