Using gene expression signatures to identify novel treatment strategies in gulf war illness

BMC Medical Genomics

Volumn 8, Issue 1, 2015, Pages

  Craddock, Travis J A ^a,b,c   Harvey, Jeanna M ^d   Nathanson, Lubov ^b   Barnes, Zachary M ^b,d,e,f   Klimas, Nancy G ^b,d,e   Fletcher, Mary Ann ^b,d   Broderick, Gordon ^a,b,c  

^a NOVA SOUTHEASTERN UNIVERSITY   (United States)

^b affiliation with Nova Southeastern College of Osteopathic Medicine   (United States)

^c UNIVERSITY OF ALBERTA   (Canada)

^d UNIVERSITY OF MIAMI MILLER SCHOOL OF MEDICINE   (United States)

^e VETERANS AFFAIRS MEDICAL CENTER   (United States)

^f UNIVERSITY OF MIAMI   (United States)

Author keywords

Bioinformatics; Complex chronic illness; Drug repurposing; Gulf war illness; Pharmacogenomics; Systems biology

Indexed keywords

ADALIMUMAB; ALKYLATING AGENT; CISPLATIN; CONJUGATED ESTROGEN; ETANERCEPT; EXEMESTANE; FULVESTRANT; IMMUNOSUPPRESSIVE AGENT; INFLIXIMAB; LEFLUNOMIDE; MEDROXYPROGESTERONE; TAMOXIFEN; TUMOR NECROSIS FACTOR ALPHA INHIBITOR;

ADOLESCENT; ARTICLE; AUTOIMMUNE DISEASE; BIOINFORMATICS; BRAIN DISEASE; CELL FUNCTION; CHRONIC DISEASE; CLINICAL ARTICLE; COHORT ANALYSIS; CONTROLLED STUDY; DRUG TARGETING; GENE EXPRESSION; GULF WAR ILLNESS; HUMAN; MALE; MUSCLE DISEASE; PHARMACOGENOMICS; PRIORITY JOURNAL; RHEUMATOID ARTHRITIS; SYSTEMS BIOLOGY; WAR; ADULT; DRUG REPOSITIONING; GENE EXPRESSION PROFILING; GENETIC DATABASE; GENETICS; MEDICAL INFORMATICS; MIDDLE AGED; MOLECULARLY TARGETED THERAPY; PERSIAN GULF SYNDROME; PHARMACOGENETICS; PROCEDURES; VETERAN;

ADULT; DATABASES, GENETIC; DRUG REPOSITIONING; GENE EXPRESSION PROFILING; HUMANS; MALE; MEDICAL INFORMATICS; MIDDLE AGED; MOLECULAR TARGETED THERAPY; PERSIAN GULF SYNDROME; PHARMACOGENETICS; VETERANS;

EID: 84936758815     PISSN: None     EISSN: 17558794     Source Type: Journal    
DOI: 10.1186/s12920-015-0111-3     Document Type: Article

References (84)

