Persistently Elevated Somatic Mutation as a Biomarker for Clinically Relevant Exposures in GWI

Gulf War Illness (GWI) consists of a set of debilitating symptoms that have been associated with deployment to the Persian Gulf theatre of war, either in 1990/91 in Kuwait or 2003-11 in Iraq. There is general agreement that physical exposures play an important role in the etiology of this disease (or diseases), yet studies to identify a single major causative exposure have been largely unproductive. Starting with radiation exposures, Dr. Grant has developed a blood-based assay to detect and quantify genotoxic carcinogenic exposures, through loss of a molecular epitope on the surface of red blood cells. This glycophorin A (GPA) mutation assay has been successfully applied in a wide array of occupational, environmental, medical and accidental exposures to radiation and chemicals. Most of these studies involve an analysis of acute exposure, since the effects of most exposures decline as the mutated progenitor cells clear the bone marrow. In some cases, however, based on the particular exposure or the susceptibility of the individual, life-long effects are evident; presumably due to effects in the stem cell compartment of the bone marrow. These persistent effects are highly associated with cancer incidence, including secondary cancer incidence attributable to the primary treatment. Thus, the GPA assay provides a cumulative dosimeter of mixed exposures impacting on bone marrow stem cells. Our hypothesis is that such exposures are associated with the incidence of clinical symptoms of GWI. To investigate this possibility, we will analyze two sets of military veterans with the GPA assay, one that was deployed to the Gulf and one which was not. If Gulf War deployment involved exposures with the capacity to damage DNA, such as radiation from depleted uranium ammunition, or polyaromatic hydrocarbons from oil fires, we should detect long term effects in the deployed cohort. Moreover, if these exposures are related to the development of clinical disease, we should further see an association between elevated somatic mutation and GWI. Since the GPA assay specifically detects genotoxic exposures, it may be more powerful in detecting aspects of GWI that are caused by this mechanism. However, in mixed exposures, it is reasonable to assume that an increased exposure to the genotoxic element of the mixture is also indicative of increased exposure to non-genotoxic agents as well. We will therefore investigate the association of somatic mutation frequency with both common and rare components of GWI, such as chronic fatigue syndrome and cancer. Since the GPA assay also integrates host effects, we will measure DNA repair capacity in those subjects, regardless of disease status, that exhibit abnormally high mutation frequencies (by any one of three criteria previously described), in order to detect those whose exposure was exacerbated by genetic predisposition. This project therefore has the potential to monitor present day Gulf War veterans to identify those at greatest risk of developing GWI, but also to identify those at risk for this disease prior to deployment