Integrating genomics and metabolomics data to identify molecular characteristics of Gulf War Veterans' illnesses

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Gulf War Illness (GWI) is a chronic, debilitating illness suffered by Veterans of the first Gulf War. Patients suffering from GWI are often subject to years of medical uncertainty as they make their way through multiple clinics to try to diagnose and ultimately treat their chronic symptoms, if possible. Complicating this medical journey is the absence of biomarkers that can be used to diagnose the conditions and that might provide clues as to treatments and etiology. A recent review of the evidence for biomarkers in GWI concluded that there were no validated biomarkers for GWI. The lack of biomarkers is accompanied by a lack of treatments demonstrated to work in a large number of Veterans. Epidemiologic studies have been successful in identifying associations with exposures common to serving in the Gulf War through development of large cohorts of Gulf War Veterans. Biomarker studies in small numbers of Gulf War Veterans have identified biomarkers for testing. Among the most fruitful of these are studies of metabolomics, the analysis of all small molecules in blood or tissue measured by specialized instruments capable of detecting very small quantities of metabolites and then comparing them to known compounds. We will test a comprehensive set of metabolites assayed by the Metabolon metabolomics platform covering over 60 metabolic pathways in over 1000 Veterans in the Gulf War Era Cohort and Biorepository (GWECB), collected and made available to researchers by the VA Office of Research and Development Gulf War Program. The metabolomics dataset will join data from other assays in GWECB designed to interrogate other biological systems. Genome-wide genotyping tests how up to 1 million genetic variants across the genome contribute to differences in Veterans with Gulf War Illness versus those without. Likewise, genome-wide epigenetic assays test how up to 800,000 DNA modifications contribute different levels of activity of genes across the genome. Putting these three modern biomedical technologies together provides a comprehensive view of physiological differences in individuals. In combining these data we hope to identify biological pathways that distinguish GWI Veterans and suggest treatments and biomarkers. We also will analyze these combined datasets to test whether smaller clusters of symptoms that make up GWI can identify specific subtypes of GWI related to the pathways we find. These data will be returned to the GWECB data repository so that it can be made available to the Gulf War research community for additional research.