1. Paul SM, Mytelka DS, Dunwiddie CT, Persinger CC, Munos BH, Lindborg SR, et al. How to improve R&D productivity: the pharmaceutical industry's grand challenge. Nat Rev Drug Discov. 2010;9:203-14.
2. Adams C, Brantner V. Estimating the cost of new drug development: is it really 802 million dollars? Health Aff (Millwood). 2006;25(2):420-8.
3. Adams CP, Brantner VV. Spending on new drug development. Health Econ. 2010;19(2):130-41.
4. DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: new estimates of drug development costs. J Health Econ. 2003;22(2):151-85.
5. Wang Y. Extracting knowledge from failed development programmes. Pharm Med. 2012;26(2):91-6.
6. RAC-GWVI (Research Advisory Committee on Gulf War Veterans' Illnesses). Gulf War Illness and the Health of Gulf War Veterans. Washington, DC: U.S. Government Printing Office; 2008.
7. Amourette C, Lamproglou I, Barbier L, Fauquette W, Zoppe A, Viret R, et al. Gulf War illness: effects of repeated stress and pyridostigmine treatment on blood-brain barrier permeability and cholinesterase activity in rat brain. Behav Brain Res. 2009;203(2):207-14.
8. Lamproglou I, Barbier L, Diserbo M, Fauvelle F, Fauquette W, Amourette C. Repeated stress in combination with pyridostigmine: part I: long-term behavioural consequences. Behav Brain Res. 2009;197(2):301-10.
9. Barbier L, Diserbo M, Lamproglou I, Amourette C, Peinnequin A, Fauquette W. Repeated stress in combination with pyridostigmine: part II: changes in cerebral gene expression. Behav Brain Res. 2009;197(2):292-300.
10. Fukuda K, Nisenbaum R, Stewart G, Thompson WW, Robin L, Washko RM, et al. Chronic multisymptom illness affecting Air Force veterans of the Gulf War. J Am Med Assoc. 1998;280:981-98.
11. Reeves WC, Lloyd A, Vernon SD, Klimas N, Jason LA, et al. Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BMC Health Serv Res. 2003;3:25.
12. Collins JF, Donta ST, Engel CC, Baseman JB, Dever LL, Taylor T, et al. The antibiotic treatment trial of Gulf War Veterans' Illnesses: issues, design, screening, and baseline characteristics. Control Clin Trials. 2002;23:333-53.
13. Broderick G, Ben-Hamo R, Vashishtha S, Efroni S, Nathanson L, Barnes Z, et al. Altered immune pathway activity under exercise challenge in Gulf War Illness: an exploratory analysis. Brain Behav Immun. 2013;28:159-69.
14. Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, et al. NCBI GEO: archive for functional genomics data sets - update. Nucleic Acids Res. 2013;41(Database issue):D991-5.
15. Edgar R, Domrachev M, Lash AE. Gene expression omnibus: NCBI gene expression and hybridization array data repository. Nucleic Acids Res. 2002;30(1):207-10.
16. Suthram S, Dudley JT, Chiang AP, Chen R, Hastie TJ, Butte AJ. Network-based elucidation of human disease similarities reveals common functional modules enriched for pluripotent drug targets. PLoS Comput Biol. 2010;6(2):e1000662.
17. Storey JD. A direct approach to false discovery rates. J R Stat Soc B. 2002;64(3):479-98.
18. Dalman MR, Deeter A, Nimishakavi G, Duan ZH. Fold change and p-value cutoffs significantly alter microarray interpretations. BMC Bioinformatics. 2012;13 Suppl 2:S11.
19. Whirl-Carrillo M, McDonagh EM, Hebert JM, Gong L, Sangkuhl K, Thorn CF, et al. Pharmacogenomics knowledge for personalized medicine. Clinic Pharmacol Therapeut. 2012;92(4):414-7.
20. Kamburov A, Wierling C, Lehrach H, Herwig R. ConsensusPathDB-a database for integrating human interaction networks. Nucleic Acids Res. 2009;37 suppl 1:D623-8.
21. Kamburov A, Pentchev K, Galicka H, Wierling C, Lehrach H, Herwig R. ConsensusPathDB: toward a more complete picture of cell biology. Nucleic Acids Res. 2011;39 suppl 1:D712-7.
