Investigating Gene-Environment Interactions in Multiple Cohorts of 1990-1991 Gulf War Veterans
Abstract
While the Gulf War (GW) was relatively short, Veterans have suffered long-lasting debilitating health effects as a result of their deployment. Gulf War Illness (GWI) is the term commonly used to describe the constellation of unexplained symptoms (e.g., fatigue, sleep disturbances, chronic pain, and cognitive difficulties) that affect an estimated 25%-30% of the 700,000 U.S. GW Veterans. The objective of the proposed project is to examine genetic predisposing factors that could have caused GWI. A constellation of environmental exposures plagued our GW Veterans’ time in the Middle East. Research studies have consistently identified particular chemical exposures as the most prominent risk factors for GWI, but an important question remains concerning why some Veterans became ill after the war while others with similar exposures did not. The most prominent exposures of concern include (1) prolonged use of pyridostigmine bromide (PB) anti-nerve gas pills, (2) excessive use of pesticides, and (3) chemical nerve agents. These compounds have a shared mechanism of action in that they inhibit an enzyme in the brain and body called acetylcholinesterase (AChE) and alter levels of the chemical transmitter called acetylcholine. Acetylcholine controls everything from muscle contractions to memory and concentration abilities. Affecting this brain transmitter can cause potential acute and long-term effects on the brain and nervous system, as seen in GWI. Despite this progress, it is still a mystery why some military personnel developed GWI after the war while others with similar wartime experiences and exposures did not. Recently, study co-investigator Dr. Lea Steele found a plausible explanation for this puzzle: she reported that GW Veterans with self-reported PB pill use during the war were at greater risk for developing GWI if they possessed the less common/less active genes for an enzyme that neutralizes the harmful chemical found in PB. This suggests that genetic variability in the body’s ability to neutralize and/or protect against certain GW-related toxic exposure is a potentially important factor in the cause of GWI. Butyrylcholinesterase (BChE) is an enzyme that provides protection from negative effects of pesticides, nerve agents, and PB pills through finding those toxicants in the body and binding to them. By doing this, BChE protects the activity levels of the major neurotransmitter acetylcholine. Dr. Steele examined the genetic variants of BChE in a cohort of 304 GW Veterans with different wartime exposures. Results showed that Veterans with less active BChE genotypes were 40 times more likely to have GWI if they used PB pills during deployment. Another metabolizing enzyme suspected of being part of the GWI puzzle is PON1. PON1 measures were also studied by Dr. Steele and colleagues, and the pilot study showed early evidence that the effects of BChE and PON1 may not be independent of one another and may actually work together to neutralize GW chemicals better in some Veterans than others depending on their genetic make-up. Overall, these analyses provide a first indication that BChE and PON1 measurements are inter-related in GW Veterans and suggest a possible role for both enzymes -- acting individually and/or together -- in relation to GWI. Because these preliminary findings support the idea that GWI may result from an interaction between BChE and PON1 genetic variability and chemical exposures, the proposed study will investigate the extent to which genetic variability in BChE’s ability to neutralize different types of chemicals and the interaction between BChE and PON1 and GW Veterans’ exposure to those chemicals contribute to their risk for developing GWI. Specifically, we will test a model that explains why certain GW Veterans developed GWI while others with similar deployment experiences and exposures remained healthy in a large (> 800) study using samples from four separate completed or ongoing stud
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710685
Entities
People
- Patricia Janulewicz Lloyd
Organizations
- Boston University Medical Campus
- United States Army