HLA-DRB1

HIGH

Major histocompatibility complex, class II, DR beta 1

Chromosome: 6p21.32

Gene Overview

HLA-DRB1 encodes the beta chain of HLA-DR, an MHC class II molecule that presents exogenous antigens to CD4+ T cells. Specific HLA-DRB1 alleles (e.g., shared epitope: *01, *04, *10) confer strong genetic risk for rheumatoid arthritis; other alleles associate with multiple sclerosis and other autoimmune diseases. The shared epitope alleles present arthritogenic peptides and shape the T cell repertoire. HLA-DRB1 is highly polymorphic with hundreds of alleles. Expression is restricted to antigen-presenting cells: B cells, dendritic cells, macrophages. Risk alleles may influence thymic selection, peptide binding, or T cell activation. The HLA region shows the strongest genetic associations in autoimmune disease.

Molecular Function

  • antigen presentation
  • peptide binding
  • T cell activation
  • immune recognition

Protein class: MHC class II

Regulatory Annotation

Promoter activity: CIITA-dependent; IFN-gamma inducible.

Enhancer associations: Disease-associated variants in linkage disequilibrium with coding alleles.

eQTL tissues: whole blood, spleen

Tissue Expression Context

whole bloodTPM range: 10-50GTEx vv8
spleenTPM range: 20-80GTEx vv8

Pathways

Linked Diseases & Exposures

Diseases

Exposures

  • tobacco— literature, strength 0.65

Mechanistic Hypotheses

Shared epitope HLA-DRB1 alleles present citrullinated peptides to CD4+ T cells; smoking promotes citrullination; G×E interaction between genotype and tobacco amplifies RA risk through adaptive immune activation.

Anti-CCP antibodies in RA; gene-environment interaction between HLA and smoking in seropositive RA.

HIGH

Confidence Rating

Overall evidence confidence for this gene entry: HIGH

References

  1. 1.Klareskog L, et al. (2006). A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis & Rheumatism. doi:10.1002/art.21575
  2. 2.GTEx Consortium (2020). GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science. doi:10.1126/science.aaz1776
  3. 3.International Multiple Sclerosis Genetics Consortium (2011). Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. doi:10.1038/nature10251