22. Kamburov A, Stelzl U, Lehrach H, Herwig R. The ConsensusPathDB interaction database: 2013 update. Nucleic Acids Res. 2013;41(D1):D793-800.
23. Kanehisa M, Goto S, Sato Y, Furumichi M, Tanabe M. KEGG for integration and interpretation of large-scale molecular data sets. Nucleic Acids Res. 2012;40:D109-14.
24. Kandasamy K, Mohan SS, Raju R, Keerthikumar S, Kumar GSS, Venugopal AK, et al. NetPath: a public resource of curated signal transduction pathways. Genome Biol. 2010;11:R3.
25. Frolkis A, Knox C, Lim E, Jewison T, Law V, Hau DD, et al. SMPDB: the small molecule pathway database. Nucleic Acids Res. 2010;38:D480-7.
26. Yamamoto S, Sakai N, Nakamura H, Fukagawa H, Fukuda K, Takagi T. INOH: ontology-based highly structured database of signal transduction pathways. Database. 2011;2011:bar052.
27. Nishimura D. Biocarta. Biotech Software & Internet Report. 2001;2(3):117-20.
28. Romero P, Wagg J, Green ML, Kaiser D, Krummenacker M, Karp PD. Computational prediction of human metabolic pathways from the complete human genome. Genome Biol. 2004;6:R2.
29. Fazekas D, Koltai M, Türei D, Módos D, Pálfy M, Dúl Z, et al. SignaLink 2.0 - a signaling pathway resource with multi-layered regulatory networks. BMC Syst Biol. 2013;7:7.
30. Hao T, Ma HW, Zhao XM, Goryanin I. Compartmentalization of the Edinburgh human metabolic network. BMC Bioinformatics. 2010;11:393.
31. Croft D, Mundo AF, Haw R, Milacic M, Weiser J, Wu G, et al. The Reactome pathway knowledgebase. Nucleic Acids Res. 2014;42(Database issue):D472-7.
32. Kelder T, van Iersel MP, Hanspers K, Kutmon M, Conklin BR, Evelo CT, et al. WikiPathways: building research communities on biological pathways. Nucleic Acids Res. 2012;40:D1301-7.
33. Schaefer CF, Anthony K, Krupa S, Buchoff J, Day M, Hannay T, et al. PID: the pathway interaction database. Nucleic Acids Res. 2009;37:D674-9.
34. Institute of Medicine. Health Consequences of Service During the Persian Gulf War: Recommendations for Research and Information Systems. Washington DC: National Academies Press; 1996.
35. Hubbard NA, Hutchison JL, Motes MA, Shokri-Kojori E, Bennett IJ, Brigante RM, et al. Central executive dysfunction and deferred prefrontal processing in veterans with gulf war illness. Clin Psychol Sci. 2014;2(3):319-27.
36. Rayhan RU, Stevens BW, Raksit MP, Ripple JA, Timbol CR, Adewuyi O, et al. Exercise challenge in Gulf War Illness reveals two subgroups with altered brain structure and function. PLoS ONE. 2013;8(6):e63903.
37. Rayhan RU, Stevens BW, Timbol CR, Adewuyi O, Walitt B, Van Meter JW, et al. Increased brain white matter axial diffusivity associated with fatigue, pain and hyperalgesia in Gulf War illness. PLoS ONE. 2013;8(3):e58493.
38. Parihar VK, Hattiangady B, Shuai B, Shetty AK. 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. Neuropsychopharmacol. 2013;38(12):2348-62.
39. Thomas HV, Stimpson NJ, Weightman A, Dunstan F, Lewis G. Pain in veterans of the Gulf War of 1991: a systematic review. BMC Musculoskel Dis. 2006;7(1):74.
40. Gopinath K, Gandhi P, Goyal A, Jiang L, Fang Y, Ouyang L, et al. FMRI reveals abnormal central processing of sensory and pain stimuli in ill Gulf War veterans. Neurotoxicol. 2012;33(3):261-71.
41. Cook DB, Stegner AJ, Ellingson LD. Exercise alters pain sensitivity in gulf war veterans with chronic musculoskeletal pain. J Pain. 2010;11(8):764-72.
42. Skowera A, Cleare A, Blair D, Bevis L, Wessely SC, Peakman M. High levels of type 2 cytokine-producing cells in chronic fatigue syndrome. Clin Exp Immunol. 2004;135(2):294-302.
43. Broderick G, Kreitz A, Fuite J, Fletcher MA, Vernon SD, Klimas N. A pilot study of immune network remodeling under challenge in Gulf War Illness. Brain Behav Immun. 2011;25:302-13.
