Infectious mononucleosis-linked HLA class I single nucleotide polymorphism is associated with multiple sclerosis

Abstract

Background: Multiple sclerosis is a presumed autoimmune disease associated with genetic and environmental risk factors such as infectious mononucleosis. Recent research has shown infectious mononucleosis to be associated with a specific HLA class I polymorphism.

Objectives: Our aim was to test if the infectious mononucleosis-linked HLA class I single nucleotide polymorphism (rs6457110) is also associated with multiple sclerosis.

Methods: Genotyping of the HLA-A single nucleotide polymorphism rs6457110 using TaqMan was performed in 591 multiple sclerosis cases and 600 controls. The association of multiple sclerosis with the HLA-A single nucleotide polymorphism was tested using logistic regression adjusted for age, sex and HLA-DRB1*1501.

Results: HLA-A minor allele (A) is associated with multiple sclerosis (OR = 0.68; p = 4.08 × 10^-5). After stratification for HLA-DRB1*1501 risk allele (T) carrier we showed a significant OR of 0.70 (p = 0.003) for HLA-A.

Conclusions: HLA class I single nucleotide polymorphism rs6457110 is associated with infectious mononucleosis and multiple sclerosis, independent of the major class II allele, supporting the hypothesis that shared genetics may contribute to the association between infectious mononucleosis and multiple sclerosis.

Keywords

Epstein-Barr virus genetically isolated population genetics infectious mononucleosis multiple sclerosis SNP

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References

Henle G. and Henle W. Immunofluorescence in cells derived from Burkitt’s lymphoma. J Bacteriol 1966; 91: 1248-1256.

Crawford DH , Macsween KF , Higgins CD , et al. A cohort study among university students: identification of risk factors for Epstein-Barr virus seroconversion and infectious mononucleosis . Clin Infect Dis 2006; 43: 276-282.

Thacker EL , Mirzaei F. and Ascherio A. Infectious mononucleosis and risk for multiple sclerosis: a meta-analysis . Ann Neurol 2006; 59: 499-503.

Ascherio A. , Munger KL , Lennette ET , et al. Epstein-Barr virus antibodies and risk of multiple sclerosis: a prospective study. JAMA 2001; 286: 3083-3088.

Lunemann JD and Munz C. Epstein-Barr virus and multiple sclerosis. Curr Neurol Neurosci Rep 2007; 7: 253-258.

Ramagopalan SV , Valdar W. , Dyment DA , et al. Association of infectious mononucleosis with multiple sclerosis. A population-based study. Neuroepidemiology 2009; 32: 257-262.

Levin LI , Munger KL , Rubertone MV , et al. Temporal relationship between elevation of Epstein-Barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis . JAMA 2005; 293: 2496-2500.

Faint JM , Annels NE , Curnow SJ , et al. Memory T cells constitute a subset of the human CD8+CD45RA+ pool with distinct phenotypic and migratory characteristics. J Immunol 2001; 167: 212-220.

International Multiple Sclerosis Genetics Consortium. Hafler DA, Compston A, et al. Risk alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 2007; 357: 851-862.

10.

De Jager PL , Jia X. , Wang J. , et al. Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat Genet 2009; 41: 776-782.

11.

Fogdell-Hahn A. , Ligers A. , Gronning M. , Hillert J. and Olerup O. Multiple sclerosis: a modifying influence of HLA class I genes in an HLA class II associated autoimmune disease. Tissue Antigens 2000; 55: 140-148.

12.

Bergamaschi L. , Leone MA , Fasano ME , et al. HLA class I markers and multiple sclerosis susceptibility in the Italian population. Genes Immun 2009; 11: 173-180.

13.

McAulay KA , Higgins CD , Macsween KF , et al. HLA class I polymorphisms are associated with development of infectious mononucleosis upon primary EBV infection. J Clin Invest 2007; 117: 3042-3048.

14.

Hoppenbrouwers IA , Cortes LM , Aulchenko YS , et al. Familial clustering of multiple sclerosis in a Dutch genetic isolate. Mult Scler 2007 ; 13: 17-24.

15.

Poser CM Revisions to the 2001 McDonald diagnostic criteria. Ann Neurol 2006; 59: 727-728.

16.

McGuigan FE and Ralston SH Single nucleotide polymorphism detection: allelic discrimination using TaqMan. Psychiatr Genet 2002; 12: 133-136.

17.

Livak KJ Allelic discrimination using fluorogenic probes and the 5′ nuclease assay. Genet Anal 1999; 14: 143-149.

18.

Hoppenbrouwers IA , Aulchenko YS , Janssens AC , et al. Replication of CD58 and CLEC16A as genome-wide significant risk genes for multiple sclerosis. J Hum Genet 2009; 54: 676-680.

19.

Ebers GC Environmental factors and multiple sclerosis. Lancet Neurol 2008; 7: 268-277.

20.

Oksenberg JR , Baranzini SE , Sawcer S. and Hauser SL The genetics of multiple sclerosis: SNPs to pathways to pathogenesis. Nat Rev Genet 2008 ; 9: 516-526.

21.

Zivkovic M. , Stankovic A. , Dincic E. , et al. The tag SNP for HLA-DRB1*1501, rs3135388, is significantly associated with multiple sclerosis susceptibility: cost-effective high-throughput detection by real-time PCR. Clin Chim Acta 2009; 406: 27-30.

22.

Yeo TW , De Jager PL , Gregory SG , et al. A second major histocompatibility complex susceptibility locus for multiple sclerosis. Ann Neurol 2007; 61: 228-236.

23.

Chao MJ , Barnardo MC , Lincoln MR , et al. HLA class I alleles tag HLA-DRB1*1501 haplotypes for differential risk in multiple sclerosis susceptibility. Proc Natl Acad Sci U S A 2008; 105: 13069-13074.

24.

Harbo HF , Lie BA , Sawcer S. , et al. Genes in the HLA class I region may contribute to the HLA class II-associated genetic susceptibility to multiple sclerosis. Tissue Antigens 2004; 63: 237-247.

25.

Ascherio A. and Munger KL Environmental risk factors for multiple sclerosis. Part I: the role of infection . Ann Neurol 2007; 61: 288-299.

26.

De Jager PL , Simon KC , Munger KL , Rioux JD , Hafler DA and Ascherio A. Integrating risk factors: HLA-DRB1*1501 and Epstein-Barr virus in multiple sclerosis. Neurology 2008; 70: 1113-1118.

27.

Chao MJ , Barnardo MC , Lui GZ , et al. Transmission of class I/II multi-locus MHC haplotypes and multiple sclerosis susceptibility: accounting for linkage disequilibrium. Hum Mol Genet 2007; 16: 1951-1958.

28.

de Bakker PI , Burtt NP , Graham RR , et al. Transferability of tag SNPs in genetic association studies in multiple populations. Nat Genet 2006; 38: 1298-1303.

29.

Handel AE , Ebers GC and Ramagopalan SV Epigenetics: molecular mechanisms and implications for disease. Trends Mol Med 2010; 16: 7-16.