Susceptibility to Lung Disease: Integrated Genetic and Genomic Approaches

Genetic background has an important role in susceptibility to complex lung diseases, and the genetic contribution to disease phenotypes varies between populations. Interaction between genetic background and exposures to environmental stimuli, and understanding the mechanisms through which environmental exposure interact with susceptibility genes, are critical to disease prevention. Inbred mouse models provide important insight to understand human disease etiologies because genetic background and environmental exposures can be controlled. Tools including in silico haplotyping, collaborative cross and diversity outcross mouse panels, bioinformatic applications, and -omics technologies have enhanced our ability to identify disease genes and pathways to guide translational investigations to human populations. Combined genetic and genomic approaches have yielded important insight to mechanisms of susceptibility to many complex traits and diseases. We have integrated inbred mouse and cell-based models with haplotype association mapping (genetic), global gene expression analyses (genomic), and expression quantitative trait locus mapping (eQTL or genetical genomics) to identify candidate susceptibility genes and associated gene networks important in toxicant-induced lung injury. The overarching goal of these investigations is to determine whether human homologues of these susceptibility genes associate with disease risk in human populations. Efforts to identify and validate susceptibility genes in mouse models of environmental disease with a goal towards translational application have enabled identification of individuals who are susceptible to disease. For example, epidemiological and clinical investigations have associated functional polymorphisms in human NRF2 (NF-E2 related factor 2) and TNF (tumor necrosis factor alpha) with susceptibility to acute lung injury and ozone-induced changes in lung function, respectively. Importantly, these discoveries may also lead to novel intervention or therapeutic strategies to prevent disease.