Brain Correlates of Human Leukocyte Antigen (HLA) Protection in Gulf War Illness (GWI)

Lisa M James; Brian Engdahl; Arthur C Leuthold; Apostolos P Georgopoulos

doi:10.1016/j.ebiom.2016.10.019

Brain Correlates of Human Leukocyte Antigen (HLA) Protection in Gulf War Illness (GWI)

Lisa M James, Brian Engdahl, Arthur C Leuthold, Apostolos P Georgopoulos

Neuroscience

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

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. Findings 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. Interpretation 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. Funding U.S. Department of Veterans Affairs and University of Minnesota.

Original language	English (US)
Pages (from-to)	72-79
Number of pages	8
Journal	EBioMedicine
Volume	13
DOIs	https://doi.org/10.1016/j.ebiom.2016.10.019
State	Published - Nov 1 2016

Bibliographical note

Funding Information:
Partial funding for this study was provided by a service directed grant from the U.S. Department of Veterans Affairs and the University of Minnesota (Brain and Genomics Fund and the American Legion Brain Sciences Chair). The sponsors had no role in the current study design, analysis or interpretation, or in the writing of this paper. The contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

Publisher Copyright:
© 2016

Keywords

Gulf War Illness (GWI)
Human Leukocyte Antigen
Magnetoencephalography
Veterans

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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. Findings 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. Interpretation 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. Funding U.S. Department of Veterans Affairs and University of Minnesota.",

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N2 - 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. Findings 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. Interpretation 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. Funding U.S. Department of Veterans Affairs and University of Minnesota.

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Brain Correlates of Human Leukocyte Antigen (HLA) Protection in Gulf War Illness (GWI)

Abstract

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