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Mult Scler. 2016 Nov;22(13):1655-1664. Epub 2016 Jan 27.

Genetic loci for Epstein-Barr virus nuclear antigen-1 are associated with risk of multiple sclerosis.

Author information

1
Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia.
2
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
3
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
4
South Texas Diabetes and Obesity Institute, University of Texas Rio Grande Valley School of Medicine, Brownsville, TX, USA.
5
Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Department of Neurology, Brigham and Women's Hospital, Boston, MA, USA/Harvard Medical School, Boston, MA, USA/Broad Institute, Cambridge, MA, USA.
6
Monash Antibody Technologies Facility, Monash University, Melbourne, VIC, Australia.
7
Statistical and Genomic Epidemiology Laboratory, Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, QLD, Australia/Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
8
Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia Bruce.Taylor@utas.edu.au.

Abstract

BACKGROUND:

Infection with the Epstein-Barr virus (EBV) is associated with an increased risk of multiple sclerosis (MS).

OBJECTIVE:

We sought genetic loci influencing EBV nuclear antigen-1 (EBNA-1) IgG titers and hypothesized that they may play a role in MS risk.

METHODS:

We performed a genome-wide association study (GWAS) of anti-EBNA-1 IgG titers in 3599 individuals from an unselected twin family cohort, followed by a meta-analysis with data from an independent EBNA-1 GWAS. We then examined the shared polygenic risk between the EBNA-1 GWAS (effective sample size (Neff) = 5555) and a large MS GWAS (Neff = 15,231).

RESULTS:

We identified one locus of strong association within the human leukocyte antigen (HLA) region, of which the most significantly associated genotyped single nucleotide polymorphism (SNP) was rs2516049 (p = 4.11 × 10-9). A meta-analysis including data from another EBNA-1 GWAS in a cohort of Mexican-American families confirmed that rs2516049 remained the most significantly associated SNP (p = 3.32 × 10-20). By examining the shared polygenic risk, we show that the genetic risk for elevated anti-EBNA-1 titers is positively correlated with the development of MS, and that elevated EBNA-1 titers are not an epiphenomena secondary to MS. In the joint meta-analysis of EBNA-1 titers and MS, loci at 1p22.1, 3p24.1, 3q13.33, and 10p15.1 reached genome-wide significance (p < 5 × 10-8).

CONCLUSIONS:

Our results suggest that apart from the confirmed HLA region, the association of anti-EBNA-1 IgG titer with MS risk is also mediated through non-HLA genes, and that studies aimed at identifying genetic loci influencing EBNA immune response provides a novel opportunity to identify new and characterize existing genetic risk factors for MS.

KEYWORDS:

EBNA-1; Epstein-Barr virus; GWAS; multiple sclerosis; non-HLA; polygenic risk

PMID:
26819262
DOI:
10.1177/1352458515626598
[Indexed for MEDLINE]

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