44. Whistler T, Fletcher MA, Lonergan W, Zeng XR, Lin JM, Laperriere A, et al. Impaired immune function in Gulf War illness. BMC Med Genomics. 2009;2:12.
45. Warnatz K, Voll RE. Pathogenesis of autoimmunity in common variable immunodeficiency. Frontiers Immunol. 2012;3:210.
46. Simpson CR, Anderson WJA, Helms PJ, Taylor MW, Watson L, Prescott GJ, et al. Coincidence of immune-mediated diseases driven by Th1 and Th2 subsets suggests a common aetiology. A population-based study using computerized General Practice data. Clin Exp Allergy. 2002;32(1):37-42.
47. Chang C, Gershwin ME. Drugs and autoimmunity - a contemporary review and mechanistic approach. J Autoimmun. 2012;34:J266-75.
48. Mutez E, Larvor L, Leprêtre F, Mouroux V, Hamalek D, Kerckaert JP, et al. Transcriptional profile of Parkinson blood mononuclear cells with LRRK2 mutation. Neurobiol Aging. 2011;32(10):1839-48.
49. Maes OC, Xu S, Yu B, Chertkow HM, Wang E, Schipper HM. Transcriptional profiling of Alzheimer blood mononuclear cells by microarray. Neurobiol Aging. 2007;28(12):1795-809.
50. Runne H, Kuhn A, Wild EJ, Pratyaksha W, Kristiansen M, Isaacs JD, et al. Analysis of potential transcriptomic biomarkers for Huntington's disease in peripheral blood. Proc Natl Acad Sci U S A. 2007;104(36):14424-9.
51. Johnson G, Slater B, Leis L, Bach R. Elevated plasma biomarkers of chronic inflammation in Gulf War illness (591.3). FASEB J. 2014;28(1 Supplement):591-3.
52. Bhatt S, Xiao Z, Meng Z, Katzenellenbogen BS. Phosphorylation by p38 mitogen-activated protein kinase promotes estrogen receptor α turnover and functional activity via the SCFSkp2 proteasomal complex. Mol Cell Biol. 2012;32(10):1928-43.
53. Gioeli D, Black BE, Gordon V, Spencer A, Kesler CT, Eblen ST, et al. Stress kinase signaling regulates androgen receptor phosphorylation, transcription, and localization. Mol Endocrinol. 2006;20(3):503-15.
54. Straub RH. The complex role of estrogens in inflammation. Endocrine Rev. 2007;28(5):521-74.
55. Dziedziejko V, Kurzawski M, Safranow K, Chlubek D, Pawlik A. The effect of ESR1 and ESR2 gene polymorphisms on the outcome of rheumatoid arthritis treatment with leflunomide. Pharmacogenom. 2011;12(1):41-7.
56. Omar EK, Adimulam S. Does the key to treat Rheumatoid nodules lie with oncology?-Is Cisplatin an option? BMC Musculoskelet Disord. 2013;14 Suppl 1:A5.
57. Turesson C. Extra-articular rheumatoid arthritis. Curr Opin Rheumatol. 2013;25(3):360-6.
58. Mitani M, Miura Y, Saura R, Kitagawa A, Fukuyama T, Hashiramoto A, et al. Estrogen specifically stimulates expression and production of osteoprotegerin from rheumatoid synovial fibroblasts. Int J Mol Med. 2005;15(5):827-32.
59. Komi J, Möttönen M, Luukkainen R, Lassila O. Non-steroidal anti-oestrogens inhibit the differentiation of synovial macrophages into dendritic cells. Rheumatol. 2001;40(2):185-91.
60. Jochems C, Islander U, Erlandsson M, Engdahl C, Lagerquist M, Gjertsson I, et al. Role of endogenous and exogenous female sex hormones in arthritis and osteoporosis development in B10. Q-ncf1∗/∗ mice with collagen-induced chronic arthritis. BMC Musculoskelet Disord. 2010;11(1):284.
61. Jordan VC. Tamoxifen: catalyst for the change to targeted therapy. Eur J Cancer. 2008;44(1):30-8.
62. Jansson L, Holmdahl R. Enhancement of collagen-induced arthritis in female mice by estrogen receptor blockage. Arthritis Rheum. 2001;44(9):2168-75.
63. Creamer P, Lim K, George E, Dieppe P. Acute inflammatory polyarthritis in association with tamoxifen. Br J Rheumatol. 1994;33(6):583-5.
64. Bertolini E, Letho-Gyselinck H, Prati C, Wendling D. Rheumatoid arthritis and aromatase inhibitors. Joint Bone Spine. 2011;78(1):62-4.
