Genomics of Gulf War Illness in U.S. Veterans Who Served during the 1990–1991 Persian Gulf War: Methods and Rationale for Veterans Affairs Cooperative Study #2006

Abstract

Background: Approximately 697,000 members of the U.S. Armed Forces were deployed to the Persian Gulf in support of the 1990–1991 Persian Gulf War (GW). Subsequently, many deployed and some non-deployed veterans developed a chronic multi-symptom illness, now named Gulf War Illness (GWI). This manuscript outlines the methods and rationale for studying the genomics of GWI within the Million Veteran Program (MVP), a VA-based national research program that has linked medical records, surveys, and genomic data, enabling genome-wide association studies (GWASs). Methods: MVP participants who served in the military during the GW era were contacted by mail and invited to participate in the GWI study. A structured health questionnaire, based on a previously tested instrument, was also included in the mailing. Data on deployment locations and exposures, symptoms associated with GWI, clinical diagnoses, personal habits, and health care utilization were collected. Self-reported data will be augmented with chart reviews and structured international classification of disease codes, to classify participants by GWI case status. We will develop a phenotyping algorithm, based on two commonly used case definitions, to determine GWI status, and then conduct a nested case-control GWAS. Genetic variants associated with GWI will be investigated, and gene–gene and gene–environment interactions studied. The genetic overlap of GWI with, and causative mechanisms linking this illness to, other health conditions and the effects of genomic regulatory mechanisms on GWI risk will also be explored. Conclusions: The proposed initial GWAS described in this report will investigate the genomic underpinnings of GWI with a large sample size and state-of-the-art genomic analyses and phenotyping. The data generated will provide a rich and expansive foundation on which to build additional analyses.

The impact of post-traumatic stress on quality of life and fatigue in women with Gulf War Illness

“…Veterans in the GWI group endorsed the presence of one or more symptoms for 6 months from at least 2 of the following categories: fatigue; mood and cognitive complaints; and musculoskeletal complaints. The CDC definition captures the three symptoms commonly reported in the literature but is broad and inclusive (especially the mild–moderate form) [ 38 ], which results in a high prevalence rate where ~ 50% of Gulf War Veterans would be classified as GWI cases when no exclusionary criteria are defined [ 39 ]. The CDC definition of GWI has been found to be useful in clinical settings to rule out disease [ 40 ], was supported by Collins et al [ 41 ] for use in controlled clinical trials, and has been recommended by the Institute of Medicine (IOM) for use in clinical practice [ 38 ].…”

“…The CDC definition captures the three symptoms commonly reported in the literature but is broad and inclusive (especially the mild–moderate form) [ 38 ], which results in a high prevalence rate where ~ 50% of Gulf War Veterans would be classified as GWI cases when no exclusionary criteria are defined [ 39 ]. The CDC definition of GWI has been found to be useful in clinical settings to rule out disease [ 40 ], was supported by Collins et al [ 41 ] for use in controlled clinical trials, and has been recommended by the Institute of Medicine (IOM) for use in clinical practice [ 38 ]. This definition has been the most commonly used and is accepted internationally [ 42 , 43 ].…”

Gene–Toxicant Interactions in Gulf War Illness: Differential Effects of the PON1 Genotype

“…Given our sample size, we cannot dismiss type I error as a possible explanation for our findings. Future work could examine data from the MVP study, including over 100,000 Gulf War Era veterans with genotypes [ 57 ], which would allow for greater statistical power to detect gene-by-environment interactions. Future work could also analyze catalytic activity of our candidate genes, specifically Pon1, which could increase confidence in these findings.…”

Modeling Neuroimmune Interactions in Human Subjects and Animal Models to Predict Subtype-Specific Multidrug Treatments for Gulf War Illness

“…Possible explanations for the cause of GWI include exposure to mild traumatic brain injury and chemical/biological weapons [7] as well as the involvement of a neuroinflammatory signaling cascade triggered by exposure to a neurotoxin (e.g., the organophosphate sarin) and exposure to a combat environment [8][9][10]. Genetic susceptibility [11,12] of veterans may further contribute to the resulting changes in brain function observed in GWI [13][14][15]. Furthermore, confounding and/or exacerbating factors often complicate this diagnosis.…”