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Large-scale Genetic Analysis Identifies 66 Novel Loci for Asthma

By Yi Han, Qiong Jia, Pedram Shafiei Jahani, Benjamin P. Hurrell, Calvin Pan, Pin Huang, Janet Gukasyan, Nicholas C. Woodward, Eleazar Eskin, Frank Gilliland, Omid Akbari, Jaana A. Hartiala, Hooman Allayee

Posted 29 Aug 2019
bioRxiv DOI: 10.1101/749598

We carried out a genome-wide association study (GWAS) for asthma in UK Biobank, followed by a meta-analysis with results from the Trans-National Asthma Genetic Consortium (TAGC). 66 novel genomic regions were identified, bringing the number of known asthma susceptibility loci to 211. Significant gene-sex interactions were also observed where susceptibility alleles, either individually or as a function of polygenic risk scores, increased asthma risk to a greater extent in men than women. Bioinformatics analyses demonstrated that asthma-associated variants were enriched for colocalizing to regions of open chromatic in immune cells and identified candidate causal genes at 52 of the novel loci, including CD52. An anti-CD52 (α-CD52) antibody mimicked the immune cell-depleting effects of an FDA-approved human α-CD52 antibody and reduced allergen-induced airway hyperreactivity in mice. These results further elucidate the genetic architecture of asthma, provide evidence that the immune system plays a prominent role in its pathogenesis, and suggest that CD52 represents a potentially novel therapeutic target for treating asthma.

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