What is the major genetic susceptibility locus for rheumatoid arthritis?

Medical Advisory BoardAll articles are reviewed for accuracy by our Medical Advisory Board
Educational purpose only • Exercise caution as content is pending human review
Article Review Status
Submitted
Under Review
Approved

Last updated: August 22, 2025 • View editorial policy

Personalize

Help us tailor your experience

Which best describes you? Your choice helps us use language that's most understandable for you.

HLA-DRB1 is the Major Genetic Susceptibility Locus for Rheumatoid Arthritis

The HLA-DRB1 gene locus, particularly alleles encoding the shared epitope (SE), is the major genetic susceptibility locus for rheumatoid arthritis. 1, 2

Genetic Basis of Rheumatoid Arthritis

HLA-DRB1 and the Shared Epitope

  • HLA-DRB1 alleles associated with rheumatoid arthritis encode a conserved amino acid sequence (QKRAA, QRRAA, or RRRAA) at positions 70-74 in the third hypervariable region of the DRβ1 chain, commonly called the "shared epitope" 2
  • These shared epitope-containing alleles are considered core genetic risk factors for RA development 1
  • Specific HLA-DRB1 alleles that increase risk include:
    • HLA-DRB1*04 (particularly *0401 and *0404)
    • HLA-DRB1*03
    • HLA-DRB1*08
    • HLA-DRB1*10
    • HLA-DRB1*11
    • HLA-DRB1*14 3

Risk Stratification by HLA-DRB1 Genotypes

  • The HLA-DRB1*0401/*0404 genotype confers particularly high risk:
    • 26-fold increased risk compared to individuals without shared epitope alleles
    • 90-fold increased risk in men
    • Even higher risk (>180-fold) in men with disease onset before age 30 4
  • Individuals carrying a single shared epitope allele have 4 times the risk of developing RA
  • Those carrying two shared epitope alleles have 8 times the risk 4

Clinical Implications of HLA-DRB1 Status

Disease Severity and Characteristics

  • HLA-DRB1*0401/*0404 genotype is associated with:
    • Higher likelihood of being rheumatoid factor positive
    • Development of subcutaneous nodules
    • Presence of radiological erosions 4
  • Specific HLA-DRB1 alleles (*03, *04, *08, *10, *11, and *14) correlate with elevated ESR values in RA patients 3

Age of Onset

  • HLA-DRB1*0401 and *0404 are strongly associated with RA onset before age 40
  • HLA-DRB1*01 is associated with RA onset after age 60 2

Protective Alleles

  • Some HLA-DRB1 alleles encoding a DERAA sequence at positions 70-74 provide protection against RA
  • Aspartic acid (D) at position 70 of the DRβ1 chain is particularly protective
  • HLA-DRB1*01/15 and DRB107/*16 genotypes appear to be protective 2, 3

Secondary Susceptibility Loci

While HLA-DRB1 is the primary genetic susceptibility locus, other genetic factors contribute to RA risk:

  • A second susceptibility gene has been identified in the HLA class III region, located within a 70-kb interval telomeric of the TNF genes 5
  • This region contains several candidate genes: NFKBIL1 (IκBL), ATP6G, BAT1, and MICB 5
  • Additional non-HLA loci (over 100) have been implicated in disease susceptibility 6

Clinical Applications

  • HLA typing can help predict RA development risk and confirm diagnosis in certain cases 3
  • The association between specific HLA-DRB1 alleles and inflammatory markers (ESR, CRP) can aid in early diagnosis and treatment initiation 3
  • Understanding genetic risk factors can help identify patients who may develop more severe disease and require more aggressive treatment 4

The genetic basis of RA is complex, with HLA-DRB1 being the predominant susceptibility locus, but with multiple other genetic and environmental factors contributing to disease development and progression.

References

1
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

6
Research

Recent Advances in Defining the Genetic Basis of Rheumatoid Arthritis.

Annual review of genomics and human genetics, 2016

Related Questions

What is the major genetic susceptibility locus for rheumatoid arthritis?
What diseases are associated with HLA (Human Leukocyte Antigen) DRB1?
What does the Human Leukocyte Antigen-DRB1 (HLA-DRB1) indicate?
What is the first-line treatment for Clostridium difficile (C. diff) infection?
What is the recommended initial dosage and titration schedule for fluoxetine (selective serotonin reuptake inhibitor) when treating anxiety?
What are the unique characteristics of Selective Serotonin Reuptake Inhibitors (SSRIs) that distinguish one agent from another?
What is the recommended depth of chest compressions?
What is the initial management for a patient with an IgM kappa monoclonal protein?
What is the next step for a patient in refractory ventricular fibrillation after a third shock?

Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

Have a follow-up question?

Our Medical A.I. is used by practicing medical doctors at top research institutions around the world. Ask any follow up question and get world-class guideline-backed answers instantly.

Ask Question