Gene-Toxicant Interactions in Gulf War Illness: Differential Effects of the PON1 Genotype

Jacqueline Vahey, Elizabeth J Gifford, Kellie J Sims, Blair Chesnut, Stephen H Boyle, Crystal Stafford, Julie Upchurch, Annjanette Stone, Saiju Pyarajan, Jimmy T Efird, Christina D Williams, Elizabeth R Hauser, Jacqueline Vahey, Elizabeth J Gifford, Kellie J Sims, Blair Chesnut, Stephen H Boyle, Crystal Stafford, Julie Upchurch, Annjanette Stone, Saiju Pyarajan, Jimmy T Efird, Christina D Williams, Elizabeth R Hauser

Abstract

About 25-35% of United States veterans who fought in the 1990-1991 Gulf War report several moderate or severe chronic systemic symptoms, defined as Gulf War illness (GWI). Thirty years later, there is little consensus on the causes or biological underpinnings of GWI. The Gulf War Era Cohort and Biorepository (GWECB) was designed to investigate genetic and environmental associations with GWI and consists of 1343 veterans. We investigate candidate gene-toxicant interactions that may be associated with GWI based on prior associations found in human and animal model studies, focusing on SNPs in or near ACHE, BCHE, and PON1 genes to replicate results from prior studies. SOD1 was also considered as a candidate gene. CDC Severe GWI, the primary outcome, was observed in 26% of the 810 deployed veterans included in this study. The interaction between the candidate SNP rs662 and pyridostigmine bromide (PB) pills was found to be associated with CDC Severe GWI. Interactions between PB pill exposure and rs3917545, rs3917550, and rs2299255, all in high linkage disequilibrium in PON1, were also associated with respiratory symptoms. These SNPs could point toward biological pathways through which GWI may develop, which could lead to biomarkers to detect GWI or to better treatment options for veterans with GWI.

Keywords: GWI; Gulf War illness; PON1; gene–environment interactions; pesticides; pyridostigmine bromide; veteran health.

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure A1
Figure A1
Exposure questions from the CSP585 questionnaire.
Figure A2
Figure A2
SNP/pesticide interaction p-values for association with the Kansas Gastrointestinal Symptom Domain (PON1).
Figure A3
Figure A3
SNP/pesticide interaction p-values for the association with the Kansas Skin Symptom Domain (ACHE).
Figure A4
Figure A4
SNP/PB pill interaction p-values for the association with the Kansas Skin Symptom Domain (ACHE).
Figure A5
Figure A5
SNP/pesticide interaction p-values for the association with the CDC Musculoskeletal Symptom Domain (ACHE).
Figure A6
Figure A6
LocusZoom plots for the four candidate genes. Plotted are the p-value for the SNP/Pesticide interaction association with CDC Severe.
Figure A7
Figure A7
R2 and D’ for the significant SNP/PB interaction association with GWI outcomes results in the CEU population. Made using LD-matrix [52].
Figure A8
Figure A8
R2 and D’ for the significant SNP/PB interaction association with GWI outcomes results in the YRI population. Made using LD-matrix [52].
Figure A9
Figure A9
Genotype proportions by exposure time (PB), with homozygous GG in blue (dotted, top), heterozygous GA in purple (striped, middle), and homozygous AA in red (solid, bottom).
Figure A10
Figure A10
CDC Severe GWI frequency, stratified by rs662 genotype and PB exposure time, among self-reported white, non-Hispanic individuals only.
Figure A11
Figure A11
CDC Severe GWI frequency, stratified by rs662 genotype and PB exposure time, among self-reported Hispanic or Black, non-Hispanic individuals only.
Figure 1
Figure 1
Block diagram: individuals in analytic dataset. Note: “Deployed to Gulf” throughout this manuscript indicates deployment to the Persian Gulf during the 1990–1991 Gulf War.
Figure 2
Figure 2
Proportion of individuals fulfilling the CDC Severe GWI case definition within each genotype-exposure group. Each block is labeled by genotype (AA, GA, GG), with each bar representing an exposure length.
