Research Article| Volume 298, ISSUE 1-2, P96-100, November 15, 2010

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Epistasis between HLA-DRB1 parental alleles in a Spanish cohort with multiple sclerosis

Published:September 02, 2010DOI:


      Background and objective

      Multiple sclerosis (MS) has been consistently associated with the HLA-DR2 haplotype and particularly with the HLA-DRB1*15 allele. Epistatic interactions between both parental alleles in the DRB1 loci have been shown to modify the MS susceptibility risk. This study investigated the frequencies of various HLA-DRB1 genotypes, their impact on MS susceptibility and their correlation with the clinical severity in a Spanish population.


      A genotype was considered as the combination of the two parental DRB1 alleles. We compared the frequencies of the genotypes in a sporadic MS population (n=380) with those of an unrelated healthy control cohort (n=1088). We correlated the different genotypes with the age at onset, gender distribution, symptoms at onset, course of the disease and progression severity by means of the time to reach the progressive phase and EDSS scores of 3 and 6.


      We found 81 different genotypes. There were four different MS-predisposing genotypes. Three of them contained the DRB1*15 allele (DRB1*03/15, DRB1*04/15, and DRB1*08/15) and the fourth was homozygote for the DRB1*03 allele. The highest odds ratio was found with the genotype DRB1*08/15 (OR=3.88, 95% CI=1.83–8.26, p<0.01), followed by DRB1*03/03 (OR=3.15, 95% CI=1.93–5.14, p<0.01), DRB1*03/15 (OR=2.72, 95% CI=1.88–3.94, p<0.01) and DRB1*04/15 (OR=2.54, 95% CI=1.64–3.98, p<0.01). The DRB1*01/04 and the DRB1*15/15 genotypes were associated with a shorter time to reach an EDSS score of 6.


      Our results show the importance of epistatic interactions among the HLA-DRB1 alleles, modifying the risk for MS as well as its clinical severity.


