Gulf War illness (GWI) is an umbrella term that describes an array of chronic symptoms that have impacted an estimated 200,000 Persian Gulf War veterans. Researchers and clinicians have spent years looking for the cause of the disorder, which can cause fatigue, diarrhea, fever, memory and concentration problems, sexual dysfunction, night sweats, chronic pain, and other issues. With a thorough genetic analysis, it seems that scientists have now determined the cause of GWI was sarin nerve gas that was released when the US targeted Iraqi storage facilities. The findings have been reported in Environmental Health Perspectives.
The investigators also learned that the risk of developing GWI is heavily influenced by a gene called PON1, which encodes an enzyme. Certain variants of this gene enable carriers of those variants to break sarin gas down more easily than others with different variants of the same gene; there are small sequence differences in the gene that modulate the function of the enzyme it generates, and its response to sarin.
Study leader Robert Haley, M.D., Professor of Internal Medicine and Director of the Division of Epidemiology at UT Southwestern, has been researching GWI for decades. He noted that there are over 100,000 veterans that are still not being treated for their illness, and he is hopeful this research can open up new treatment options, and help those veterans.
"Quite simply, our findings prove that Gulf War illness was caused by sarin, which was released when we bombed Iraqi chemical weapons storage and production facilities," said Dr. Haley. Satellite imagery documented a large cloud emanating from a chemical weapons storage facility in Iraq that was hit with US-led coalition bombs. That cloud moved toward US ground troops, where nerve gas alarms rang out; they had detected sarin.
Other causes of GWI have been considered over the years of research, including pesticides, depleted uranium, vaccinations, and medications. Now the research team has built what Haley calls "an irrefutable case" that shows sarin, a synthetic chemical that was first engineered to be a pesticide and was ultimately used in chemical warfare, is the cause of GWI. Sarin can simply move through the skin to enter the body, and attacks the nervous system. Exposure to a lot of sarin is fatal. While exposure to sarin is survivable at lower levels, brain function may still be impaired over time.
The strength of this study, noted Haley, comes from the interaction between the gene and the nerve agent. This sets it apart from studies in which veterans have only self-reported symptoms and exposure.
In this work, two groups of 508 deployed veterans, one with GWI and the other without GWI, were selected at random from 8,000 Gulf War vets who took the U.S. Military Health Survey. Veterans were asked if they heard chemical nerve gas alarms while deployed, and blood and DNA samples were taken.
The scientists focused on the two variants of one gene, PON1. The first variant, called Q, produces an enzyme that breaks sarin down efficiently. The other variant, R, is ok at performing the enzyme's other jobs, but is not great at breaking down sarin. Since we carry two copies of most genes, one from each parent, an individual may have a QQ, RR, or QR PON1 genotype.
When vets carrying the QQ genotype were exposed to sarin, their risk of GWI was increased 3.75 times, compared to those not exposed, while QR vets' risk was increased 4.43 times, and RR vets' risk was increased 8.91 times. A person's risk of GWI was significantly affected by the PON1 variant they carried, and the variants are a measure of how good a person is at inactivating sarin. "It doesn't mean you can't get Gulf War illness if you have the QQ genotype," noted Haley, "because even the highest-level genetic protection can be overwhelmed by higher intensity exposure."
This study has not eliminated other causes completely, Haley added. Some chemical exposures might have caused GWI in a few cases. But this research has suggested that there aren't other influences. "There's no other risk factor coming anywhere close to having this level of causal evidence for Gulf War illness," said Haley.
The scientists want to find biomarkers that could indicate whether a person has been exposed to sarin, or has GWI, as well as learning more about how GWI affects people.
Sources: UT Southwestern Medical Center, Haley et al Environmental Health Perspectives 2022, Weisskopf et al Environmental Health Perspectives 2022, Scientific Reports
