Examination of Plasma PON1 Paraoxonase Activity and Genotype in Gulf War Veterans
Abstract
Despite the brevity of the 1990-1991 Gulf War (GW), which ended after just 6 weeks of air strikes and 4 days of ground combat, nearly a quarter of a century later military personnel who served in that conflict continue to experience health problems that are not adequately explained by established medical or psychiatric diagnoses. Gulf War iIllness (GWI) is the term commonly used to describe the constellation of unexplained symptoms (e.g., fatigue, sleep disturbances, pain, mood-related disorders, and cognitive difficulties) that plague an estimated 25%-30% of the approximately 700,000 U.S. GW Veterans. The objective of the proposed project is to examine the specific cause or causes of GWI. Although there is epidemiological evidence suggesting that GWI may be associated with exposure to a limited number of potentially hazardous chemicals used during the war (e.g., nerve agents, pesticides, and pyridostigmine bromide (PB) pills, which were taken to protect against the acute effects of nerve agents), it has long been 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 use during the Gulf War were at greater risk for developing GWI if they possessed the less common/less active genetic variants of an enzyme that neutralizes the harmful chemical found 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. Nerve agents such as sarin and cyclosarin and many of the pesticides used by military personnel during the Gulf War belong to group of chemicals known as organophosphates (OP). Population studies of environmental and occupational exposure to OP have shown that damage to the nervous system can result from OP exposure. Paraoxonase-1 (PON1) is an enzyme in the human body that can neutralize several different kinds of OPs. Like the enzyme that neutralizes the harmful chemical found PB, there are different genetic variants of PON1 that affect the efficiency with which PON1 neutralizes different kinds of OPs. Although a handful of previous studies have examined genetic variability in PON1 as a possible contributing factor to GWI, these studies produced mixed results and no clear insight about PON1 differences in GWI or response to exposures in theater. However, it is noteworthy that none of these previous studies considered the associations between GWI and GW-related exposures in different subgroups of GW Veterans with different genetic variants of PON1. Utilizing this approach in a pilot study with 58 GW Veterans, study co-investigator Dr. Steele found preliminary evidence suggesting that GW Veterans who possess the genetic variant of PON1 that is less effective at neutralizing certain types of pesticides were at greater risk for GWI if they reported using pesticides during the Gulf War. In contrast, GW Veterans who possess the genetic variant of PON1 that is less effective at neutralizing nerve agents were at greater risk for GWI if they reported hearing chemical alarms during deployment. Because these preliminary findings support the idea that GWI may result from an interaction between genetic and environmental factors, the proposed study will investigate the extent to which genetic variability in PON1 s ability to neutralize different types of OPs and GW Veterans exposure to those OPs 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) sample of GW Veterans. The proposed study is innovative in that it will combine existing and newly acquired data about PON1 genotype and activit
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610558
Entities
People
- Linda L Chao
Organizations
- Northern California Institute for Research and Education
- United States Army