title: Brain Correlates of Human Leukocyte Antigen (HLA) Protection in Gulf War Illness (GWI).
abstract: BACKGROUND
  We recently reported that six alleles from class II genes of the Human Leukocyte Antigen (HLA) confer protection from Gulf War Illness (GWI) (Georgopoulos et al., 2015). The most significant effect is exerted on Neurological-Cognitive-Mood (NCM), Pain, and Fatigue symptoms, such that higher number of copies of the protective alleles are associated with lower symptom severity. Here we tested the hypothesis that this effect is exerted by modulating the strength of neural synchronicity.
  
  
  METHODS
  Eighty-one Gulf War veterans (65 with GWI and 16 healthy controls) underwent a magnetoencephalography (MEG) scan to assess the strength of brain synchronicity by computing zero-lag crosscorrelations (and their Fisher z transforms) between prewhitened MEG time series. A high-resolution HLA genotyping determined the number of copies, k, of the 6 protective alleles above in each participant. We tested the hypothesis above by regressing NCM, Pain and Fatigue symptom severity against the interaction term, k×z (HLA-related effect), while including z (non-HLA-related effect), gender and age as covariates. The k×z and z terms assessed HLA- and non-HLA-related effects, respectively, of neural synchronicity on symptom severity. The distributions of these effects in sensor space were visualized using statistical heatmaps.
  
  
  RESULTS
  We found significant, graded HLA- and non-HLA-related effects: (a) NCM>Pain>Fatigue for HLA-related effects, (b) NCM>Fatigue>Pain for non-HLA-related effects, and (c) HLA-related>non-HLA-related effects for all symptoms. These effects had widespread but distinct distributions in sensor space that allowed the orderly separation of the 6 terms (3 symptom domains×2 HLA factors) in a multidimensional plot, where one dimension separated the symptoms and the other the HLA relation.
  
  
  CONCLUSIONS
  These findings demonstrate the presence of substantial, widespread, distinct and orderly HLA- and non-HLA-related neural influences on NCM, Pain and Fatigue symptom severity in GWI.
  
  
  BACKGROUND
  U.S. Department of Veterans Affairs and University of Minnesota.
authors.affiliation: Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN 55417, USA; Center for Cognitive Sciences, University of Minnesota, Minneapolis, MN 55455, USA; Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: James
authors.affiliation: Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN 55417, USA; Center for Cognitive Sciences, University of Minnesota, Minneapolis, MN 55455, USA; Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Department of Psychology, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Engdahl
authors.affiliation: Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN 55417, USA; Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
authors.forename: Arthur C
authors.initials: AC
authors.lastname: Leuthold
authors.affiliation: Brain Sciences Center, Department of Veterans Affairs Health Care System, Minneapolis, MN 55417, USA; Center for Cognitive Sciences, University of Minnesota, Minneapolis, MN 55455, USA; Department of Psychiatry, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN 55455, USA; Department of Neurology, University of Minnesota Medical School, Minneapolis, MN 55455, USA. Electronic address: omega@umn.edu.
authors.forename: Apostolos P
authors.initials: AP
authors.lastname: Georgopoulos
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D001921:Brain / Q000276:immunology* / Q000378:metabolism*; D004198:Disease Susceptibility; D005260:Female; D005838:Genotype; D047830:Gulf War; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology*; D006801:Humans; D015225:Magnetoencephalography; D008297:Male; D008875:Middle Aged; D015213:Neuroimmunomodulation; D018923:Persian Gulf Syndrome / Q000175:diagnosis / Q000209:etiology*; D012720:Severity of Illness Index
chemical_list: D006680:HLA Antigens
keywords: Gulf War Illness (GWI); Human Leukocyte Antigen; Magnetoencephalography; Veterans