Figure 3
Figure 3
LocusZoom plots for CDC Severe GWI. Top SNP in each region is marked as a purple diamond, with linkage disequilibrium highlighted according to the r2 legend in upper right.
Figure 4
Figure 4
Kansas Respiratory Domain: PON1. Bonferroni corrected significance level of p = 0.00013 is 3.89 on the y-axis (−log10 scale). Three SNPs (purple and two red) are above that line. Rs662 is labeled for convenience (light blue dot).

References

    1. Institute of Medicine . Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined. The National Academies Press; Washington, DC, USA: 2014.
    1. Kipen H.M., Hallman W., Kang H., Fiedler N., Natelson B.H. Prevalence of Chronic Fatigue and Chemical Sensitivities in Gulf Registry Veterans. Arch. Environ. Health Int. J. 1999;54:313–318. doi: 10.1080/00039899909602493.
    1. Fukuda K., Strauss S., Hickie I., Sharpe M., Dobbins J., Komaroff A. The Chronic Fatigue Syndrome: A Comprehensive Approach to Its Definition and Study. J. Chronic Fatigue Syndr. 1995;1:67–84. doi: 10.1300/J092v01n02_06.
    1. Fukuda K., Nisenbaum R., Stewart G., Thompson W.W., Robin L., Washko R.M., Noah D.L., Barrett D.H., Randall B., Herwaldt B.L., et al. Chronic Multisymptom Illness Affecting Air Force Veterans of the Gulf War. JAMA. 1998;280:981–988. doi: 10.1001/jama.280.11.981.
    1. 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;152:992–1002. doi: 10.1093/aje/152.10.992.
    1. Gifford E.J., Vahey J., Hauser E.R., Sims K.J., Efird J.T., Dursa E.K., Steele L., Helmer D.A., Provenzale D. Gulf War illness in the Gulf War Era Cohort and Biorepository: The Kansas and Centers for Disease Control definitions. Life Sci. 2021;278:119454. doi: 10.1016/j.lfs.2021.119454.
    1. White R.F., Steele L., O’Callaghan J.P., Sullivan K., Binns J.H., Golomb B.A., Bloom F.E., Bunker J.A., Crawford F., Graves J.C., et al. Recent research on Gulf War illness and other health problems in veterans of the 1991 Gulf War: Effects of toxicant exposures during deployment. Cortex. 2016;74:449–475. doi: 10.1016/j.cortex.2015.08.022.
    1. Eisen S.A., Kang H.K., Murphy F.M., Blanchard M.S., Reda D.J., Henderson W.G., Toomey R., Jackson L.W., Alpern R., Parks B.J., et al. Gulf War Veterans’ Health: Medical Evaluation of a U.S. Cohort. Ann. Intern. Med. 2005;142:881–890. doi: 10.7326/0003-4819-142-11-200506070-00005.
    1. Blanchard M.S., Eisen S.A., Alpern R., Karlinsky J., Toomey R., Reda D.J., Murphy F.M., Jackson L.W., Kang H.K. Chronic Multisymptom Illness Complex in Gulf War I Veterans 10 Years Later. Am. J. Epidemiol. 2005;163:66–75. doi: 10.1093/aje/kwj008.
    1. Smith B.N., Wang J.M., Vogt D., Vickers K., King D.W., King L.A. Gulf War Illness. J. Occup. Environ. Med. 2013;55:104–110. doi: 10.1097/JOM.0b013e318270d709.
    1. Cory-Slechta D.A., Wedge R. Gulf War and Health. Gulf War Health. 2016;10:1–292. doi: 10.17226/21840.
    1. Updated Scientific Findings and Recommendations Research Advisory Committee on Gulf War Veterans’ Illnesses. Research Advisory Committee; Washington, DC, USA: 2014.
    1. Steele L., Lockridge O., Gerkovich M.M., Cook M.R., Sastre A. 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. Environ. Health. 2015;14:4. doi: 10.1186/1476-069X-14-4.
    1. Haley R.W., Billecke S., La Du B.N. Association of Low PON1 Type Q (Type A) Arylesterase Activity with Neurologic Symptom Complexes in Gulf War Veterans. Toxicol. Appl. Pharmacol. 1999;157:227–233. doi: 10.1006/taap.1999.8703.