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        • Ramagopalan S.V.
        • Ebers G.C.
        Epistasis: multiple sclerosis and the major histocompatibility complex.
        Neurology. 2009; 72: 566-567
        • Dyment D.A.
        • Ebers G.C.
        • Sadovnick A.D.
        Genetics of multiple sclerosis.
        Lancet Neurol. 2004; 3: 104-110
        • Schmidt H.
        • Williamson D.
        • Ashley-Koch A.
        HLA-DR15 haplotype and multiple sclerosis: a HuGE review.
        Am J Epidemiol. 2007; 165: 1097-1109
        • Chao M.J.
        • Barnardo M.C.
        • Lincoln M.R.
        • Ramagopalan S.V.
        • Herrera B.M.
        • Dyment D.A.
        • 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
        • Hafler D.A.
        • Compston A.
        • Sawcer S.
        • Lander E.S.
        • Daly M.J.
        • De Jager P.L.
        • et al.
        Risk alleles for multiple sclerosis identified by a genomewide study.
        N Engl J Med. 2007; 357: 851-862
        • Sawcer S.
        The complex genetics of multiple sclerosis: pitfalls and prospects.
        Brain. 2008; 131: 3118-3131
        • Baranzini S.E.
        • Wang J.
        • Gibson R.A.
        • Galwey N.
        • Naegelin Y.
        • Barkhof F.
        • et al.
        Genome-wide association analysis of susceptibility and clinical phenotype in multiple sclerosis.
        Hum Mol Genet. 2009; 18: 767-778
        • Fernández O.
        • Fernández V.
        • Alonso A.
        • Caballero A.
        • Luque G.
        • Bravo M.
        • et al.
        DQB1*0602 allele shows a strong association with multiple sclerosis in patients in Malaga, Spain.
        J Neurol. 2004; 251: 440-444
        • Lincoln M.R.
        • Ramagopalan S.V.
        • Chao M.J.
        • Herrera B.M.
        • Deluca G.C.
        • Orton S.M.
        • et al.
        Epistasis among HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci determines multiple sclerosis susceptibility.
        Proc Natl Acad Sci USA. 2009; 106: 7542-7547
        • DeLuca G.C.
        • Ramagopalan S.V.
        • Herrera B.M.
        • Dyment D.A.
        • Lincoln M.R.
        • Montpetit A.
        • et al.
        An extremes of outcome strategy provides evidence that multiple sclerosis severity is determined by alleles at the HLA-DRB1 locus.
        Proc Natl Acad Sci U S A. 2007; 104: 20896-20901
        • Ramagopalan S.V.
        • Morris A.P.
        • Dyment D.A.
        • Herrera B.M.
        • DeLuca G.C.
        • Lincoln M.R.
        • et al.
        The inheritance of resistance alleles in multiple sclerosis.
        PLoS Genet. 2007; 3: 1607-1613
        • Dyment D.A.
        • Herrera B.M.
        • Cader M.Z.
        • Willer C.J.
        • Lincoln M.R.
        • Sadovnick A.D.
        • et al.
        Complex interaction among MHC haplotypes in multiple sclerosis: susceptibility and resistance.
        Hum Mol Genet. 2005; 14: 2019-2026
        • Wu J.S.
        • Qiu W.
        • Castley A.
        • James I.
        • Mastaglia F.L.
        • Christiansen F.T.
        • et al.
        Modifying effects of HLA-DRB1 allele interactions on age at onset of multiple sclerosis in Western Australia.
        Mult Scler. 2010; 16: 15-20
        • Wu J.S.
        • Qiu W.
        • Castley A.
        • James I.
        • Joseph J.
        • Christiansen F.T.
        • et al.
        Presence of CSF oligoclonal bands (OCB) is associated with the HLA-DRB1 genotype in a West Australia multiple sclerosis cohort.
        J Neurol Sci. 2010; 288: 63-67
        • Confavreux C.
        • Compston D.A.
        • Hommes O.R.
        • McDonald W.I.
        • Thompson A.J.
        EDMUS, a European database for multiple sclerosis.
        J Neurol Neurosurg Psychiatry. 1992; 55: 671-676
        • Polman C.H.
        • Reingold S.C.
        • Edan G.
        • Filippi M.
        • Hartung H.P.
        • Kappos L.
        • et al.
        Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”.
        Ann Neurol. 2005; 58: 840-846
        • Lublin F.D.
        • Reingold S.C.
        Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis.
        Neurology. 1996; 46: 907-911
        • Kurtzke J.F.
        Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS).
        Neurology. 1983; 33: 1444-1452
        • Olerup O.
        • Zetterquist H.
        HLA-DR typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours: an alternative serological DR typing in clinical practice including donor–recipient matching in cadaveric transplantation.
        Tissue Antigens. 1992; 39: 225-235
      1. Romero-Pinel L, Pujal JM, Martínez-Yélamos S, Gubieras L, Matas E, Bau L, et al. HLA-DRB1: genetic susceptibility and disability progression in a Spanish multiple sclerosis population. Eur J Neurol in press, doi:10.1111/j.1468-1331.2010.03148.x.

