HLA associations with multiple sclerosis in Greece

https://doi.org/10.1016/j.jns.2011.06.037Get rights and content

Abstract

Background

Multiple sclerosis (MS) is a demyelinating inflammatory disease of the central nervous system originated by a complex interplay of environmental and genetic factors. The association of MS with the human leukocyte antigen (HLA) class II alleles was investigated in MS patients in northwest Greece, in the geographical region of Epirus.

Objective

Our aim was to estimate the prevalence of the HLA-DRB1*1501, HLA-DQB1*0602 and HLA-DQA1*0102 alleles, consisting the most common susceptibility haplotype in North European and North American Caucasians.

Methods

We studied 126 MS patients and 93 age and sex matched healthy controls. HLA typing was performed by a polymerase chain reaction (PCR) amplification with sequence-specific primers (PCR-SSP) method.

Results

We found that HLA-DRB1*1501, HLA-DQB1*0602 and HLA-DQA1*0102 alleles were significantly more frequent among patients (34% versus 11%, p = 0.00015; 69% versus 51%, p = 0.01; 76% versus 55%, p = 0.002, respectively). HLA-DRB1*1501, HLA-DQB1*0602, HLA-DQA1*0102 haplotype was significantly more common among patients (p = 0.00067). HLA-DRB1*1501 and HLA-DQB1*0602 alleles were more frequently detected in patients with initial symptoms from the brainstem or the cerebellum (p = 0.024). No significant correlation was observed among these alleles with sex, disease clinical course, or age at onset.

Conclusion

This is the first study to investigate genetic susceptibility to MS in Greece. Our results are in line with previous reports in North European and North American patients.

Introduction

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system responsible for demyelinating lesions within white matter in young adults [1]. Although the causes of MS are largely unknown, there is evidence to support the view that MS is a complex trait determined by both genetic and environmental factors [2], [3]. It is widely believed that MS is the result of an autoimmune process in which T-lymphocytes mediate a reaction against myelin self-antigens. The major histocompatibility complex (MHC) is the most powerful genetic component in MS [4] and many other autoimmune diseases. An association between MS and MHC alleles was found in the 1970s, notably involving the class II human leukocyte antigen (HLA)-DR2 [5]. HLA molecules play a key role in the selection and establishment of the antigen-specific T cell repertoire, as well as in the subsequent activation of T cells during the initiation of an immune response [6].

Polymorphisms among class-II genes identify specific haplotypes associated with a diversity of autoimmune diseases such as type-I diabetes, rheumatoid arthritis, celiac disease, and pemphigus vulgaris [7]. More specific, using genomic typing techniques the DR15 haplotype (DRB1*1501, DQA1*0102, DQB1*0602) and its individual alleles have been linked with a number of diseases, such as systemic lupus erythematosus, and most prominently MS, in case-control and family-based studies in various countries around the world [8].

Recently, Schmidt et al reviewed 70 papers on the association between the DR15 haplotype and MS and reported a higher frequency of the DR15 haplotype and/or its component alleles among MS cases than among controls [9]. It is intriguing that different HLA alleles are correlated with MS in different ethnic groups, including predominantly DR2 in northern European and American Caucasians, DR4 in Arabs and Sardinians, and DR6 in Japanese and Mexicans [10], [11], [12], [13], [14], [15].

The majority of the HLA population studies in MS have focused on European and American Caucasians, Australians, Chinese, Japanese, Jewish, and Turkish where the predisposition of the disease has been consistently associated with DRB1*15 and its associated alleles DRB1*1501, DQA1*0102, DQB1*0602 [16]. In addition, there are studies indicating that patients with demyelinating disorders with distinct phenotype may have distinct HLA-DRB profiles [17]. Interestingly in a study, differences in DRB1*15 allele expression may explain phenotypic differences between MS in African- and European-Americans [18].

So far, there are no data concerning the genetic susceptibility of MS patients in Greece. In this study, we investigated the association of MS with the HLA class II loci DR2 and DQ6 (short for DRB1*1501, DQA1*0102, DQB1*0602) haplotypes in MS patients in Greece, in the geographical region of Epirus (northwest Greece). Our objective was to estimate the prevalence of the HLA-DRB1*1501, HLA-DQB1*0602 and HLA-DQA1*0102 alleles in our cohort of MS patients and examine probable relationship among these alleles with gender, sex, age of onset, initial symptoms, course of disease, expanded disability scale score (EDSS), and positive family history.