    1. Abdullah L., Evans J.E., Montague H., Reed J.M., Moser A., Crynen G., Gonzalez A., Zakirova Z., Ross I., Mullan C., et al. Chronic elevation of phosphocholine containing lipids in mice exposed to Gulf War agents pyridostigmine bromide and permethrin. Neurotoxicol. Teratol. 2013;40:74–84. doi: 10.1016/j.ntt.2013.10.002.
    1. Abdel-Rahman A., Abou-Donia S.M., El-Masry E.M., Shetty A., Abou-Donia M.B. Stress and Combined Exposure to Low Doses of Pyridostigmine Bromide, DEET, and Permethrin Produce Neurochemical and Neuropathological Alterations in Cerebral Cortex, Hippocampus, and Cerebellum. J. Toxicol. Environ. Health Part A. 2004;67:163–192. doi: 10.1080/15287390490264802.
    1. Ashbrook D.G., Hing B., Michalovicz L.T., Kelly K.A., Miller J.V., De Vega W.C., Miller D.B., Broderick G., O’Callaghan J.P., McGowan P.O. Epigenetic impacts of stress priming of the neuroinflammatory response to sarin surrogate in mice: A model of Gulf War illness. J. Neuroinflamm. 2018;15:86. doi: 10.1186/s12974-018-1113-9.
    1. Nettleman M. Gulf War Illness: Challenges Persist. Trans. Am. Clin. Climatol. Assoc. 2015;126:237–247.
    1. Emmerich T., Zakirova Z., Klimas N., Sullivan K., Shetty A.K., Evans J.E., Ait-Ghezala G., Laco G.S., Hattiangady B., Shetty G.A., et al. Phospholipid profiling of plasma from GW veterans and rodent models to identify potential biomarkers of Gulf War Illness. PLoS ONE. 2017;12:e0176634. doi: 10.1371/journal.pone.0176634.
    1. Chao L., Abadjian L.R., Esparza I.L., Reeb R. Insomnia Severity, Subjective Sleep Quality, and Risk for Obstructive Sleep Apnea in Veterans With Gulf War Illness. Mil. Med. 2016;181:1127–1134. doi: 10.7205/MILMED-D-15-00474.
    1. Belgrad J., Dutta D.J., Bromley-Coolidge S., Kelly K.A., Michalovicz L.T., Sullivan K.A., O’Callaghan J.P., Fields R.D. Oligodendrocyte involvement in Gulf War Illness. Glia. 2019;67:2107–2124. doi: 10.1002/glia.23668.
    1. Gulf War Illness and the Health of Gulf War Veterans. Research Advisory Committee; Washington, DC, USA: 2008.
    1. Ojo J.O., Abdullah L., Evans J., Reed J.M., Montague H., Mullan M.J., Crawford F.C. Exposure to an organophosphate pesticide, individually or in combination with other Gulf War agents, impairs synaptic integrity and neuronal differentiation, and is accompanied by subtle microvascular injury in a mouse model of Gulf War agent exposure. Neuropathology. 2014;34:109–127. doi: 10.1111/neup.12061.
    1. Miller J.V., LeBouf R., A Kelly K., Michalovicz L.T., Ranpara A., Locker A.R., Miller D.B., O’Callaghan J.P. The Neuroinflammatory Phenotype in a Mouse Model of Gulf War Illness is Unrelated to Brain Regional Levels of Acetylcholine as Measured by Quantitative HILIC-UPLC-MS/MS. Toxicol. Sci. 2018;165:302–313. doi: 10.1093/toxsci/kfy130.
    1. Carpenter J., Gordon H., Ludwig H., Wagner J., Harn D., Norberg T., Filipov N. Neurochemical and neuroinflammatory perturbations in two Gulf War Illness models: Modulation by the immunotherapeutic LNFPIII. NeuroToxicology. 2020;77:40–50. doi: 10.1016/j.neuro.2019.12.012.
