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Research Topics
Health and Human Services Department of Defense Veterans Affairs Health and Human Services Gulf War Information Department of Defense Gulf War Information Veterans Affairs Gulf War Information Home Home Advanced Search Glossary FAQs Site Map Contact Us
 Research Topics    |    Major Focus Areas
Research Topics
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Genetic Studies
Project Summary

Title: Autonomic Dysfunction in Gulf War Veterans
Synopsis: This study will analyze genes and measures of nervous system response in both of ill and healthy veterans, in order to determine whether some individuals may be more prone to develop Gulf War illnesses when exposed to certain forms of stress because their nervous system reacts differently.
Overall Project Objective: Test the hypothesis that autonomic dysfunction in the cholinergic metabolic pathways (developmentally or genetically based) is correlated with Gulf War Illness.
Status/Results to Date: Study 1 was completed after recruiting 160 controls and 144 cases. Statistical analysis did not support the original form of the hypothesis that veterans complaining of GWI symptoms (cases) were more likely to carry the A, K or F butyrylcholinesterase mutations. There was one notable exception, however. Analysis of the 13 individuals homozygous for the K mutation (genotype K/K) revealed a statistically-significant excess of cases and symptom scores over the controls. This was not seen in heterozygotes (genotype U/K) or even when pooling homozygotes with individuals with genotype U/AK. Study 1 had another unusual finding. When the 304 samples were first phenotyped by measuring enzyme activity with benzoylcholine, and inhibition of activity by dibucaine, sodium fluoride, and RO2-0683 (as is done for tentative identification of mutations, prior to more definitive mutation determination by sequencing), one sample was found to have a combination of values not previously observed in human butyrylcholinesterases. Upon sequencing, a single mutation was found in one allele. Codon 70 had C in place of G, thus changing Asp 70 (GAT) to His (CAT), nucleotide 208G->C. The Asp70His mutation has never previously been described. Study 2 received final DoD-IRB approval in March, 2001. As of October 15, 2001, we have collected physiologic and questionnaire data from 62 veterans (43 who were deployed and 19 non-deployed controls). We have genotyped 33 of those 62 subjects. It is expected that physiologic data collection will be complete in March, 2002. Genotyping and data reduction should be complete by June, 2002 and statistical analyses will begin at that time.
Project:DoD-111
Agency:Department Of Defense
Location:Midwest Research Institute
P.I. Name:Antonio Sastre, Ph. D.
Research Type:Clinical
Research Focus:Brain & Nervous System
Focus Category:Genetic Studies
Status:Ongoing
Study Start Date:January 31,2000
Estimated Completion Date:June 30,2003
Specific Aims: Test the hypotheses that individuals who are autonomically hyperresponsive are more prone to GWI when exposed to physiological and psychological combat stress; and that alteration in the central and peripheral acetylcholine transmitter neural pathways is an underlying factor in the autonomic dysfunction.
Methodology: The hypotheses will be tested in an epidemiological study, and in a study of autonomic reactivity to stress. Study 1 is a case-control epidemiologic and genetic study, attempting to confirm Dr O. Lockridge's observation that veterans complaining of GWI symptoms were more likely to carry the A or F butyrylcholinesterase mutations than those who are not ill. The subject population was genotyped and questionnaire data obtained. Study 2 is a matched case-control biochemical/genetic and physiologic study. The subject population will be genotyped to provide evidence to support whether individuals who are heterozygous for the A or F alleles or homozygous for the K allele are at greater risk for developing GWI than individuals with the wild-type U allele. Genotypic analysis will also be correlated to autonomic responses in physiological and psychophysiologic studies (measures include heart rate variability, blood pressure, respiration, startle response, sustained hand grip, mental arithmetic, emotional stress, head-up tilt, and affinity for carbamate inhibitors).
Most Recent Publications:

Boeck AT, Fry DL, Sastre A, Lockridge O. Naturally occurring mutation, Asp70his, in human butyrylcholinesterase. Annals of Clinical Biochemistry, 39(Pt 2):154-6, Mar 2002. Abstract