Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity

Elife. 2016 Feb 15;5:e12089. doi: 10.7554/eLife.12089.


Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism. Variations modifying the consensus binding motifs of IRF4 and CTCF in the XL9 regulatory complex modified the transcription of HLA-DRB1, HLA-DQA1 and HLA-DQB1 in a chromosome-specific manner, resulting in a 2.5-fold increase in the surface expression of HLA-DR and DQ molecules on dendritic cells with SLE risk genotypes, which increases to over 4-fold after stimulation. Similar analyses of fifteen other SLE risk loci identified 1206 functional variants tightly linked with disease-associated SNPs and demonstrated that common disease alleles contain multiple causal variants modulating multiple immune system genes.

Keywords: HLA; LD; SLE risk; evolutionary biology; genomics; haplotype; human; human biology; medicine; risk allele; targeted sequencing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoimmunity*
  • Dendritic Cells / chemistry
  • Europe
  • Gene Expression Regulation*
  • HLA-D Antigens / biosynthesis*
  • HLA-D Antigens / genetics*
  • Humans
  • Lupus Erythematosus, Systemic / pathology
  • Membrane Proteins / analysis
  • Polymorphism, Genetic*
  • United States
  • Whites


  • HLA-D Antigens
  • Membrane Proteins