A genome-wide association study of asthma hospitalizations in adults

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.

Keywords: HLA-II genes; adults; asthma; hospitalizations.

Figure 1.. Flow chart for inclusion and exclusion of subjects in the genome-wide association study (GWAS) of hospitalizations for asthma using data from the UK Biobank.

Definition of hospitalizations for asthma in the United Kingdom Biobank: Independent whites were determined by Data-Field 21000 including individuals coded as White (1), British (1001), Irish (1002) or Any other white background (1003). Relatedness was calculated based on the genotype data and the results were provided by UK Biobank. Individuals related beyond 3rd degree were considered as independent. Note that only one patient with at least one hospitalization for asthma was excluded due to relatedness. ICD10: 10th revision of the International Statistical Classification of Diseases and Related Health Problems. J43: Emphysema; J44: Other chronic obstructive pulmonary disease; J45: Asthma; J46: Status asthmaticus; and J47: Bronchiectasis. ICD9: 9th revision of the International Statistical Classification of Diseases and Related Health Problems. 490: Bronchitis, not specified as acute or chronic; 491: Chronic bronchitis; 492: Emphysema; 493: Asthma; 494: Bronchiectasis; and 496: Chronic airways obstruction, not elsewhere classified.

Figure 2.. Results of the GWAS of asthma hospitalizations in the UK Biobank.

(A) Manhattan plot. The chromosomal position of each single nucleotide polymorphism (SNP) is displayed along the X-axis and the negative logarithm of the association P-value is displayed on the Y-axis. The red line represents the genome-wide significance line (P < 5×10⁻⁸). (B) QQ plot. λ is the genomic control value. (C) Regional plot for SNP rs56151658. The relative location of genes and the direction of transcription are shown in the lower portion of the figure, and the chromosomal position is shown on the x axis. The y axis shows the significance of the associations. The purple diamond shows the P-value for rs56151658, the most significant SNP. The circles show the P-values for all other SNPs and are color coded according to the level of linkage disequilibrium (LD) with rs56151658 in the 1000 Genomes Project phase 3 EUR population. Thus, the LD values may be different from the ones calculated in the UKB cohort. SNP rs9275503 (in a brown circle) is in strong LD with rs56151658 (r² = 0.97) in the UKB, and it was replicated in HPR and GALA II. A1 is both the minor allele and the test allele.