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Multiple sclerosis risk variant HLA-DRB1*1501 associates with high expression of DRB1 gene in different human

Antonio Alcina1, María Del Mar Abad-Grau, María Fedetz

  • 1Instituto de Parasitología y Biomedicina "López Neyra", Consejo Superior de Investigaciones Científicas (IPBLN-CSIC), Granada, Spain. pulgoso@ipb.csic.es

Plos One
|January 19, 2012
PubMed

Insights

The human leukocyte antigen (HLA) DRB1*1501 allele is linked to higher expression of HLA-DRB1, HLA-DRB5, and HLA-DQB1 genes, suggesting gene expression levels, not just antigen presentation, contribute to multiple sclerosis (MS) risk.

Area of Science:

  • Immunogenetics
  • Neuroimmunology
  • Human Genetics

Background:

  • The human leukocyte antigen (HLA) DRB1*1501 is strongly associated with multiple sclerosis (MS) risk across diverse populations.
  • While antigen presentation is implicated, the precise pathogenic mechanism remains unclear.
  • Expression quantitative trait loci (eQTLs) within the HLA locus raise questions about the role of gene expression in MS susceptibility.

Purpose of the Study:

  • To investigate the relationship between MS-associated HLA variants and gene expression levels in the HLA region.
  • To determine if altered expression of HLA genes contributes to MS pathogenesis.

Main Methods:

  • Analysis of eQTLs in the HLA region using genome-wide association study (GWAS) data.
  • Correlation of MS-risk variants (rs3135388 A allele) with expression levels of HLA-DRB1, HLA-DRB5, and HLA-DQB1 in Caucasian populations.
  • Haplotype analysis in a Spanish MS cohort.
  • Comparison with HLA associations in other immune-related diseases.

Main Results:

  • The MS-risk rs3135388 A allele strongly correlates with increased expression of HLA-DRB1, HLA-DRB5, and HLA-DQB1.
  • MS-risk genotype carriers showed significantly higher expression (15.7-fold for DQB1, 5.2-fold for DRB5, 8.3-fold for DRB1) compared to non-risk carriers.
  • High expression of DRB1 and DQB1 alone did not confer disease risk in the Spanish cohort.
  • Consistent high expression of DRB1*1501 was observed across Caucasian, Asian, and African American populations.
  • GWAS-associated HLA SNPs in other immune diseases were also eQTLs for HLA Class II genes.

Conclusions:

  • Altered expression levels of HLA-DR/DQ genes, in conjunction with specific allele structures, appear to be a key factor in the pathogenesis of MS.
  • This mechanism may also be relevant for other immune-mediated diseases.
  • Gene expression modulation offers a new perspective on HLA-associated disease susceptibility beyond simple antigen presentation.

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