Division of Pediatric Pulmonary Medicine, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pa.
Genomics and Health Group, Department of Biochemistry, Microbiology, Cell Biology and Genetics, Universidad de La Laguna, La Laguna, Spain.
J Allergy Clin Immunol. 2021 Mar;147(3):933-940. doi: 10.1016/j.jaci.2020.08.020. Epub 2020 Sep 2.
Little is known about the genetic determinants of severe asthma exacerbations.
We aimed to identify genetic variants associated with asthma hospitalizations.
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.
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); 21 additional SNPs in this locus were associated with asthma hospitalizations at a P value less than 1 × 10. 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.
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.
关于严重哮喘发作的遗传决定因素知之甚少。
我们旨在确定与哮喘住院相关的遗传变异。
我们对 34167 名白种英国哮喘患者进行了全基因组关联研究，其中 1658 名患者至少有 1 次哮喘相关住院。该分析采用逻辑回归，在加性遗传模型下进行，调整年龄、性别、体重指数、吸烟状况和来自基因型数据的前 5 个主成分。然后，我们分析了 2 个拉丁裔儿童和青少年队列的数据以进行复制，并进行了数量性状基因座和功能注释分析。
在 6p21.3 染色体上，单核苷酸多态性 (SNP) rs56151658（距 HLA-DQB1 启动子 8 kb）与哮喘住院最显著相关（对于测试等位基因 A，比值比为 1.36 [95%CI 为 1.22-1.52]；P = 3.11×10）；该基因座的 21 个其他 SNP 与哮喘住院相关，P 值小于 1×10。在复制队列中，与 rs56151658 强烈连锁不平衡的多个 SNP 与严重哮喘加重相关，在与发现队列相同的关联方向上，P 值小于等于.01。还表明 3 个 HLA 基因（HLA-DQA2、HLA-DRB6 和 HLA-DOB）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 的估计效应。
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，我们在成人哮喘住院的 II 类 HLA 基因区域确定了与哮喘住院密切相关的候选基因。
