Extensive epidemiologic and clinical research over the past 17 years has derived a working definition of Gulf War illness, called the Overall Factor case definition, which identifies veterans with such symptoms as fatigue, thinking/memory problems, and chronic pain who test positive for brain dysfunction on several types of specialized objective brain scans. A recent study also found a gene that largely determines whether or not soldiers exposed to low-level nerve gas in the Gulf War later developed these chronic brain symptoms measured by our Overall Factor case definition. The association of this protective gene with Gulf War illness was so strong that a broader study of the functioning of thousands of genes seems to have a good chance of finding a few other genes on which new diagnostic tests and treatments could be based. Over the past several years, we have conducted a national survey of Gulf War veterans and collected blood with which we can measure the functioning of this broad array of genes and measure its association with the Overall Factor case definition.

In this project we will measure the level of functioning of all the human genes that can be detected in blood using the latest Next-Generation Sequencing (RNA-seq) gene expression techniques. We will perform these tests on 103 Gulf War veterans from our national survey meeting our Overall Factor case definition and 47 non-ill veteran "controls" with whom to compare the level of gene functioning of the ill veterans. The ill veterans can also be classified into three subgroups with different combinations of symptoms, known as syndromes 1-3.

This resulting large database will be analyzed with the latest bioinformatics (statistical) techniques to identify a few genes that are functioning more actively or less actively in the ill veterans than in the control group. We will then group the abnormally functioning genes into groups with similar biological functions based on what is written about the genes in scientific journals. Then a team of scientists, including an epidemiologist, a biochemist, an immunologist, and a medical bioinformatics (statistics) expert, will study these groups of abnormal genes to identify patterns that give clues to the nature of the underlying brain disease processes that are making the veterans with Gulf War syndrome ill. The resulting new understanding of the disease process will provide ideas for new treatments that might interrupt these processes and thereby reduce the symptoms or even control the illness completely.

Finally, the research team will perform a complex statistical analysis, called a discriminant analysis, in which they develop an equation with which the level of abnormal functioning of some of the genes identified in the prior phase will correctly classify veterans into the four clinical groups (syndromes 1-4 or controls). This classification equation will be developed in one segment of the 150 study veterans and will be tested in the other segment for validation. We expect that this classification equation will provide a practical blood test that Department of Veterans Affairs or civilian doctors could order to make a medical diagnosis of Gulf War illness. This would provide an objective basis for diagnosing and compensating Gulf War veterans for this illness and might provide an objective means of monitoring response to new treatments.