proteins. For example, polymorphisms in the PON1 gene include the coding variants L55M and Q192R, as well as regulatory polymorphisms C-108T and A-162G (Brophy et al., 2001; Costa et al., 2005; Davies et al., 1996). There are also functionally significant polymorphisms in the butyrylcholinesterase (BuChE) gene that reduce BuChE levels and activity (Jensen et al., 1995). Variants in these genes have been implicated as determinants of normal aging and in various disorders, such as neurodegenerative and cardiovascular diseases (Benmoyal-Segal et al., 2005). Several studies have incriminated PON1 polymorphisms in ALS (reviewed by Wills et al., 2009).

Golomb (2008) reviewed studies found through a search of the National Library of Medicine’s PubMed database, using the key words “Gulf War,” “epidemiology,” and “acetylcholinesterase inhibitors.” She concluded that these studies—combined with veterans’ self-reports of exposures in the Gulf War theatre (including those cited earlier in this report), and studies of people occupationally exposed to cholinesterase inhibitors—supported, through “triangular evidence,” a causative association between exposure to cholinesterase inhibitors during deployment in the Gulf War and Gulf War illness. However, after a review of the primary sources cited by Golomb, the Update committee believes that more study is needed before any clear association can be inferred between Gulf War illness (multisymptom illness) and any inherited variability in PON1 or BChE genes.

An initial association between rare PON1 genotypes and multisymptom illness was first suggested by Haley et al. (1999) in a study of 25 symptomatic US Gulf War veterans, but the finding failed to reach statistical significance (p = 0.08 before correction for multiple comparisons). The authors also reported that the rare genotypes had reduced functional activity (Haley et al., 1999). In contrast to Haley et al., Mackness et al. (2000), in a larger study of 152 UK veterans with multisymptom illness, could find no association between genotype status and multisymptom illness and, furthermore, no function-genotype association for PON1 could be identified either in veterans with multisymptom illness or in controls. Although Mackness et al. (2000) did initially report an association of symptoms of Gulf War illness with reduced PON1 activity, in a follow-up study apparently with a different UK veteran cohort, Hotopf et al. (2003) concluded that reduced PON1 activity was found in deployed veterans regardless of whether they had symptoms of multisymptom illness. Because reduced PON1 activity may accompany states of chronic inflammation, the author postulated that inflammation might explain the reduced activity in deployed soldiers.

Golomb (2008) cites a US Army report (Lockridge, 1999) that states that rare genetic variants of BChE are present at a statistically increased frequency in Gulf War veterans with multisymptom sufferers. A second Department of Defense study (Sastre and Cook, 2004) found no evidence of any genotype-function correlations with BChE but, like the Lockridge study, did find an association between multisymptom illness symptoms and carriers of rare BChE genotypes who also self-reported PB exposure. However, the numbers of carriers of rare genotypes were small in both these studies—11 out of 226 veterans in Lockridge (1999) and 28 out of 304 veterans in Sastre and Cook (2004).

Thus, the Update committee concludes that current evidence raises the possibility of an association between multisymptom illness and genotypes of both BChE and PON1, but no definitive conclusions can be drawn. These data may represent an extremely important clue to the etiology of chronic symptoms seen both in the Gulf War veterans and in some civilian populations. The committee strongly recommends that well-designed studies be undertaken and replicated to more robustly test the hypothesis that naturally occurring variants in detoxifying

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