    1. Zakirova Z., Tweed M., Crynen G., Reed J., Abdullah L., Nissanka N., Mullan M., Mullan M.J., Mathura V., Crawford F., et al. Gulf War Agent Exposure Causes Impairment of Long-Term Memory Formation and Neuropathological Changes in a Mouse Model of Gulf War Illness. PLoS ONE. 2015;10:e0119579. doi: 10.1371/journal.pone.0119579.
    1. Hernandez S., Fried D.E., Grubišić V., McClain J.L., Gulbransen B.D. Gastrointestinal neuroimmune disruption in a mouse model of Gulf War illness. FASEB J. 2019;33:6168–6184. doi: 10.1096/fj.201802572R.
    1. Koo B.-B., Michalovicz L.T., Calderazzo S., Kelly K., Sullivan K., Killiany R.J., O’Callaghan J.P. Corticosterone potentiates DFP-induced neuroinflammation and affects high-order diffusion imaging in a rat model of Gulf War Illness. Brain Behav. Immun. 2018;67:42–46. doi: 10.1016/j.bbi.2017.08.003.
    1. Michalovicz L.T., Kelly K.A., Sullivan K., O’Callaghan J.P. Acetylcholinesterase inhibitor exposures as an initiating factor in the development of Gulf War Illness, a chronic neuroimmune disorder in deployed veterans. Neuropharmacology. 2020;171:108073. doi: 10.1016/j.neuropharm.2020.108073.
    1. Mackness B., Durrington P.N., Mackness M.I. Low Paraoxonase in Persian Gulf War Veterans Self-Reporting Gulf War Syndrome. Biochem. Biophys. Res. Commun. 2000;276:729–733. doi: 10.1006/bbrc.2000.3526.
    1. Saccon R.A., Bunton-Stasyshyn R.K.A., Fisher E.M., Fratta P. Is SOD1 loss of function involved in amyotrophic lateral sclerosis? Brain. 2013;136:2342–2358. doi: 10.1093/brain/awt097.
    1. Haley R.W. Excess incidence of ALS in young Gulf War veterans. Neurology. 2003;61:750–756. doi: 10.1212/WNL.61.6.750.
    1. Horner R., Kamins K., Feussner J., Grambow S., Hoff-Lindquist J., Harati Y., Mitsumoto H., Pascuzzi R., Spencer P., Tim R., et al. Occurrence of amyotrophic lateral sclerosis among Gulf War veterans. Neurology. 2003;61:742–749. doi: 10.1212/.
    1. Merwin S.J., Obis T., Nunez Y., Re D.B. Organophosphate neurotoxicity to the voluntary motor system on the trail of environment-caused amyotrophic lateral sclerosis: The known, the misknown, and the unknown. Arch. Toxicol. 2017;91:2939–2952. doi: 10.1007/s00204-016-1926-1.
    1. A van Es M., Dahlberg C., Birve A., Veldink J.H., Berg L.H.V.D., Andersen P.M. Large-scale SOD1 mutation screening provides evidence for genetic heterogeneity in amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatry. 2010;81:562–566. doi: 10.1136/jnnp.2009.181453.
    1. Zhu G.-D., Dawson E., Huskey A., Gordon R.J., Del Tredici A.L. Genetic Testing for BCHE Variants Identifies Patients at Risk of Prolonged Neuromuscular Blockade in Response to Succinylcholine. Pharmacogenomics Pers. Med. 2020;13:405–414. doi: 10.2147/PGPM.S263741.
    1. Costa L.G., Cole T.B., Jarvik G.P., Furlong C.E. Functional Genomics of the Paraoxonase (PON1) Polymorphisms: Effects on Pesticide Sensitivity, Cardiovascular Disease, and Drug Metabolism. Annu. Rev. Med. 2003;54:371–392. doi: 10.1146/annurev.med.54.101601.152421.
    1. Slowik A., Tomik B., Wolkow P.P., Partyka D., Turaj W., Malecki M.T., Pera J., Dziedzic T., Szczudlik A., Figlewicz D.A. Paraoxonase gene polymorphisms and sporadic ALS. Neurology. 2006;67:766–770. doi: 10.1212/01.wnl.0000219565.32247.11.
