Asthma and lower airway disease
A genome-wide association study of asthma hospitalizations in adults

https://doi.org/10.1016/j.jaci.2020.08.020Get rights and content

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.

Section snippets

Study population and GWAS of asthma hospitalizations

The UKB is a long-term prospective cohort13 that includes extensive phenotypic data and health care information on 502,530 subjects recruited from across the United Kingdom. Study participants were between 40 and 70 years old at the time of recruitment in 2006-2010, when most completed a baseline visit (some participants had 1 or 2 follow-up visits). We used the UKB data released in March 2019. Of the participants, 94% self-identified as white and 88.3% self-identified as both white and

Results

Table I shows the characteristics of the participants in the UKB. Compared with subjects with asthma but no asthma hospitalizations (controls), those with asthma and at least 1 asthma hospitalization (case patients) were significantly more likely to be female. There were no significant differences in age, smoking status, or BMI between case patients and controls.

In the GWAS conducted in the UKB, a locus on chromosome 6p21.3 was significantly associated with asthma hospitalizations (P < 5 × 10–8

Discussion

In a GWAS conducted in white adults with asthma, the SNP rs56151658 was significantly associated with 1.36 times higher odds of hospitalizations for asthma (a type of SAE requiring more intensive health care). Despite differences in case definition, statistical modeling, age, and ethnicity, as well as smaller sample size, several SNPs in strong LD (r2 ≥ 0.90) with rs56151658 were associated with SAEs (including, but not limited to, hospitalizations) in our replication cohorts of Latinos, in the

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    The UK Biobank Resource was accessed under application no. 43252. The current analysis, like that in the Hartford–Puerto Rico and EVA-PR studies, was supported by the following grants from the US National Institutes of Health (NIH): HL079966, HL117191, and MD011764 (to J.C.C.), HL138098 (to Q.Y.) and U54MD007587 (to the University of Puerto Rico). The Genes-Environments and Admixture in Latino Americans study was supported by NIH grants HL117004 and HL134589; enrollment was supported by the Sandler Family Foundation, the American Asthma Foundation, the RWJF Amos Medical Faculty Development Program, Harry Wm. and Diana V. Hind Distinguished Professorship in Pharmaceutical Sciences II, and NIH grant ES015794. M.P.Y. was supported by grants SAF2017-83417R awarded by the Spanish Ministry of Economy, Industry, and Competitiveness; the State Research Agency and the European Regional Development Funds from the European Union (MINECO/AEI/FEDER, UE); and grant RYC-2015-17205 awarded by the Ramón y Cajal Program by the Spanish Ministry of Economy, Industry, and Competitiveness. E.H.L. was funded by a fellowship (PRE2018-083837) from the Spanish Ministry of Science, Innovation, and Universities.

    Disclosure of potential conflict of interest: J. C. Celedon has received research materials from Pharmavite (vitamin D and placebo capsules) and GSK and Merck (inhaled steroids) to provide medications free of charge to participants in National Institutes of Health–funded studies unrelated to the current work. The rest of the authors declare that they have no relevant conflicts of interest.

    These authors shared first authorship.

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