Genome-wide analysis highlights contribution of immune system pathways to the genetic architecture of asthma
Genome-wide analysis highlights contribution of immune system pathways to the genetic architecture of asthma
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DOI：
10.1038/s41467-020-15649-3
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发表时间：
2020-04-15
影响因子：
16.6
通讯作者：
Allayee, Hooman
中科院分区：
文献类型：
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作者：
Han, Yi;Jia, Qiong;Allayee, Hooman
哮喘是一种慢性和遗传复杂的呼吸系统疾病，影响着全世界3亿多人。在这里，我们报告了使用来自英国生物银行和跨国哮喘遗传联盟的数据进行哮喘全基因组分析。我们确定了66个以前未知的哮喘基因座，并证明这些区域的易感等位基因，无论是单独的还是作为累积遗传负担的功能，与男性的风险相关程度大于女性。生物信息学分析优先考虑了52个位点的候选致病基因，包括CD52，并证明哮喘相关变异在免疫细胞的开放染色质区域富集。最后，我们展示了一种小鼠抗cd52抗体模仿临床使用的人类抗cd52抗体的免疫细胞消耗作用，并减少了过敏原诱导的小鼠气道高反应性。这些结果进一步阐明了哮喘的遗传结构，并为哮喘相关风险变异的免疫学和性别特异性相关性提供了重要的见解。
Asthma is a chronic and genetically complex respiratory disease that affects over 300 million people worldwide. Here, we report a genome-wide analysis for asthma using data from the UK Biobank and the Trans-National Asthma Genetic Consortium. We identify 66 previously unknown asthma loci and demonstrate that the susceptibility alleles in these regions are, either individually or as a function of cumulative genetic burden, associated with risk to a greater extent in men than women. Bioinformatics analyses prioritize candidate causal genes at 52 loci, including CD52, and demonstrate that asthma-associated variants are enriched in regions of open chromatin in immune cells. Lastly, we show that a murine anti-CD52 antibody mimics the immune cell-depleting effects of a clinically used human anti-CD52 antibody and reduces allergen-induced airway hyperreactivity in mice. These results further elucidate the genetic architecture of asthma and provide important insight into the immunological and sex-specific relevance of asthma-associated risk variants.