Section snippets

Patients

We studied 126 Greek MS patients born or long-term residents in the geographical region of Epirus (northwest Greece) recruited in the department of Neurology at the University Hospital of Ioannina, during a 2 year period from 2008 to 2009. All the subjects satisfied the Mc Donald criteria for MS diagnosis [19]. Detailed clinical parameters including age, gender, age at onset of disease, ethnicity, disease course, initial symptoms, EDSS, positive family history, as well as signs from the

Statistical analysis

Statistical significance was defined by a p-value of less than 0.05. We carried out univariate associations for continuous variables using t-test or non parametric Wilcoxon test depending on the normality of the continuous variables. We analyzed binary outcomes using the Chi-squared test. Logistic regression analysis was used to analyse the potential prognostic significance of the various HLA subtypes. Analysis was performed using TIBCO Spotfire S+® 8.1 (TIBCO Software Inc, //spotfire.tibco.com

Clinical features

The demographic and clinical features of the patients are summarized in Table 1. Among the 126 patients with MS there were 65 females and 28 males. There was no difference in age or sex between groups (p = 0.12 and p = 0.81, respectively). Mean age was 39.5 years +/− 11.8 (CI 37.8–41, range: 19 to 65 years). Mean age at onset was 31.4 years +/− 10.7 (CI 29.4–33.3), mean disease duration was 9.1 years +/− 6.4 (CI 8–10.2, range: 4 months to 29 years). Mean EDSS was 3 +/− 2.5 (CI 2.6–3.5, range: 0.5–9.5). Most of

Discussion

An association between MS and HLA II was first noted in 1973 [5]. Thereafter, numerous studies have been conducted on the correlation of HLA antigens and MS. In a number of studies, the DR15 haplotype (DRB1*1501-DQA1*0102-DQB1*0602) has been hypothesized to be the primary HLA genetic susceptibility factor for MS [14], [15], [22], [23], [24], [25]. Masterman et al studied a large number of Swedish MS patients and found that the DR15 haplotype was overrepresented among patients [26]. Fernandez et

Conflict of interests

The authors declare that they have no conflicts of interest.

Funding

This research was partially funded by a grant from Merck-Serono pharmaceutical company, Greece.

Acknowledgements

The authors would like to thank Assistant Professor Georgia Salanti (Department of Hygiene and Epidemiology, School of Medicine, University of Ioannina, Greece) for her valuable contribution during statistical analysis of the data. We also wish to thank all participants (MS patients and controls) in this study.

References (39)

  • D.A. Laplaud et al.

    Etiology of multiple sclerosis

    Rev Prat

    (2006)
  • G.C. Ebers

    Genetics and multiple sclerosis: an overview

    Ann Neurol

    (1994)
  • C.J. Willer et al.

    Susceptibility to multiple sclerosis: interplay between genes and environment

    Curr Opin Neurol

    (2000)
  • HLA sequence database maintained by the International ImMunoGeneTics (IMGT) project. Cited 15 May 2010. Available from...
  • G.T. Nepom et al.

    MHC class-II molecules and autoimmunity

    Annu Rev Immunol

    (1991)
  • O. Olerup et al.

    HLA class II-associated genetic susceptibility in multiple sclerosis: a critical evaluation

    Tissue Antigens

    (1991)
  • H. Schmidt et al.

    HLA-DR15 Haplotype and Multiple Sclerosis: A HuGE Review

    Am J Epidemiol

    (2007)
  • S. Naito et al.

    HLA and Japanese MS

    Tissue Antigens

    (1978)
  • M.G. Marrosu et al.

    Sardinian multiple sclerosis is associated with HLA-DR4: a serologic and molecular analysis

    Neurology

    (1988)

    • Cited by (15)

    • Relationship between HLA-DRB1∗ 11/15 genotype and susceptibility to multiple sclerosis in IRAN

      2014, Journal of the Neurological Sciences
      Citation Excerpt :

      Brynedal et al. [5] found that some HLA-DRB1*15 haplotypes determined susceptibility to MS while others did not. Other researchers failed to prove it as a prognostic factor [3,14,22]. Moreover, the relationship of the HLA DRB1*15 allele with MRI changes in the brainstem supports the opinion that this allele might be associated with a worse prognosis of the disease [2,20].

    • Prevalence of cerebrospinal fluid oligoclonal IgG bands in Greek patients with clinically isolated syndrome and multiple sclerosis

      2013, Clinical Neurology and Neurosurgery
      Citation Excerpt :

      Additionally, DRB1*15 patients were found to have a higher percentage of OCB positivity compared with patients carrying other alleles [18]. It is intriguing that although the carriage frequency of HLA-DRB1*15 allele in an Australian population with MS was similar to Northern European MS patients, higher than the frequency reported in Mediterranean MS populations (54.5% vs. 24–34%), the percentage of OCB positivity was comparable with that found in our study [2,18–20]. In Sweden, OCB-negative MS seems to be associated with HLA-DRB1*04, which is rare in Northern Europe but common in Asia and the Mediterranean countries [7,21,22].

    • Exercise Reverses Immune‑Related Genes in the Hippocampus of Multiple Sclerosis Patients

      2024, Neurology India

    • Association of hla-dr2-related haplotype (Hla-drb5*01-drb1*1501-dqb1*0602) in patients with multiple sclerosis in khuzestan province

      2021, Iranian Journal of Child Neurology

    • Association of multiple sclerosis with vitiligo: a systematic review and meta-analysis

      2020, Scientific Reports

    • Replication study of GWAS risk loci in Greek multiple sclerosis patients

      2019, Neurological Sciences
    View all citing articles on Scopus
    View full text
    Copyright © 2011 Elsevier B.V. All rights reserved.