Butyrylcholinesterase Genotype and Enzyme Activity in Relation to Gulf War Illness: Preliminary Evidence of Gene-exposure Interaction from a Case-control Study of 1991 Gulf War Veterans

Overview

Journal Environ Health

Publisher Biomed Central

Specialty Environmental Health

Date 2015 Jan 11

PMID 25575675

Citations 31

Authors

Lea Steele

Oksana Lockridge

Mary M Gerkovich

Mary R Cook

Antonio Sastre

Affiliations

Soon will be listed here.

Abstract

Background: Epidemiologic studies have implicated wartime exposures to acetylcholinesterase (AChE)-inhibiting chemicals as etiologic factors in Gulf War illness (GWI), the multisymptom condition linked to military service in the 1991 Gulf War. It is unclear, however, why some veterans developed GWI while others with similar exposures did not. Genetic variants of the enzyme butyrylcholinesterase (BChE) differ in their capacity for metabolizing AChE-inhibiting chemicals, and may confer differences in biological responses to these compounds. The current study assessed BChE enzyme activity and BChE genotype in 1991 Gulf War veterans to evaluate possible association of this enzyme with GWI.

Methods: This case-control study evaluated a population-based sample of 304 Gulf War veterans (144 GWI cases, meeting Kansas GWI criteria, and 160 controls). BChE enzyme activity levels and genotype were compared, overall, in GWI cases and controls. Potential differences in risk associated with cholinergic-related exposures in theater were explored using stratified analyses to compare associations between GWI and exposures in BChE genetic and enzyme activity subgroups.

Results: Overall, GWI cases and controls did not differ by mean BChE enzyme activity level or by BChE genotype. However, for the subgroup of Gulf War veterans with less common, generally less active, BChE genotypes (K/K, U/AK, U/A, A/F, AK/F), the association of wartime use of pyridostigmine bromide (PB) with GWI (OR=40.00, p=0.0005) was significantly greater than for veterans with the more common U/U and U/K genotypes (OR=2.68, p=0.0001).

Conclusions: Study results provide preliminary evidence that military personnel with certain BChE genotypes who used PB during the 1991 Gulf War may have been at particularly high risk for developing GWI. Genetic differences in response to wartime exposures are potentially important factors in GWI etiology and should be further evaluated in conjunction with exposure effects.

Citing Articles

Association of deployment characteristics and exposures with persistent ill health among 1990-1991 Gulf War veterans in the VA Million Veteran Program.

Steele L, Quaden R, Ahmed S, Harrington K, Duong L, Ko J Environ Health. 2024; 23(1):92.

PMID: 39456027 PMC: 11520114. DOI: 10.1186/s12940-024-01118-7.

PON1 Status in Relation to Gulf War Illness: Evidence of Gene-Exposure Interactions from a Multisite Case-Control Study of 1990-1991 Gulf War Veterans.

Steele L, Furlong C, Richter R, Marsillach J, Janulewicz P, Krengel M Int J Environ Res Public Health. 2024; 21(8).

PMID: 39200575 PMC: 11353671. DOI: 10.3390/ijerph21080964.

Gulf war illness: a tale of two genomes.

Golomb B, Kelley R, Han J, Miller B, Bui L BMC Res Notes. 2024; 17(1):230.

PMID: 39169443 PMC: 11337741. DOI: 10.1186/s13104-024-06871-z.

Crisis in the gut: navigating gastrointestinal challenges in Gulf War Illness with bioengineering.

Collier C, Salikhova A, Sabir S, Foncerrada S, Raghavan S Mil Med Res. 2024; 11(1):45.

PMID: 38978144 PMC: 11229309. DOI: 10.1186/s40779-024-00547-2.

The Million Veteran Program 1990-1991 Gulf War Era Survey: An Evaluation of Veteran Response, Characteristics, and Representativeness of the Gulf War Era Veteran Population.

Harrington K, Quaden R, Steele L, Helmer D, Hauser E, Ahmed S Int J Environ Res Public Health. 2024; 21(1).

PMID: 38248536 PMC: 10815483. DOI: 10.3390/ijerph21010072.

References

Bartels C, Jensen F, Lockridge O, van der Spek A, Rubinstein H, Lubrano T . DNA mutation associated with the human butyrylcholinesterase K-variant and its linkage to the atypical variant mutation and other polymorphic sites. Am J Hum Genet. 1992; 50(5):1086-103. PMC: 1682596. View

Haley R, Vongpatanasin W, Wolfe G, Bryan W, Armitage R, Hoffmann R . Blunted circadian variation in autonomic regulation of sinus node function in veterans with Gulf War syndrome. Am J Med. 2004; 117(7):469-78. DOI: 10.1016/j.amjmed.2004.03.041. View