65. Bruzzese V, Hassan C, Zullo A, Zampa G. Rheumatoid arthritis: a complication of aromatase inhibitor therapy? Int J Immunopathol Pharmacol. 2010;24(4):1099-101.
66. Morel B, Marotte H, Miossec P. Will steroidal aromatase inhibitors induce rheumatoid arthritis? Ann Rheumatic Dis. 2007;66(4):557-8.
67. Hemieda FAKES. Influence of gender on tamoxifen-induced biochemical changes in serum of rats. Mol Cell Biochem. 2007;301(1-2):137-42.
68. Dluzen DE, Mickley KR. Gender differences in modulatory effects of tamoxifen upon the nigrostriatal dopaminergic system. Pharmacol Biochem Behav. 2005;80(1):27-33.
69. Osório J. Reproductive endocrinology: less estrogen, more neuroinflammation? Nat Rev Endocrinol. 2012;8:381.
70. Spence RD, Hamby ME, Umeda E, Itoh N, Du S, Wisdom AJ, et al. Neuroprotection mediated through estrogen receptor-α in astrocytes. Proc Natl Acad Sci U S A. 2011;108(21):8867-72.
71. Brown CM, Mulcahey TA, Filipek NC, Wise PM. Production of proinflammatory cytokines and chemokines during neuroinflammation: novel roles for estrogen receptors α and β. Endocrinol. 2010;151:4916-25.
72. Rubio N, Cerciat M, Unkila M, Garcia-Segura LM, Arevalo MA. An in vitro experimental model of neuroinflammation: the induction of interleukin-6 in murine astrocytes infected with Theiler's murine encephalomyelitis virus, and its inhibition by oestrogenic receptor modulators. Immunol. 2011;133(3):360-9.
73. Giraud SN, Caron CM, Pham-Dinh D, Kitabgi P, Nicot AB. Estradiol inhibits ongoing autoimmune neuroinflammation and NFκB-dependent CCL2 expression in reactive astrocytes. Proc Natl Acad Sci U S A. 2010;107(18):8416-21.
74. McCombe PA, Henderson RD. Effects of gender in amyotrophic lateral sclerosis. Gender Medicine. 2010;7(6):557-70.
75. Cardona-Rossinyol A, Mir M, Caraballo-Miralles V, Lladó J, Olmos G. Neuroprotective effects of estradiol on motoneurons in a model of rat spinal cord embryonic explants. Cell Mol Neurobiol. 2013;33(3):421-32.
76. de Jong S, Huisman M, Sutedja N, van der Kooi A, de Visser M, Schelhaas J, et al. Endogenous female reproductive hormones and the risk of amyotrophic lateral sclerosis. J Neurol. 2013;260(2):507-12.
77. Haley RW. Excess incidence of ALS in young Gulf War veterans. Neurology. 2003;61(6):750-6.
78. Horner RD, Kamins KG, Feussner JR, Grambow SC, Hoff-Lindquist J, Harati Y, et al. Occurrence of amyotrophic lateral sclerosis among Gulf War veterans. Neurology. 2003;61:742-9.
79. Traynor BJ, Bruijn L, Conwit R, Beal F, O'Neill G, Fagan SC, et al. Neuroprotective agents for clinical trials in ALS: a systematic assessment. Neurology. 2006;67:20-7.
80. Brooks B, Sanjak M, Roelke K. Phase 2B randomized dose-ranging clinical trial of tamoxifen, a selective estrogen receptor modulator [SERM], in amyotrophic lateral sclerosis (ALS): sensitivity analyses of discordance between survival and functional outcomes with long-term follow-up. Amyotroph Lateral Scler. 2005;6 Suppl 1:118.
81. Das A, Smith JA, Gibson C, Varma AK, Ray SK, Banik NL. Estrogen receptor agonists and estrogen attenuate TNF-α-induced apoptosis in VSC4.1 motoneurons. J Endocrinol. 2011;208(2):171-82.
82. Craddock TJA, Fritsch P, Rice Jr MA, del Rosario RM, Miller DB, Fletcher MA, et al. A role for homeostatic drive in the perpetuation of complex chronic illness: Gulf War illness and chronic fatigue syndrome. PLoS ONE. 2014;9(1):e84839.
83. Fritsch P, Craddock TJA, del Rosario RM, Rice Jr MA, Smylie AL, Folcik VA, et al. Succumbing to the laws of attraction: exploring the sometimes pathogenic versatility of discrete immune logic. Sys Biomed. 2014;1(3):179-91.
84. Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A, et al. ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics. 2009;2009(25):1091-3.