Genes May Determine Who Developed Gulf War Syndrome, UB Researchers Find

BUFFALO, N.Y. -- Veterans of the first Persian Gulf War suffering from medically unexplained fatigue associated with Gulf War Syndrome may have a genetic predisposition for developing the condition, geneticists at the University at Buffalo have found.

Their research, involving healthy veterans and veterans with severe and chronic fatigue, as well as non-veterans with chronic fatigue syndrome, showed that affected veterans, in comparison with healthy controls, had an increased frequency of a nonbeneficial genetic variant in a gene involved in the production of angiotension-converting-enzyme (ACE), an enzyme important in the control of blood pressure and electrolyte balance.

Unexpectedly, the nonbeneficial variant was less common among non-veterans with symptoms identical to those of Gulf War Syndrome, indicating that the genetic variant rendered the carriers more susceptible to triggers present in the Gulf-War environment.

Results were reported in the July issue of Muscle and Nerve.

"The results of this study are somewhat controversial, because people don't necessarily want to accept the possibility of a genetic predisposition," said Georgirene Vladutiu, Ph.D., UB professor of pediatrics, neurology and pathology and first author on the study. "The idea of something external as the cause is much more palatable."

Vladutiu directs the Robert Guthrie Biochemical Genetics Laboratory at the Women and Children's Hospital of Buffalo and specializes in the laboratory diagnosis of metabolic muscle diseases.

External or environmental factors do play a role in Gulf War Syndrome, said Vladutiu, but likely as triggers in those with a genetic predilection, rather than as the initial cause.

"These triggers may be extreme exertion, heat, chemical exposures, infections, multiple vaccinations, emotional stress and a combination of these conditions or something else entirely.

"We don't know if the triggers are specific to the first Persian Gulf War," she noted. "Soldiers serving now are exposed to different environmental triggers. In addition, our sample is small. We need to prove or disprove these findings in a larger group of veterans from different theaters of war."

Chronic fatigue manifests in two distinct forms. Unexplained fatigue with no other symptoms is diagnosed as idiopathic chronic fatigue (ICF). Fatigue accompanied by infections, painful joints or neuropsychiatric symptoms is called chronic fatigue syndrome (CFS). CFS/ICF is nearly four times as prevalent in veterans of the first Persian Gulf War as in non-veterans, earning the label Gulf War Syndrome in that population.

CFS/ICF has been studied extensively, but the cause remains unknown. Vladutiu and her colleague, Benjamin Natelson, M.D., at the War-Related Illness and Injury Study Center in Washington, D.C., and the CFS Cooperative Research Center at the UMDNJ- New Jersey Medical School, set out to determine if genetics may play a role.

Earlier research had shown that persons with an insertion variant (added genetic material) of the ACE gene had higher endurance, appearing to derive a beneficial effect from the variant. Vladutiu theorized that persons with CFS would have a lower prevalence of the insertion variant with a correspondingly higher prevalence of the deletion variant (no added genetic material), which rendered them especially susceptible to a variety of environmental triggers that can bring on the muscle pain and reduced physical abilities characteristic of CFS/ICF.

To test this theory, Vladutiu and Natelson analyzed DNA from banked blood samples from Gulf War veterans and non-veterans who were healthy or had CFS/ICF, looking for differences in the segment of the ACE gene that contains either the insertion or deletion of genetic material, called the I/D polymorphism. The possible combinations of the variants, known as genotypes, are II, ID, and DD. The II and ID genotypes are known to be beneficial, or at least not harmful, while the DD variant is believed to have a potentially negative impact on muscle function and has been associated with a number of other illnesses, such as multivessel cardiac disease, said Vladutiu.

The samples were collected from 49 Gulf War veterans with CFS, 61 non-veterans with CFS, 30 healthy veterans and 45 healthy non-veterans. Results of the genetic analysis showed that the frequency of the II genotype (beneficial) was significantly lower in veterans with Gulf-War Syndrome compared to healthy veterans, and both healthy and ill non-veterans. The II genotype was four times lower in the ill veterans than healthy veterans, results showed.

Moreover, 76 percent of Gulf War veterans with the DD (nonbeneficial) genotype had CFS or ICF, compared with only 45 percent of veterans with the ID variant and 27 percent with the II variant. Those with the DD genotype were eight times more likely to have CFS/ICF than those with the II variant, results showed.

"Our genetic make-up determines how we respond to our environment in every sense of the word, including our interior environment," said Vladutiu. "The lower prevalence of the II genotype and the increased prevalence of the DD genotype in Gulf War veterans with medically unexplained chronic fatigue points to an interaction between these genetic variants and some factor or factors specific to the Persian Gulf."

The next step is to study these and other variants in the ACE gene in a larger group of affected and unaffected veterans of the first Gulf War, and compare the results with studies in veterans of the second Gulf War, as well as in veterans of other wars, such as in Bosnia and Vietnam, said Vladutiu.

"If the results of this study are reproducible in terms of the association with the ACE gene variant, then the stresses associated with war activity generally act as an external trigger on the function of a substance (ACE) that has multiple impacts on the physiology of the body.

"If the results show a specific association only in veterans of the first Gulf War," she said, "then there was likely an environmental factor, such as one or more chemical exposures that, combined with variations in the ACE gene, predisposed certain individuals to the development of medically unexplained chronic fatigue."

The research was supported by grants from the Muscular Dystrophy Association, the Children's Guild of Buffalo, UB, the Veterans Administration and the U.S. Public Health Service.

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