        • Barcellos L.F.
        • Sawcer S.
        • Ramsay P.P.
        • Baranzini S.E.
        • Thomson G.
        • Briggs F.
        • et al.
        Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis.
        Hum Mol Genet. 2006; 15: 2813-2824
        • Silva A.M.
        • Pereira C.
        • Bettencourt A.
        • Carvalho C.
        • Couto A.R.
        • Leite M.I.
        • et al.
        The role of HLA-DRB1 alleles on susceptibility and outcome of a Portuguese multiple sclerosis population.
        J Neurol Sci. 2007; 258: 69-74
        • Weatherby S.J.
        • Thomson W.
        • Pepper L.
        • Donn R.
        • Worthington J.
        • Mann C.L.
        • et al.
        HLA-DRB1 and disease outcome in multiple sclerosis..
        J Neurol. 2001; 248: 304-310
        • Stankovich J.
        • Butzkueven H.
        • Marriott M.
        • Chapman C.
        • Tubridy N.
        • Tait B.D.
        • et al.
        HLA-DRB1 associations with disease susceptibility and clinical course in Australians with multiple sclerosis.
        Tissue Antigens. 2009; 74: 17-21
        • Marrosu M.G.
        • Murru M.R.
        • Costa G.
        • Murru R.
        • Muntoni F.
        • Cucca F.
        DRB1, DQA1-DQB1 loci and multiple sclerosis predisposition in Sardinian population.
        Hum Mol Genet. 1998; 7: 1235-1237
        • Saruhan-Direskeneli G.
        • Esin S.
        • Baykan-Kurt B.
        • Ornek I.
        • Vaughan R.
        • Eraksoy M.
        HLA-DR and -DQ associations with multiple sclerosis in Turkey.
        Hum Immunol. 1997; 55: 59-65
        • Coraddu F.
        • Reyes-Yanez M.P.
        • Parra A.
        • Gray J.
        • Smith S.I.
        • Taylor C.J.
        • et al.
        HLA associations with multiple sclerosis in the Canary Islands.
        J Neuroimmunol. 1998; 87: 130-135
        • Barcellos L.F.
        • Oksenberg J.R.
        • Begovich A.B.
        • Martin E.R.
        • Schmidt S.
        • Vittinghoff E.
        • et al.
        HLA-DR2 dose effect on susceptibility to multiple sclerosis and influence on disease course.
        Am J Hum Genet. 2003; 72: 710-716
        • Ballerini C.
        • Guerini F.R.
        • Rombolà G.
        • Rosati E.
        • Massacesi L.
        • Ferrante P.
        • et al.
        HLA-multiple sclerosis association in Continental Italy and correlation with disease prevalence in Europe.
        J Neuroimmunol. 2004; 150: 178-185
        • Fernández O.
        • R-Antigüedad A.
        • Pinto-Medel M.J.
        • Mendibe M.M.
        • Acosta N.
        • Oliver B.
        • et al.
        HLA class II alleles in patients with multiple sclerosis in the Biscay province (Basque Country, Spain).
        J Neurol. 2009; 256: 1977-1988
        • Masterman T.
        • Ligers A.
        • Olsson T.
        • Andersson M.
        • Olerup O.
        • Hillert J.
        HLA-DR15 is associated with lower age at onset in multiple sclerosis.
        Ann Neurol. 2000; 48: 211-219
        • Wu J.S.
        • James I.
        • Qiu W.
        • Castley A.
        • Christiansen F.T.
        • Carroll W.M.
        • et al.
        HLA-DRB1 allele heterogeneity influences multiple sclerosis severity as well as risk in Western Australia.
        J Neuroimmunol. 2010; 219: 109-113
        • Hensiek A.E.
        • Sawcer S.J.
        • Feakes R.
        • Deans J.
        • Mander A.
        • Akesson E.
        • et al.
        HLA-DR15 is associated with female sex and younger age at diagnosis in multiple sclerosis.
        J Neurol Neurosurg Psychiatry. 2002; 72: 184-187
        • Cournu-Rebeix I.
        • Génin E.
        • Leray E.
        • Babron M.C.
        • Cohen J.
        • Gout C.
        • et al.
        HLA-DRB1*15 allele influences the later course of relapsing remitting multiple sclerosis.
        Genes Immun. 2008; 9: 570-574
        • Vasconcelos C.C.
        • Fernández O.
        • Leyva L.
        • Thuler L.C.
        • Alvarenga R.M.
        Does the DRB1*1501 allele confer more severe and faster progression in primary progressive multiple sclerosis patients? HLA in primary progressive multiple sclerosis.
        J Neuroimmunol. 2009; 214: 101-103
        • Okuda D.T.
        • Srinivasan R.
        • Oksenberg J.R.
        • Goodin D.S.
        • Baranzini S.E.
        • Beheshtian A.
        • et al.
        Genotype–phenotype correlations in multiple sclerosis: HLA genes influence disease severity inferred by 1HMR spectroscopy and MRI measures.
        Brain. 2009; 132: 250-259