Since the 1990s, scientists have debated the underlying cause of Gulf War illness (GWI), a constellation of unexplained and chronic symptoms affecting veterans of the Persian Gulf War. Now researchers have solved the mystery, showing through a detailed genetic study that the nerve gas sarin was largely responsible for the syndrome. The findings were published in Environmental Health Perspectives.
Dr Haley’s research group not only discovered that veterans with exposure to sarin were more likely to develop GWI, but also found that the risk was modulated by a gene that helps break down the nerve gas. Sarin-exposed Gulf War veterans with a weak variant of the gene were more likely to develop symptoms of GWI than other exposed veterans with the strong form of the gene.
“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 Robert Haley, MD, at UT Southwestern, a medical epidemiologist who had led that study and has been investigating GWI for 28 years. “There are still more than 100 000 Gulf War veterans who are not getting help for this illness and our hope is that these findings will accelerate the search for better treatment.”
Multiple causes of Gulf War illness suggested
After the Gulf War, more than a quarter of the US and coalition veterans began reporting a range of chronic symptoms, including fatigue, fever, night sweats, memory and concentration problems, difficulty finding words, diarrhoea, sexual dysfunction, and chronic body pain. Since then, military and academic researchers have studied a list of possible causes of GWI, ranging from stress, vaccinations, and burning oil wells to exposure to pesticides, nerve gas, anti-nerve gas medication, and depleted uranium used in weapons.
“What makes this new study a game-changer is that it links GWI with a very strong gene-environment interaction that cannot be explained away by errors in recalling the environmental exposure or other biases in the data.”Study leader Robert Haley, MD, medical epidemiologist
Over the years, these studies have identified statistical associations with several of these, but no cause has been widely accepted. Most recently, Dr Haley and a colleague reported a large study testing veterans’ urine for depleted uranium that would still be present if it had caused GWI and found none.
Studies have shown statistical associations with several of these causes, though none received wide acceptance. Dr Haley and a colleague recently reported a large study that found no depleted uranium in veterans’ urine, which would have still been present if it had caused GWI.
“As far back as 1995, when we first defined Gulf War illness, the evidence was pointing toward nerve agent exposure, but it has taken many years to build an irrefutable case,” said Dr Haley.
Sarin is a toxic nerve agent, production of which was banned in 1997. When people are exposed to either the liquid or gas form, sarin enters the body through the skin or breathing and attacks the nervous system. High-level sarin often results in death, but studies on survivors have revealed that lower-level sarin exposure can lead to long-term impairment of brain function. A large release of this gas occurred when a chemical weapons storage plant was bombed, causing thousands of nerve gas alarms to sound.
Previous studies have found an association between Gulf War veterans who self-reported exposure to sarin and GWI symptoms. However, this has raised criticisms of recall bias. “What makes this new study a game-changer is that it links GWI with a very strong gene-environment interaction that cannot be explained away by errors in recalling the environmental exposure or other biases in the data,” Dr Haley said.
In the new paper, Dr Haley and his colleagues studied 508 deployed veterans with GWI and 508 deployed veterans who did not develop any GWI symptoms. They asked whether the veterans had heard chemical nerve gas alarms, indicating sarin exposure, and also collected blood and DNA samples.
The role of PON1
The researchers tested the samples for variants of a gene called PON1, which has two variants. The Q variant generates a blood enzyme that efficiently breaks down sarin while the R variant helps the body break down other chemicals but is not efficient at destroying sarin. Everyone has either a QQ, RR or QR genotype.
For Gulf War veterans with the QQ genotype, hearing nerve agent alarms — a proxy for chemical exposure — raised their chance of developing GWI by 3.75 times, those with the QR genotype had an a 4.43 fold risk increase. And for those with RR genotype, the chance of GWI increased by 8.91 times. Those soldiers with both the RR genotype and low-level sarin exposure were over seven times more likely to get GWI due to the interaction per se, over and above the increase in risk from both risk factors acting alone. For genetic epidemiologists, this number leads to a high degree of confidence that sarin is a causative agent of GWI.
“Your risk is going up step by step depending on your genotype, because those genes are mediating how well your body inactivates sarin,” said Dr Haley. “It doesn’t mean you can’t get Gulf War illness if you have the QQ genotype, because even the highest-level genetic protection can be overwhelmed by higher intensity exposure.”
This kind of strong gene-environment interaction is considered a gold standard for showing that an illness like GWI was caused by a particular environmental toxic exposure, he added. The research doesn’t rule out that other chemical exposures could be responsible for a small number of cases of Gulf War illness. However, Dr. Haley and his team carried out additional genetic analyses on the new data, testing other factors that could be related, and found no other contributing causes.
“There’s no other risk factor coming anywhere close to having this level of causal evidence for Gulf War illness,” said Dr Haley.
The team is continuing research on GWI’s impacts on the body, particularly the immune system, whether any of its effects are reversible, and whether there are biomarkers to detect prior sarin exposure or GWI.
Source: UT Southwestern Medical Center