Université de Nantes, Centrale Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, Nantes, France.
Université de Nantes, Centrale Nantes, CHU Nantes, Inserm, Centre de Recherche en Transplantation et Immunologie, Nantes, France; Ecole Centrale de Nantes, Nantes, France.
J Allergy Clin Immunol. 2020 Jul;146(1):147-155. doi: 10.1016/j.jaci.2020.01.011. Epub 2020 Jan 22.
Asthma is a complex chronic inflammatory disease of the airways. Association studies between HLA and asthma were first reported in the 1970s, and yet, the precise role of HLA alleles in asthma is not fully understood. Numerous genome-wide association studies were recently conducted on asthma, but were always limited to simple genetic markers (single nucleotide polymorphisms) and not complex HLA gene polymorphisms (alleles/haplotypes), therefore not capturing the biological relevance of this complex locus for asthma pathogenesis.
To run the first HLA-centric association study with asthma and specific asthma-related phenotypes in a large cohort of African-ancestry individuals.
We collected high-density genomics data for the Consortium on Asthma among African-ancestry Populations in the Americas (N = 4993) participants. Using computer-intensive machine-learning attribute bagging methods to infer HLA alleles, and Easy-HLA to infer HLA 5-gene haplotypes, we conducted a high-throughput HLA-centric association study of asthma susceptibility and total serum IgE (tIgE) levels in subjects with and without asthma.
Among the 1607 individuals with asthma, 972 had available tIgE levels, with a mean tIgE level of 198.7 IU/mL. We could not identify any association with asthma susceptibility. However, we showed that HLA-DRB1∗09:01 was associated with increased tIgE levels (P = 8.5 × 10; weighted effect size, 0.51 [0.15-0.87]).
We identified for the first time an HLA allele associated with tIgE levels in African-ancestry individuals with asthma. Our report emphasizes that by leveraging powerful computational machine-learning methods, specific/extreme phenotypes, and population diversity, we can explore HLA gene polymorphisms in depth and reveal the full extent of complex disease associations.
哮喘是一种复杂的气道慢性炎症性疾病。20 世纪 70 年代首次报道了 HLA 与哮喘之间的关联研究，但 HLA 等位基因在哮喘中的确切作用尚未完全阐明。最近对哮喘进行了大量全基因组关联研究，但这些研究始终局限于简单的遗传标记（单核苷酸多态性），而不是复杂的 HLA 基因多态性（等位基因/单倍型），因此无法捕捉到该复杂基因座对哮喘发病机制的生物学相关性。
在一个大型非洲裔个体队列中，针对哮喘和特定哮喘相关表型开展首次以 HLA 为中心的关联研究。
我们收集了美洲非洲裔人群哮喘联盟（Consortium on Asthma among African-ancestry Populations in the Americas，COALA）中 4993 名参与者的高密度基因组学数据。使用计算机密集型机器学习属性袋装方法推断 HLA 等位基因，并使用 Easy-HLA 推断 HLA 5 基因单倍型，我们对哮喘易感性和哮喘患者与非哮喘患者的总血清 IgE（tIgE）水平进行了高通量 HLA 中心关联研究。
在 1607 名哮喘患者中，有 972 名患者有可用的 tIgE 水平，平均 tIgE 水平为 198.7 IU/mL。我们没有发现与哮喘易感性相关的任何关联。然而，我们表明 HLA-DRB1∗09:01 与升高的 tIgE 水平相关（P=8.5×10-4；加权效应大小为 0.51[0.15-0.87]）。
我们首次发现 HLA 等位基因与哮喘的非洲裔个体 tIgE 水平相关。我们的报告强调，通过利用强大的计算机器学习方法、特定/极端表型和人群多样性，我们可以深入探索 HLA 基因多态性，并揭示复杂疾病关联的全部范围。
