Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
Department of Biochemistry & Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
Nat Commun. 2020 Apr 15;11(1):1776. doi: 10.1038/s41467-020-15649-3.
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.
哮喘是一种慢性、遗传复杂的呼吸道疾病，影响着全球超过 3 亿人。在这里，我们利用来自英国生物银行和跨民族哮喘遗传合作组织的数据，对哮喘进行了全基因组分析。我们鉴定出 66 个以前未知的哮喘位点，并证明这些区域中的易感等位基因，无论是单独的还是作为累积遗传负担的函数，与男性比女性的风险更大相关。生物信息学分析优先考虑 52 个位点的候选因果基因，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，我们表明，一种鼠抗 CD52 抗体模拟了临床上使用的人抗 CD52 抗体的免疫细胞耗竭作用，并降低了小鼠过敏原诱导的气道高反应性。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。
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