    1. Verde F., Tiloca C., Morelli C., Doretti A., Poletti B., Maderna L., Messina S., Gentilini D., Fogh I., Ratti A., et al. PON1 is a disease modifier gene in amyotrophic lateral sclerosis: Association of the Q192R polymorphism with bulbar onset and reduced survival. Neurol. Sci. 2019;40:1469–1473. doi: 10.1007/s10072-019-03834-2.
    1. Huo X., Guo Y., Zhang Y., Li J., Wen X., Liu J. Paraoxonase 1 gene (Q192R) polymorphism confers susceptibility to coronary artery disease in type 2 diabetes patients: Evidence from case-control studies. Drug Discov. Ther. 2019;13:80–88. doi: 10.5582/ddt.2019.01003.
    1. Jarvik G.P., Hatsukami T.S., Carlson C., Richter R.J., Jampsa R., Brophy V.H., Margolin S., Rieder M., Nickerson D., Schellenberg G.D., et al. Paraoxonase Activity, But Not Haplotype Utilizing the Linkage Disequilibrium Structure, Predicts Vascular Disease. Arter. Thromb. Vasc. Biol. 2003;23:1465–1471. doi: 10.1161/01.ATV.0000081635.96290.D3.
    1. Jarvik G.P., Jampsa R., Richter R.J., Carlson C.S., Rieder M.J., Nickerson D.A., Furlong C.E. Novel paraoxonase (PON1) nonsense and missense mutations predicted by functional genomic assay of PON1 status. Pharmacogenetics Genom. 2003;13:291–295. doi: 10.1097/00008571-200305000-00009.
    1. Shapira M., Tur-Kaspa I., Bosgraaf L., Livni N., Grant A.D., Grisaru D., Korner M., Ebstein R.P., Soreq H. A transcription-activating polymorphism in the ACHE promoter associated with acute sensitivity to anti-acetylcholinesterases. Hum. Mol. Genet. 2000;9:1273–1281. doi: 10.1093/hmg/9.9.1273.
    1. Khalil L., McNeil R.B., Sims K.J., A Felder K., Hauser E.R., Goldstein K.M., I Voils C., Klimas N.G., Brophy M.T., Thomas C.M., et al. The Gulf War Era Cohort and Biorepository: A Longitudinal Research Resource of Veterans of the 1990–1991 Gulf War Era. Am. J. Epidemiol. 2018;187:2279–2291. doi: 10.1093/aje/kwy147.
    1. Vahey J., Hauser E.R., Sims K.J., Helmer D.A., Provenzale D., Gifford E.J. Research tool for classifying Gulf War illness using survey responses: Lessons for writing replicable algorithms for symptom-based conditions. Life Sci. 2021;282:119808. doi: 10.1016/j.lfs.2021.119808.
    1. Chang C.C., Chow C.C., Tellier L.C.A.M., Vattikuti S., Purcell S.M., Lee J.J. Second-generation PLINK: Rising to the challenge of larger and richer datasets. GigaScience. 2015;4:7. doi: 10.1186/s13742-015-0047-8.
    1. Chen Y., Meyer J., Hill H.Z., Lange G., Condon M.R., Klein J.C., Ndirangu D., Falvo M.J. Role of mitochondrial DNA damage and dysfunction in veterans with Gulf War Illness. PLoS ONE. 2017;12:e0184832. doi: 10.1371/journal.pone.0184832.
    1. Pruim R.J., Welch R.P., Sanna S., Teslovich T.M., Chines P.S., Gliedt T.P., Boehnke M., Abecasis G., Willer C.J. LocusZoom: Regional visualization of genome-wide association scan results. Bioinformatics. 2010;26:2336–2337. doi: 10.1093/bioinformatics/btq419.
    1. Goodall R. Cholinesterase: Phenotyping and genotyping. Ann. Clin. Biochem. Int. J. Lab. Med. 2004;41:98–110. doi: 10.1258/000456304322879971.
