Interaction between HLA-DRB1-DQB1 haplotypes in Sardinian multiple sclerosis population

PLoS One. 2013 Apr 8;8(4):e59790. doi: 10.1371/journal.pone.0059790. Print 2013.

Abstract

We performed a case-control study in 2,555 multiple sclerosis (MS) Sardinian patients and 1,365 healthy ethnically matched controls, analyzing the interactions between HLA-DRB1-DQB1 haplotypes and defining a rank of genotypes conferring a variable degree of risk to the disease. Four haplotypes were found to confer susceptibility (*13:03-*03:01 OR = 3.3, Pc 5.1 × 10(-5), *04:05-*03:01 OR = 2.1, Pc 9.7 × 10(-8), *15:01-*06:02 OR = 2.0, Pc = 9.1 × 10(-3), *03:01-*02:01 OR = 1.7 Pc = 7.9 × 10(-22)) and protection (*11, OR = 0.8, Pc = 2.7 × 10(-2), *16:01-*05:02 OR = 0.6, Pc = 4.8 × 10(-16), *14:01-4-*05:031 = OR = 0.5, Pc = 9.8 × 10(-4) and *15:02-*06:01 OR = 0.4, Pc = 5.1 × 10(-4)). The relative predispositional effect method confirms all the positively associated haplotypes and showed that also *08 and *04 haplotypes confers susceptibility, while the *11 was excluded as protective haplotype. Genotypic ORs highlighted two typologies of interaction between haplotypes: i) a neutral interaction, in which the global risk is coherent with the sum of the single haplotype risks; ii) a negative interaction, in which the genotypic OR observed is lower than the sum of the OR of the two haplotypes. The phylogenic tree of the MS-associated DRB1 alleles found in Sardinian patients revealed a cluster represented by *14:01, *04:05, *13∶03, *08:01 and *03:01 alleles. Sequence alignment analysis showed that amino acids near pocket P4 and pocket P9 differentiated protective from predisposing alleles under investigation. Furthermore, molecular dynamics simulation performed on alleles revealed that position 70 is crucial in binding of MBP 85-99 peptide. All together, these data suggest that propensity to MS observed in Sardinian population carried by the various HLA-DRB1-DQB1 molecules can be due to functional peculiarity in the antigen presentation mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigen Presentation / genetics
  • Case-Control Studies
  • Female
  • Genetic Predisposition to Disease / genetics
  • HLA-DQ beta-Chains / chemistry
  • HLA-DQ beta-Chains / genetics*
  • HLA-DRB1 Chains / chemistry
  • HLA-DRB1 Chains / genetics*
  • Haplotypes / genetics*
  • Humans
  • Italy
  • Male
  • Models, Molecular
  • Models, Statistical
  • Multiple Sclerosis / genetics*
  • Multiple Sclerosis / immunology
  • Protein Conformation
  • Sequence Alignment

Substances

  • HLA-DQ beta-Chains
  • HLA-DQB1 antigen
  • HLA-DRB1 Chains

Grants and funding

This work was supported by grant project by a grant by “Ministero dell’Istruzione, dell’Università e della Ricerca” (call: PRIN 2008). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.