Abstract
BackgroundA challenge in the post-GWAS era is to assign function to disease-associated variants. However, available resources do not include all tissues or environmental exposures that are relevant to all diseases. For example, exaggerated bronchoconstriction of airway smooth muscle cells (ASMCs) defines airway hyperresponsiveness (AHR), a cardinal feature of asthma. However, the contribution of ASMC to genetic and genomic studies has largely been overlooked. Our study aimed to address the gap in data availability from a critical tissue in genomic studies of asthma.MethodsWe developed a cell model of AHR to discover variants associated with transcriptional, epigenetic, and cellular responses to two AHR promoting cytokines, IL-13 and IL-17A, and performed a GWAS of bronchial responsiveness (BRI) in humans.ResultsOur study revealed significant response differences between ASMCs from asthma cases and controls, including genes implicated in asthma susceptibility. We defined molecular quantitative trait loci (QTLs) for expression (eQTLs) and methylation (meQTLs), and cellular QTLs for contractility (coQTLs) and performed a GWAS of BRI in human subjects. Variants in asthma GWAS were significantly enriched for ASM QTLs and BRI-associated SNPs, and near genes enriched for ASM function, many with small P values that did not reach stringent thresholds of significance in GWAS.ConclusionsOur study identified significant differences between ASMCs from asthma cases and controls, potentially reflecting trained tolerance in these cells, as well as a set of variants, overlooked in previous GWAS, which reflect the AHR component of asthma.
Highlights
A challenge in the post-Genome-wide association studies (GWASs) era is to assign function to disease-associated variants
We observed profound response differences between cultured airway smooth muscle cells (ASMCs) from asthma cases and controls, suggesting that ASMCs have trained immunity [21], a sustained immune activation or tolerance to re-stimulation, likely due to epigenetic modifications that lead to longlasting altered transcriptional responses, a feature previously described in leukocytes and coronary artery smooth muscle cells [22] that we suggest for the first time in ASMCs
In this paper, we report the results of a novel cell model of airway hyperresponsiveness (AHR) using primary airway smooth muscle cells exposed to IL-13 alone, IL-17A alone, and the combination of IL-13+IL-17A
Summary
A challenge in the post-GWAS era is to assign function to disease-associated variants. Recent large asthma GWASs have reported enrichments for SNPs located in regions with enhancer activity in immune cells [13,14,15] or with genes that are most highly expressed in skin, lung tissue, spleen, small intestine, and immune cells [16] These inferences are limited to available resources, such as the Gene-Tissue Expression (GTEx) Consortium [17], the Roadmap Epigenomics [18], and the Encyclopedia of DNA Elements (ENCODE) [19], none of which include ASMCs. In addition, many variants with small P values that do not reach stringent criteria for significance in GWAS may contribute to risk (i.e., the “mid-hanging fruit” [20]) or have contextdependent effects (i.e., genotype by environment interactions). One strategy to assign function to associated GWAS variants and to identify novel variants from among the mid-hanging fruit is to use cell cultures to model environment-specific responses in disease-relevant tissues and examine molecular and cellular endpoints
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