    1. Dardiotis E., Aloizou A.-M., Siokas V., Tsouris Z., Rikos D., Marogianni C., Aschner M., Kovatsi L., Bogdanos D.P., Tsatsakis A. Paraoxonase-1 genetic polymorphisms in organophosphate metabolism. Toxicology. 2019;411:24–31. doi: 10.1016/j.tox.2018.10.012.
    1. Davies H.G., Richter R.J., Keifer M., Broomfield C.A., Sowal J., Furlong C.E. The Effect of the Human Serum Paraoxonase Polymorphism is Reversed with Diazoxon, Soman and Sarin. Nat. Genet. 1996;14:334–336. doi: 10.1038/ng1196-334.
    1. Machiela M.J., Chanock S.J. LDlink: A web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants: Fig. Bioinformatics. 2015;31:3555–3557. doi: 10.1093/bioinformatics/btv402.
    1. Furlong C.E., Marsillach J., Jarvik G.P., Costa L.G. Paraoxonases-1, -2 and -3: What are their functions? Chem. Interact. 2016;259:51–62. doi: 10.1016/j.cbi.2016.05.036.
    1. Buniello A., MacArthur J.A.L., Cerezo M., Harris L.W., Hayhurst J., Malangone C., McMahon A., Morales J., Mountjoy E., Sollis E., et al. The NHGRI-EBI GWAS Catalog of published genome-wide association studies, targeted arrays and summary statistics. Nucleic Acids Res. 2019;47:D1005–D1012. doi: 10.1093/nar/gky1120.
    1. Sun B.B., Maranville J.C., Peters J.E., Stacey D., Staley J.R., Blackshaw J., Burgess S., Jiang T., Paige E., Surendran P., et al. Genomic atlas of the human plasma proteome. Nature. 2018;558:73–79. doi: 10.1038/s41586-018-0175-2.
    1. Marees A.T., De Kluiver H., Stringer S., Vorspan F., Curis E., Marie-Claire C., Derks E. A tutorial on conducting genome-wide association studies: Quality control and statistical analysis. Int. J. Methods Psychiatr. Res. 2018;27:e1608. doi: 10.1002/mpr.1608.
    1. Radhakrishnan K., Hauser E., Polimanti R., Helmer D., Provenzale D., McNeil R., Maffucci A., Quaden R., Zhao H., Whitbourne S., et al. Genomics of Gulf War Illness in U.S. Veterans Who Served during the 1990–1991 Persian Gulf War: Methods and Rationale for Veterans Affairs Cooperative Study #2006. Brain Sci. 2021;11:845. doi: 10.3390/brainsci11070845.
    1. Parihar V.K., Hattiangady B., Shuai B., Shetty A.K. Mood and Memory Deficits in a Model of Gulf War Illness Are Linked with Reduced Neurogenesis, Partial Neuron Loss, and Mild Inflammation in the Hippocampus. Neuropsychopharmacology. 2013;38:2348–2362. doi: 10.1038/npp.2013.158.
    1. Golomb B.A. Acetylcholinesterase inhibitors and Gulf War illnesses. Proc. Natl. Acad. Sci. USA. 2008;105:4295–4300. doi: 10.1073/pnas.0711986105.
    1. Janulewicz P., Krengel M., Quinn E., Heeren T., Toomey R., Killiany R., Zundel C., Ajama J., O’Callaghan J., Steele L., et al. The Multiple Hit Hypothesis for Gulf War Illness: Self-Reported Chemical/Biological Weapons Exposure and Mild Traumatic Brain Injury. Brain Sci. 2018;8:198. doi: 10.3390/brainsci8110198.
    1. Phillips K.F., Deshpande L.S. Repeated low-dose organophosphate DFP exposure leads to the development of depression and cognitive impairment in a rat model of Gulf War Illness. NeuroToxicology. 2016;52:127–133. doi: 10.1016/j.neuro.2015.11.014.
    1. Haley R.W. Self-reported Exposure to Neurotoxic Chemical Combinations in the Gulf WarA Cross-sectional Epidemiologic Study. JAMA. 1997;277:231–237. doi: 10.1001/jama.1997.03540270057027.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться