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September 26, 2017; 89 (13) Article

Epstein-Barr virus, cytomegalovirus, and multiple sclerosis susceptibility

A multiethnic study

Annette Langer-Gould, Jun Wu, Robyn Lucas, Jessica Smith, Edlin Gonzales, Lilyana Amezcua, Samantha Haraszti, Lie Hong Chen, Hong Quach, Judith A. James, Lisa F. Barcellos, Anny H. Xiang
First published August 30, 2017, DOI: https://doi.org/10.1212/WNL.0000000000004412
Annette Langer-Gould
From Department of Research & Evaluation (A.L.-G., J.W., J.S., E.G., S.H., L.H.C., A.H.X.), Kaiser Permanente Southern California, Pasadena; Neurology Department (A.L.-G.), Southern California Permanente Medical Group, Los Angeles Medical Center; Biology & Environment (R.L.), National Centre for Epidemiology and Population Health, College of Medicine, Australian National University, Canberra; Department of Neurology (L.A.), Keck School of Medicine, University of Southern California, Los Angeles; QB3 Genetic Epidemiology and Genomics Laboratory (H.Q., L.F.B.), School of Public Health, University of California, Berkeley; and Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center (J.A.J.), Oklahoma City. S. Haraszti is now at Philadelphia College of Osteopathic Medicine, PA.
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Jun Wu
From Department of Research & Evaluation (A.L.-G., J.W., J.S., E.G., S.H., L.H.C., A.H.X.), Kaiser Permanente Southern California, Pasadena; Neurology Department (A.L.-G.), Southern California Permanente Medical Group, Los Angeles Medical Center; Biology & Environment (R.L.), National Centre for Epidemiology and Population Health, College of Medicine, Australian National University, Canberra; Department of Neurology (L.A.), Keck School of Medicine, University of Southern California, Los Angeles; QB3 Genetic Epidemiology and Genomics Laboratory (H.Q., L.F.B.), School of Public Health, University of California, Berkeley; and Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center (J.A.J.), Oklahoma City. S. Haraszti is now at Philadelphia College of Osteopathic Medicine, PA.
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Robyn Lucas
From Department of Research & Evaluation (A.L.-G., J.W., J.S., E.G., S.H., L.H.C., A.H.X.), Kaiser Permanente Southern California, Pasadena; Neurology Department (A.L.-G.), Southern California Permanente Medical Group, Los Angeles Medical Center; Biology & Environment (R.L.), National Centre for Epidemiology and Population Health, College of Medicine, Australian National University, Canberra; Department of Neurology (L.A.), Keck School of Medicine, University of Southern California, Los Angeles; QB3 Genetic Epidemiology and Genomics Laboratory (H.Q., L.F.B.), School of Public Health, University of California, Berkeley; and Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center (J.A.J.), Oklahoma City. S. Haraszti is now at Philadelphia College of Osteopathic Medicine, PA.
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Jessica Smith
From Department of Research & Evaluation (A.L.-G., J.W., J.S., E.G., S.H., L.H.C., A.H.X.), Kaiser Permanente Southern California, Pasadena; Neurology Department (A.L.-G.), Southern California Permanente Medical Group, Los Angeles Medical Center; Biology & Environment (R.L.), National Centre for Epidemiology and Population Health, College of Medicine, Australian National University, Canberra; Department of Neurology (L.A.), Keck School of Medicine, University of Southern California, Los Angeles; QB3 Genetic Epidemiology and Genomics Laboratory (H.Q., L.F.B.), School of Public Health, University of California, Berkeley; and Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center (J.A.J.), Oklahoma City. S. Haraszti is now at Philadelphia College of Osteopathic Medicine, PA.
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Edlin Gonzales
From Department of Research & Evaluation (A.L.-G., J.W., J.S., E.G., S.H., L.H.C., A.H.X.), Kaiser Permanente Southern California, Pasadena; Neurology Department (A.L.-G.), Southern California Permanente Medical Group, Los Angeles Medical Center; Biology & Environment (R.L.), National Centre for Epidemiology and Population Health, College of Medicine, Australian National University, Canberra; Department of Neurology (L.A.), Keck School of Medicine, University of Southern California, Los Angeles; QB3 Genetic Epidemiology and Genomics Laboratory (H.Q., L.F.B.), School of Public Health, University of California, Berkeley; and Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center (J.A.J.), Oklahoma City. S. Haraszti is now at Philadelphia College of Osteopathic Medicine, PA.
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Lilyana Amezcua
From Department of Research & Evaluation (A.L.-G., J.W., J.S., E.G., S.H., L.H.C., A.H.X.), Kaiser Permanente Southern California, Pasadena; Neurology Department (A.L.-G.), Southern California Permanente Medical Group, Los Angeles Medical Center; Biology & Environment (R.L.), National Centre for Epidemiology and Population Health, College of Medicine, Australian National University, Canberra; Department of Neurology (L.A.), Keck School of Medicine, University of Southern California, Los Angeles; QB3 Genetic Epidemiology and Genomics Laboratory (H.Q., L.F.B.), School of Public Health, University of California, Berkeley; and Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center (J.A.J.), Oklahoma City. S. Haraszti is now at Philadelphia College of Osteopathic Medicine, PA.
