Asthma is a common, chronic disease that affects millions of people of all ages globally, and the prevalence of asthma has increased markedly in recent years. Similar to other complex, chronic diseases that are also major health burdens, one of the key drivers in asthma pathogenesis is inflammation. A deeper understanding of metabolic pathways that play a critical role in inflammation, the genetic variation that underpin these pathways, and how these factors relate to asthma, is warranted. Both environmental exposures and genetic factors influence asthma susceptibility, severity and disease progression. Metabolites are also influenced by both genetic variation and environmental factors, and metabolomics is a powerful new `omics' tool for elucidating disease pathogenesis. Although inflammatory processes represent one of the key pathways associated with asthma risk to date, metabolomic studies on asthma have been limited in terms of sample size and number. Furthermore, the integration of genomics and metabolomics has the potential to clarify causal disease mechanisms. Genes encode enzymes, and the downstream effect of genetic variation on enzymatic activity is also captured by metabolomics. Genetic variants that are associated with metabolite variation are referred to as metabolite quantitative trait loci (mtQTLs). The intersection of genotype-metabolite and genotype-phenotype associations can deliver new insights into complex disease. Between 1993-2001, our team performed a whole population ascertainment of Tangier Island, Virginia, an isolated European-ancestry population in the Chesapeake Bay. We characterized the full extended pedigree tracing back to three founders in 1722, and collected biospecimens and clinical phenotype measurements of cardiovascular and allergic disease (including asthma), on all eligible, consenting participants. This cohort also has a homogenous dietary environment typical of modern Western diets, which is itself a risk factor for inflammatory disease. Here, we propose using the Tangier Island biobank to generate a metabolomics and genomics data resource to characterize the underpinnings of asthma. Specifically, we aim to: 1A) Identify perturbations between asthma cases and controls of molecules and pathways previously known to be associated with lung inflammation; 1B) Identify sets of correlated metabolites most closely associated with asthma and its associated trait, total serum IgE (tIgE), and identify biological pathways enriched for these metabolite sets; 2) Estimate metabolite heritability to elucidate the genetic vs. environmental contribution to metabolite variation; 3) Perform mtQTL mapping and use these results to identify genetic variants contributing to the relative abundance of metabolites affecting asthma. Findings from these aims will provide critical data for a future R01 application to refine and pinpoint causal mechanisms in inflammation and asthma, and will provide an invaluable integrative omics resource to the scientific community.
Inflammatory processes play an important role in a number of complex, chronic diseases, including asthma and allergic disease. In this study, we propose a closer examination of the metabolites that underlie inflammation and that are associated with asthma and associated phenotypes, and the genetic variation that in turn underpins enzymes involved in these inflammatory processes. Our proposed research promises to yield novel insights into asthma, and may additionally provide insights into other chronic diseases that are also a major health burden.
