期刊
MULTIPLE SCLEROSIS JOURNAL
卷 22, 期 13, 页码 1655-1664出版社
SAGE PUBLICATIONS LTD
DOI: 10.1177/1352458515626598
关键词
Epstein-Barr virus; EBNA-1; multiple sclerosis; GWAS; polygenic risk; non-HLA
资金
- Australia National Health and Medical Research Council (NHMRC) [486682, 1009064, 389875]
- NIH [HL080149, HL045522, DK053889, DK047482]
- MS Research Australia Postdoctoral Research Fellowship
- Australian Research Council [FT0991022]
- National Health and Medical Research Council [APP0613674]
- Australian Research Council Future Fellowship
- National Multiple Sclerosis Society
- Australian Research Council [FT0991022] Funding Source: Australian Research Council
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 (N-eff) = 5555) and a large MS GWAS (N-eff = 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 x 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 x 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 x 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.
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