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Samantha Haraszti
From Department of Research & Evaluation (A.L.-G., J.W., J.S., E.G., S.H., L.H.C., A.H.X.), Kaiser Permanente Southern California, Pasadena; Neurology Department (A.L.-G.), Southern California Permanente Medical Group, Los Angeles Medical Center; Biology & Environment (R.L.), National Centre for Epidemiology and Population Health, College of Medicine, Australian National University, Canberra; Department of Neurology (L.A.), Keck School of Medicine, University of Southern California, Los Angeles; QB3 Genetic Epidemiology and Genomics Laboratory (H.Q., L.F.B.), School of Public Health, University of California, Berkeley; and Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center (J.A.J.), Oklahoma City. S. Haraszti is now at Philadelphia College of Osteopathic Medicine, PA.
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Lie Hong Chen
From Department of Research & Evaluation (A.L.-G., J.W., J.S., E.G., S.H., L.H.C., A.H.X.), Kaiser Permanente Southern California, Pasadena; Neurology Department (A.L.-G.), Southern California Permanente Medical Group, Los Angeles Medical Center; Biology & Environment (R.L.), National Centre for Epidemiology and Population Health, College of Medicine, Australian National University, Canberra; Department of Neurology (L.A.), Keck School of Medicine, University of Southern California, Los Angeles; QB3 Genetic Epidemiology and Genomics Laboratory (H.Q., L.F.B.), School of Public Health, University of California, Berkeley; and Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center (J.A.J.), Oklahoma City. S. Haraszti is now at Philadelphia College of Osteopathic Medicine, PA.
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Hong Quach
From Department of Research & Evaluation (A.L.-G., J.W., J.S., E.G., S.H., L.H.C., A.H.X.), Kaiser Permanente Southern California, Pasadena; Neurology Department (A.L.-G.), Southern California Permanente Medical Group, Los Angeles Medical Center; Biology & Environment (R.L.), National Centre for Epidemiology and Population Health, College of Medicine, Australian National University, Canberra; Department of Neurology (L.A.), Keck School of Medicine, University of Southern California, Los Angeles; QB3 Genetic Epidemiology and Genomics Laboratory (H.Q., L.F.B.), School of Public Health, University of California, Berkeley; and Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center (J.A.J.), Oklahoma City. S. Haraszti is now at Philadelphia College of Osteopathic Medicine, PA.
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Judith A. James
From Department of Research & Evaluation (A.L.-G., J.W., J.S., E.G., S.H., L.H.C., A.H.X.), Kaiser Permanente Southern California, Pasadena; Neurology Department (A.L.-G.), Southern California Permanente Medical Group, Los Angeles Medical Center; Biology & Environment (R.L.), National Centre for Epidemiology and Population Health, College of Medicine, Australian National University, Canberra; Department of Neurology (L.A.), Keck School of Medicine, University of Southern California, Los Angeles; QB3 Genetic Epidemiology and Genomics Laboratory (H.Q., L.F.B.), School of Public Health, University of California, Berkeley; and Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center (J.A.J.), Oklahoma City. S. Haraszti is now at Philadelphia College of Osteopathic Medicine, PA.
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Lisa F. Barcellos
From Department of Research & Evaluation (A.L.-G., J.W., J.S., E.G., S.H., L.H.C., A.H.X.), Kaiser Permanente Southern California, Pasadena; Neurology Department (A.L.-G.), Southern California Permanente Medical Group, Los Angeles Medical Center; Biology & Environment (R.L.), National Centre for Epidemiology and Population Health, College of Medicine, Australian National University, Canberra; Department of Neurology (L.A.), Keck School of Medicine, University of Southern California, Los Angeles; QB3 Genetic Epidemiology and Genomics Laboratory (H.Q., L.F.B.), School of Public Health, University of California, Berkeley; and Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center (J.A.J.), Oklahoma City. S. Haraszti is now at Philadelphia College of Osteopathic Medicine, PA.
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Anny H. Xiang
From Department of Research & Evaluation (A.L.-G., J.W., J.S., E.G., S.H., L.H.C., A.H.X.), Kaiser Permanente Southern California, Pasadena; Neurology Department (A.L.-G.), Southern California Permanente Medical Group, Los Angeles Medical Center; Biology & Environment (R.L.), National Centre for Epidemiology and Population Health, College of Medicine, Australian National University, Canberra; Department of Neurology (L.A.), Keck School of Medicine, University of Southern California, Los Angeles; QB3 Genetic Epidemiology and Genomics Laboratory (H.Q., L.F.B.), School of Public Health, University of California, Berkeley; and Oklahoma Medical Research Foundation and University of Oklahoma Health Sciences Center (J.A.J.), Oklahoma City. S. Haraszti is now at Philadelphia College of Osteopathic Medicine, PA.
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Full PDF
Citation
Epstein-Barr virus, cytomegalovirus, and multiple sclerosis susceptibility
A multiethnic study
Annette Langer-Gould, Jun Wu, Robyn Lucas, Jessica Smith, Edlin Gonzales, Lilyana Amezcua, Samantha Haraszti, Lie Hong Chen, Hong Quach, Judith A. James, Lisa F. Barcellos, Anny H. Xiang
Neurology Sep 2017, 89 (13) 1330-1337; DOI: 10.1212/WNL.0000000000004412

