Influence of HLA-DRB1 allele heterogeneity on disease risk and clinical course in a West Australian MS cohort: a high-resolution genotyping study

Background: Previous studies on the influence of HLA-DRB1 alleles on multiple sclerosis (MS) susceptibility and clinical course have mostly employed the 2-point genotyping method. Objective: To assess the influence of HLA-DRB1 alleles and allele interactions on disease risk and clinical course in a large West Australian MS patient cohort using high-resolution genotyping. Methods: Four digit HLA-DRB1 genotyping was performed on a group of 466 clinically definite or probable MS patients from the Perth Demyelinating Diseases Database and 189 healthy Caucasian controls from the Busselton Community Health Study. Results: In addition to the known risk allele HLA-DRB1*1501, evidence of increased susceptibility to MS was found for three additional alleles, DRB1*0405, DRB1*1104 and DRB1*1303, though the power was insufficient to sustain significance for these when crudely Bonferroni corrected over all alleles considered. DRB1*0701 was found to be protective even after correction for multiple comparisons. In addition we found evidence that the DRB1*04 sub-allele HLA-DRB1*0407 and HLA-DRB1*0901 may be protective. Among the diplotypes, the highest estimated risk was in HLA-DRB1*1501/*0801 heterozygotes and DRB1*1501 homozygotes and the lowest in HLA-DRB1*0701/*0101 heterozygotes. There was no significant gender association with HLA-DRB1*1501 overall, but the HLA-DRB1*1501/*1104 risk genotype was significantly associated with female gender. HLA-DRB1*1501 was the strongest risk allele in both primary progressive MS and relapsing—remitting MS. Conclusion: Our results demonstrate the advantages of high-resolution HLA genotyping in recognizing risk-modifying alleles and allele combinations in this patient cohort and in recognizing the differential effects of HLA-DRB1*04 and DRB1*11 sub-alleles.

[1]  I. James,et al.  Modifying effects of HLA-DRB1 allele interactions on age at onset of multiple sclerosis in Western Australia , 2010, Multiple sclerosis.

[2]  M. Pinto-Medel,et al.  HLA class II alleles in patients with multiple sclerosis in the Biscay province (Basque Country, Spain) , 2009, Journal of Neurology.

[3]  T. Kilpatrick,et al.  HLA-DRB1 associations with disease susceptibility and clinical course in Australians with multiple sclerosis. , 2009, Tissue antigens.

[4]  Sreeram V Ramagopalan,et al.  Epistasis among HLA-DRB1, HLA-DQA1, and HLA-DQB1 loci determines multiple sclerosis susceptibility , 2009, Proceedings of the National Academy of Sciences.

[5]  G. Ebers,et al.  Epistasis , 2009, Neurology.

[6]  S. Baranzini,et al.  Uncoupling the Roles of HLA-DRB1 and HLA-DRB5 Genes in Multiple Sclerosis1 , 2008, The Journal of Immunology.

[7]  A. Montpetit,et al.  HLA class I alleles tag HLA-DRB1*1501 haplotypes for differential risk in multiple sclerosis susceptibility , 2008, Proceedings of the National Academy of Sciences.

[8]  Arne Svejgaard,et al.  The immunogenetics of multiple sclerosis , 2008, Immunogenetics.

[9]  A. Kermode,et al.  Characterisation of the spectrum of demyelinating disease in Western Australia , 2008, Journal of Neurology, Neurosurgery, and Psychiatry.

[10]  David Heckerman,et al.  Statistical Resolution of Ambiguous HLA Typing Data , 2008, PLoS Comput. Biol..

[11]  A. Verma,et al.  Risk Alleles for Multiple Sclerosis Identified by a Genomewide Study , 2008 .

[12]  D. Williamson,et al.  HLA-DR15 haplotype and multiple sclerosis: a HuGE review. , 2007, American journal of epidemiology.

[13]  J. Bell,et al.  Parental transmission of HLA-DRB1*15 in multiple sclerosis , 2007, Human Genetics.

[14]  Pablo Villoslada,et al.  Heterogeneity at the HLA-DRB1 locus and risk for multiple sclerosis. , 2006, Human molecular genetics.

[15]  Vincent Ferretti,et al.  A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis , 2005, Nature Genetics.

[16]  M. Z. Cader,et al.  Complex interactions among MHC haplotypes in multiple sclerosis: susceptibility and resistance. , 2005, Human molecular genetics.

[17]  G. Salemi,et al.  Multiple Sclerosis Severity Score: Using disability and disease duration to rate disease severity , 2005, Neurology.

[18]  F. Guerini,et al.  HLA–multiple sclerosis association in Continental Italy and correlation with disease prevalence in Europe , 2004, Journal of Neuroimmunology.

[19]  S. Sawcer,et al.  HLA-DR 15 is associated with female sex and younger age at diagnosis in multiple sclerosis , 2002, Journal of neurology, neurosurgery, and psychiatry.

[20]  F. Cucca,et al.  Dissection of the HLA association with multiple sclerosis in the founder isolated population of Sardinia. , 2001, Human molecular genetics.

[21]  A. Compston,et al.  Recommended diagnostic criteria for multiple sclerosis: Guidelines from the international panel on the diagnosis of multiple sclerosis , 2001, Annals of neurology.

[22]  F. Christiansen,et al.  HLA-DRB1 DNA sequencing based typing: an approach suitable for high throughput typing including unrelated bone marrow registry donors. , 2001, Tissue antigens.

[23]  J. Hillert,et al.  HLA‐DR15 is associated with lower age at onset in multiple sclerosis , 2000, Annals of neurology.

[24]  Z. Meiner,et al.  HLA class II susceptibility to multiple sclerosis among Ashkenazi and non-Ashkenazi Jews. , 1999, Archives of neurology.

[25]  F. Muntoni,et al.  DRB1-DQA1-DQB1 loci and multiple sclerosis predisposition in the Sardinian population. , 1998, Human molecular genetics.

[26]  T. Welborn.  The Busselton Study. Mapping population health. Cardiovascular and respiratory diseasea risk factors , 1998 .

[27]  D. Silberberg,et al.  New diagnostic criteria for multiple sclerosis: Guidelines for research protocols , 1983, Annals of neurology.