Gene Expression to Advance Understanding, Aid Diagnosis, and Define Treatment Targets in Gulf War Illness
Abstract
Rationale and Objective: With the same gene (within your DNA -- the main genetic template), two people can differ in activity of the gene product. How much RNA is copied from that DNA is measured as “gene expression” (GE). (The RNA is then “translated” into proteins.) Environmental factors can alter GE. Altered GE can contribute to illness. Or, in the presence of factors promoting illness, GE may alter adaptively, to defend against it. Patterns of GE alterations, considering all genes, can provide important information. GE differences that distinguish those who are ill from those who are healthy -- including both exposed and unexposed healthy -- ensures signatures are reflecting illness rather than exposure and may advance understanding of mechanisms of illness. Comparing those who are exposed -- whether or not ill -- to those who are not exposed provides markers of exposure, separate from illness, that can be used in future studies. And, GE differences that distinguish those who are exposed but did not become ill, from both exposed and ill, and also from unexposed, provide markers that signify protection against illness -- and may provide important avenues for identifying effective treatments. GE signatures have been able to distinguish exposed from unexposed, even 20 years or more after the exposure, and have distinguished “with” versus “without” a health consequence, among those with exposure. Small studies have already shown GE differences in GWI; they did not consider all genes (the whole “transcriptome”) and there was a prior emphasis on immune-relevant mechanisms and interpretation. Prior GE studies in chronic fatigue syndrome did not have such a predefined focus and in those GE differences emphasized mitochondria and programmed cell death (apoptosis). (They also emphasized organophosphate mechanisms, underscoring relevance to GWI.) These emphases -- mitochondrial and apoptotic -- parallel the emphases we saw in assessing metabolomic (MO) data in GWI versus controls (measurement of products in the blood) and fits with our hypothesized GWI pathways. We propose to examine GE patterns in the “whole transcriptome” at rest and with exercise in a subset: (a) 50 Gulf War Veterans (GWV) with GWI, (b) 50 healthy controls, including (i) Gulf-deployed but healthy, and (ii) non-Veteran healthy controls. Differences that distinguish GWI from both other groups serve as GE signatures of GWI. Differences that distinguish those who are healthy despite Gulf deployment from both other groups serve as GE signatures of protection. And differences that distinguish both Gulf groups from the non-Gulf-deployed group serve as signatures of exposure. The findings will be processed through advanced statistical tools to produce an objective GE diagnostic classifier -- a means to objectively diagnose GWI. Advances of the study include that it: (1) Uses the whole genome. (2) Generates a diagnostic classifier (has an expert in this). (3) Distinguishes GE patterns of illness versus exposure. (4) Integrates GE with MO signatures we have already identified for GWI. Access to each form of data, MO and GE, enhances understanding of the other. Shared change in a pathway, in both GE and MO data, reinforces involvement of the pathway in GWI. Same versus opposite direction of change in GE versus MO may help determine if a GE change caused the MO change (same) or responded adaptively to it (opposite), e.g., more breakdown of a product can cause MO (product levels) to be low; GE for a product may be high in response. Having both can protect one from misinterpreting and trying to “treat” what was actually a beneficial GE change. (5) Benefits success (+ cost) through pre-collection of (rest) samples in 4/5 of the required sample of GWV with GWI, as well as non-Veteran controls. (6) Is larger, enabling subset analysis (by sex, age, exposure, and symptoms). (7) Importantly, identifies GE signatures of GWI protection -- of not h
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710654
Entities
People
- Beatrice Golomb
Organizations
- United States Army
- University of California, San Diego