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Abstract

Objective: To determine whether Epstein-Barr virus (EBV) or cytomegalovirus (CMV) seropositivity is associated with multiple sclerosis (MS) in blacks and Hispanics and to what extent measures of the hygiene hypothesis or breastfeeding could explain these findings. EBV and CMV have been associated with MS risk in whites, and the timing and frequency of both viruses vary by factors implicated in the hygiene hypothesis.

Methods: Incident cases of MS or its precursor, clinically isolated syndrome (CIS), and matched controls (blacks, 111 cases/128 controls; Hispanics, 173/187; whites, 235/256) were recruited from the membership of Kaiser Permanente Southern California. Logistic regression models accounted for HLA-DRB1*1501 status, smoking, socioeconomic status, age, sex, genetic ancestry, and country of birth.

Results: Epstein-Barr nuclear antigen-1 (EBNA-1) seropositivity was independently associated with an increased odds of MS/CIS in all 3 racial/ethnic groups (p < 0.001 for blacks and whites, p = 0.02 for Hispanics). In contrast, CMV seropositivity was associated with a lower risk of MS/CIS in Hispanics (p = 0.004) but not in blacks (p = 0.95) or whites (p = 0.96). Being born in a low/middle-income country was associated with a lower risk of MS in Hispanics (p = 0.02) but not after accounting for EBNA-1 seropositivity. Accounting for breastfeeding did not diminish the association between CMV and MS in Hispanics.

Conclusions: The consistency of EBNA-1 seropositivity with MS across racial/ethnic groups and between studies points to a strong biological link between EBV infection and MS risk. The association between past CMV infection and MS risk supports the broader hygiene hypothesis, but the inconsistency of this association across racial/ethnic groups implies noncausal associations.

GLOSSARY

CI=
confidence interval;
CIS=
clinically isolated syndrome;
CMV=
cytomegalovirus;
EBNA-1=
Epstein-Barr nuclear antigen-1;
EBV=
Epstein-Barr virus;
EHR=
electronic health record;
ICD-9=
International Classification of Diseases, ninth revision;
IM=
infectious mononucleosis;
KPSC=
Kaiser Permanente Southern California;
MS=
multiple sclerosis;
OR=
odds ratio;
SAQ=
self-administered questionnaire

Footnotes

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Supplemental data at Neurology.org

  • Received November 10, 2016.
  • Accepted in final form June 30, 2017.
  • © 2017 American Academy of Neurology
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