For three decades, scientists have been debating the root cause of Gulf War disease (GWI), a series of unexplained chronic symptoms affecting Persian Gulf War veterans. Now researchers led by Robert Haley, MD, Professor of internal medicine and director of epidemiology at the University of Texas Southwestern Medical Center, have solved the mystery.
Through detailed genetic research, they found that the nerve gas sarin is largely the cause of the syndrome.
The results of the study were published in environmental health perspectives on May 11, a peer-reviewed journal supported by the National Institute of Environmental Health Sciences of the United States, with an editorial of a paper written by a well-known environmental epidemiologist.
Dr Haley's team not only found that veterans exposed to sarin were more likely to develop GWI, but also found that the risk was regulated by a gene that usually allows some people's bodies to better decompose nerve gas. Among Gulf War soldiers exposed to sarin, soldiers with a weak variant of the gene are more likely to develop GWI symptoms than other veterans exposed to sarin because they have a strong form of the gene.
"Very simply, our findings prove that the Gulf War disease was caused by sarin, which was released when we bombed Iraq's chemical weapons storage and production facilities. There are still more than 100000 Gulf War veterans who are not helped by the disease, and we hope these findings will accelerate the search for better treatments," Dr. Haley said
In the years after the Gulf War, more than a quarter of American and coalition veterans began to report a range of chronic symptoms - including fatigue, fever, night sweats, memory and inattention, difficulty finding words, diarrhea, sexual dysfunction and chronic physical pain. Since then, academic researchers and researchers within the Department of military and Veterans Affairs have studied a range of possible causes of GWI, from pressure, vaccination, burning oil wells to exposure to pesticides, nerve gas, anti nerve gas drugs and depleted uranium.
Over the years, these studies have identified statistical associations with several of them, but for no reason have they been widely accepted. Recently, Dr. Haley and a colleague reported on a large study. The study tested depleted uranium in veterans' urine. If depleted uranium led to GWI, it would still exist, but they didn't find it.
"As early as 1995, when we first defined the Gulf War disease, the evidence pointed to nerve agent exposure, but it took many years to establish an irrefutable case," Dr. Haley said
Sarin is a toxic artificial nerve agent. It was originally developed as an insecticide and used in chemical war. Its production was banned in 1997. When people are exposed to liquid or gaseous forms, sarin enters the body through skin or breathing and attacks the nervous system. High concentrations of sarin usually lead to death, but studies of survivors have shown that low concentrations of sarin exposure can lead to long-term damage to brain function. The US military has confirmed that chemical agents including sarin were found in Iraq during the Gulf War. In particular, satellite images recorded a huge debris cloud rising from an Iraqi chemical weapons storage site bombed by U.S. and coalition aircraft and passing over U.S. ground force positions. It triggered thousands of nerve gas alarms and was confirmed to contain sarin.
Previous studies have found an association between self-reported exposure to sarin and GWI symptoms in Gulf War veterans. However, critics raise the question of recall bias, including whether veterans with severe traumatic diseases are just more likely to remember and report exposure because they assume it may be related to their disease. "This new study changes the rules of the game because it links GWI to very powerful gene environment interactions that cannot be explained by recalling errors in environmental exposure or other deviations in the data," Dr. Haley said.
In this study, Dr. Haley and his colleagues studied 508 deployed veterans with GWI and 508 deployed veterans without any GWI symptoms, all randomly selected from more than 8000 representative Gulf War veterans who completed the U.S. military health survey. They not only measured sarin exposure by asking veterans if they heard a chemical nerve gas alarm during deployment, but also collected blood and DNA samples from each veteran.
The researchers tested a gene variant called PON1 in the sample. PON1 has two versions: the Q variant produces a blood enzyme that can effectively break down sarin, while the R variant helps the body break down other chemicals, but is not efficient in destroying sarin. Each person carries two copies of PON1, giving them a QQ, RR or QR genotype.
For Gulf War veterans with QQ genotype, hearing the nerve agent alarm - a substitute for chemical contact - increased their risk of GWI by 3.75 times. For those with QR genotype, the alarm increased their chance of GWI by 4.43 times. For those with two copies of R gene, the decomposition of sarin was inefficient, and the chance of GWI increased by 8.91 times. Soldiers with both RR genotype and low-level sarin exposure were more than seven times more likely to obtain GWI due to the interaction itself, which exceeded the increased risk of two risk factors acting alone. For genetic epidemiologists, this figure brings a high degree of confidence that sarin is a pathogenic factor of GWI.
"Your risk is rising step by step, depending on your genotype, because these genes are mediating your body's inactivation of sarin. That doesn't mean you won't get Gulf War disease if you have QQ genotype, because even the highest level of genetic protection will be overwhelmed by higher levels of exposure," Dr. Haley said
He added that this strong gene environment interaction is considered to be the gold standard for indicating that diseases such as GWI are caused by specific exposure to environmental poisons. The study does not rule out that exposure to other chemicals may be responsible for a small number of Gulf War disease cases. However, Dr. Haley and his team conducted additional genetic analysis of the new data and tested other possible factors, and they finally found no other triggers.
At present, the team is continuing to study how GWI affects the body - especially the immune system, whether any of its effects are reversible and whether there are biomarkers to detect previous sarin exposure or the Gulf War.