Genome-wide analysis highlights contribution of immune system pathways to the genetic architecture of asthma

Author:

Han YiORCID,Jia Qiong,Jahani Pedram Shafiei,Hurrell Benjamin P.,Pan CalvinORCID,Huang Pin,Gukasyan Janet,Woodward Nicholas C.,Eskin Eleazar,Gilliland Frank D.ORCID,Akbari Omid,Hartiala Jaana A.ORCID,Allayee HoomanORCID

Abstract

AbstractAsthma 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.

Funder

U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute

U.S. Department of Health & Human Services | NIH | National Institute of Environmental Health Sciences

Division of Intramural Research, National Institute of Allergy and Infectious Diseases

U.S. Environmental Protection Agency

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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