Genes May Determine Who Developed Gulf War Syndrome, University at Buffalo
Researchers Find; Variant in ACE Gene Appears to Cause Susceptibility to
Environmental Triggers

By Ascribe, 8/10/2004 14:05BUFFALO, N.Y., Aug. 10 (AScribe Newswire) --
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. --- CONTACT: John Della Contrada, University at Buffalo Media
Relations, dellacon(at)buffalo.edu or 716-645-5000, ext. 1409 The University
at Buffalo is a premier research-intensive public university, the largest
and most comprehensive campus in the State University of New York. UB's more
than 27,000 students pursue their academic interests through more than 300
undergraduate, graduate and professional degree programs.
Jim Bunker

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