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.

中文翻译：

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成人哮喘住院的全基因组关联研究

背景

关于严重哮喘发作的遗传决定因素知之甚少。

目标

我们旨在确定与哮喘住院相关的基因变异。

方法

我们对 34,167 名患有哮喘的英国白人成人进行了一项全基因组关联研究，其中 1,658 人至少有 1 次与哮喘相关的住院治疗。该分析是通过在加性遗传模型下使用逻辑回归进行的，该模型对年龄、性别、体重指数、吸烟状况和来自基因型数据的前 5 个主要成分进行了调整。然后，我们分析了来自 2 组拉丁裔儿童和青少年的重复数据，并进行了数量性状基因座和功能注释分析。

结果

在染色体 6p21.3 基因座上，单核苷酸多态性 (SNP) rs56151658（距HLA-DQB1启动子 8 kb ）与哮喘住院最显着相关（对于测试等位基因 A，优势比 = 1.36 [95% CI = 1.22-1.52]；P  = 3.11 × 10 ^–8 )；该基因座中另外 21 个 SNP 与哮喘住院相关，P值小于 1 × 10 ^–6。在复制队列中，与 rs56151658 存在强连锁不平衡的多个 SNP 与严重哮喘发作相关，P值为 0.01 或更低，与发现队列中的关联方向相同。三个 HLA 基因 ( HLA-DQA2 , HLA-DRB6和HLA-DOB）也被证明通过对肺组织中基因表达的影响来介导与哮喘住院相关的 SNP 的估计影响。

结论

我们通过基因组、数量性状基因座和基于汇总数据的孟德尔随机化分析，确定了该地区成人哮喘住院治疗的 II 类HLA基因的强候选基因。