Haley R, Charuvastra E, Shell W, Buhner D, Marshall W, Biggs M . Cholinergic autonomic dysfunction in veterans with Gulf War illness: confirmation in a population-based sample. JAMA Neurol. 2013; 70(2):191-200. DOI: 10.1001/jamaneurol.2013.596. View

Golier J, Schmeidler J, Legge J, Yehuda R . Twenty-four hour plasma cortisol and adrenocorticotropic hormone in Gulf War veterans: relationships to posttraumatic stress disorder and health symptoms. Biol Psychiatry. 2007; 62(10):1175-8. DOI: 10.1016/j.biopsych.2007.04.027. View

Furlong C . PON1 status and neurologic symptom complexes in Gulf War veterans. Genome Res. 2000; 10(2):153-5. DOI: 10.1101/gr.10.2.153. View

Li B, Sedlacek M, Manoharan I, Boopathy R, Duysen E, Masson P . Butyrylcholinesterase, paraoxonase, and albumin esterase, but not carboxylesterase, are present in human plasma. Biochem Pharmacol. 2005; 70(11):1673-84. DOI: 10.1016/j.bcp.2005.09.002. View

Lepage L, Schiele F, Gueguen R, Siest G . Total cholinesterase in plasma: biological variations and reference limits. Clin Chem. 1985; 31(4):546-50. View

Giacobini E . Cholinesterase inhibitors: new roles and therapeutic alternatives. Pharmacol Res. 2004; 50(4):433-40. DOI: 10.1016/j.phrs.2003.11.017. View

Fukuda K, Nisenbaum R, Stewart G, Thompson W, Robin L, Washko R . Chronic multisymptom illness affecting Air Force veterans of the Gulf War. JAMA. 1998; 280(11):981-8. DOI: 10.1001/jama.280.11.981. View

10.

Zhang Q, Zhou X, Denny T, Ottenweller J, LANGE G, LaManca J . Changes in immune parameters seen in Gulf War veterans but not in civilians with chronic fatigue syndrome. Clin Diagn Lab Immunol. 1999; 6(1):6-13. PMC: 95652. DOI: 10.1128/CDLI.6.1.6-13.1999. View

11.

Ozakinci G, Hallman W, Kipen H . Persistence of symptoms in veterans of the First Gulf War: 5-year follow-up. Environ Health Perspect. 2006; 114(10):1553-7. PMC: 1626433. DOI: 10.1289/ehp.9251. View

12.

Chao L, Abadjian L, Hlavin J, Meyerhoff D, Weiner M . Effects of low-level sarin and cyclosarin exposure and Gulf War Illness on brain structure and function: a study at 4T. Neurotoxicology. 2011; 32(6):814-22. DOI: 10.1016/j.neuro.2011.06.006. View

13.

Kamel F, Hoppin J . Association of pesticide exposure with neurologic dysfunction and disease. Environ Health Perspect. 2004; 112(9):950-8. PMC: 1247187. DOI: 10.1289/ehp.7135. View

14.

Steele L . Prevalence and patterns of Gulf War illness in Kansas veterans: association of symptoms with characteristics of person, place, and time of military service. Am J Epidemiol. 2000; 152(10):992-1002. DOI: 10.1093/aje/152.10.992. View

15.

Jensen F, Nielsen L, Schwartz M . Detection of the plasma cholinesterase K variant by PCR using an amplification-created restriction site. Hum Hered. 1996; 46(1):26-31. DOI: 10.1159/000154321. View

16.

Toomey R, Alpern R, Vasterling J, Baker D, Reda D, Lyons M . Neuropsychological functioning of U.S. Gulf War veterans 10 years after the war. J Int Neuropsychol Soc. 2009; 15(5):717-29. DOI: 10.1017/S1355617709990294. View

17.

Howard T, Hsu F, Grzywacz J, Chen H, Quandt S, Vallejos Q . Evaluation of candidate genes for cholinesterase activity in farmworkers exposed to organophosphorus pesticides: association of single nucleotide polymorphisms in BCHE. Environ Health Perspect. 2010; 118(10):1395-9. PMC: 2957918. DOI: 10.1289/ehp.0901764. View

18.

Beck K, Zhu G, Beldowicz D, Brennan F, Ottenweller J, Moldow R . Central nervous system effects from a peripherally acting cholinesterase inhibiting agent: interaction with stress or genetics. Ann N Y Acad Sci. 2002; 933:310-4. DOI: 10.1111/j.1749-6632.2001.tb05833.x. View

19.

Nogueira C, Bartels C, Mcguire M, Adkins S, Lubrano T, Rubinstein H . Identification of two different point mutations associated with the fluoride-resistant phenotype for human butyrylcholinesterase. Am J Hum Genet. 1992; 51(4):821-8. PMC: 1682781. View

20.

Furlong C, Li W, Richter R, Shih D, Lusis A, Alleva E . Genetic and temporal determinants of pesticide sensitivity: role of paraoxonase (PON1). Neurotoxicology. 2000; 21(1-2):91-100. View