Abstract
Asthma is a common chronic respiratory disease characterized by airway hyperresponsiveness (AHR). The genetics of asthma have been widely studied in mouse and human, and homologous genomic regions have been associated with mouse AHR and human asthma-related phenotypes. Our goal was to identify asthma-related genes by integrating AHR associations in mouse with human genome-wide association study (GWAS) data. We used Efficient Mixed Model Association (EMMA) analysis to conduct a GWAS of baseline AHR measures from males and females of 31 mouse strains. Genes near or containing SNPs with EMMA p-values <0.001 were selected for further study in human GWAS. The results of the previously reported EVE consortium asthma GWAS meta-analysis consisting of 12,958 diverse North American subjects from 9 study centers were used to select a subset of homologous genes with evidence of association with asthma in humans. Following validation attempts in three human asthma GWAS (i.e., Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG) and two human AHR GWAS (i.e., SHARP, DAG), the Kv channel interacting protein 4 (KCNIP4) gene was identified as nominally associated with both asthma and AHR at a gene- and SNP-level. In EVE, the smallest KCNIP4 association was at rs6833065 (P-value 2.9e-04), while the strongest associations for Sepracor/LOCCS/LODO/Illumina, GABRIEL, DAG were 1.5e-03, 1.0e-03, 3.1e-03 at rs7664617, rs4697177, rs4696975, respectively. At a SNP level, the strongest association across all asthma GWAS was at rs4697177 (P-value 1.1e-04). The smallest P-values for association with AHR were 2.3e-03 at rs11947661 in SHARP and 2.1e-03 at rs402802 in DAG. Functional studies are required to validate the potential involvement of KCNIP4 in modulating asthma susceptibility and/or AHR. Our results suggest that a useful approach to identify genes associated with human asthma is to leverage mouse AHR association data.
Highlights
Asthma is a common chronic respiratory disease with a rise in prevalence over the past decades, affecting over 25 million Americans and 300 million people world-wide [1,2]
The mouse is commonly used to model the genetics of human diseases because mice are physiologically similar to humans, the mouse genome has been sequenced, and many tools exist that allow for direct testing of genetic alterations in mice [3,4]
Mouse airway hyperresponsiveness (AHR) quantitative trait loci (QTL) observed on chromosome 17 in three studies [9,12,13] overlap with human chromosome 6p QTLs identified in four studies of asthma and allergic phenotypes [14,15,16,17]
Summary
Asthma is a common chronic respiratory disease with a rise in prevalence over the past decades, affecting over 25 million Americans and 300 million people world-wide [1,2]. The most common asthma phenotype studied in the mouse is AHR, and several regions that have been associated with mouse AHR are homologous with genomic regions linked with asthma-related phenotypes in human cohorts. Two linkage studies [8,9] in mouse identified AHR quantitative trait loci (QTL) on chromosome 7 that are homologous with human AHR QTL on chromosome 19q observed in Hutterites and Chinese individuals [10,11]. Mouse AHR QTL observed on chromosome 17 in three studies [9,12,13] overlap with human chromosome 6p QTLs identified in four studies of asthma and allergic phenotypes [14,15,16,17]. It is likely that mouse and human share genetic variants that predispose both species to asthma-related phenotypes, and mouse AHR is an appropriate phenotype to identify some of these shared genetic variants
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