What diseases are associated with HLA (Human Leukocyte Antigen) DRB1?

Diseases Associated with HLA-DRB1

HLA-DRB1 alleles are most strongly associated with autoimmune diseases, particularly type 1 diabetes, rheumatoid arthritis, multiple sclerosis, and autoimmune hepatitis, with specific alleles conferring either susceptibility or protection depending on the disease.

Type 1 Diabetes

Susceptibility Alleles:

• HLA-DRB104:01-DQA103:01-DQB103:02 (DR4-DQ8) combined with DRB103-DQA105:01-DQB102:01 (DR3-DQ2) confers the highest genetic risk for type 1 diabetes 1, 2
• DRB1*04:01, *04:04, and *04:07 subtypes are susceptible alleles 1
• These HLA genes account for 30-50% of familial susceptibility to type 1 diabetes 1, 2

Protective Alleles:

• DRB115-DQA102:01-DQB106:02 (DRB11501-DQB1*06:02) strongly protects against type 1 diabetes at young ages 1, 2
• DRB1*04:03 and *04:06 subtypes are negatively associated with disease 1
• DRB1*11 or 04 with DQB103:01 are unlikely to develop type 1 diabetes at young ages 1

Rheumatoid Arthritis (RA)

Susceptibility Alleles:

• *HLA-DRB104:01 shows the strongest association with RA, particularly when homozygous or combined with 04:04* 3, 4
• DRB1*04:01/*04:04 heterozygosity carries a 26-fold increased risk overall and a 90-fold increased risk in men 5
• DRB1*01 is associated with RA susceptibility (OR = 1.79) 3
• Valine at position 11 of HLA-DRB1 (the "shared epitope") is most strongly associated with radiological damage (OR = 1.75), with 74% of homozygote carriers developing erosions by year 5 versus 48% of noncarriers 3
• Valine at position 11 is also associated with 16% higher all-cause mortality (hazard ratio 1.16) but paradoxically with better response to TNF inhibitor therapy 3

Protective Alleles:

• HLA-DRB1*13 is consistently underrepresented in RA (16.3% versus 29.8% in controls, OR = 0.58) 6

Multiple Sclerosis (MS)

Susceptibility Alleles:

• HLA-DRB115 (DRB11501) is the primary MS susceptibility allele (OR = 2.17) 6, 7
• The MS-risk variant rs3135388 AA genotype is associated with 8.3-fold higher expression of DRB1 compared to non-risk carriers 7
• DRB1*03 also shows association with MS (OR = 1.81) 6

Protective Alleles:

• HLA-DRB1*13 shows protective effects against MS 6

Autoimmune Hepatitis (AIH)

Susceptibility Alleles:

• Type 1 AIH is associated with HLA-DRB103:01 (DRB10301) and DRB104:01 (DRB10401) 1
• DRB1*0301 is associated with younger age at presentation, higher treatment failure rates, more frequent relapse after drug withdrawal, and greater need for liver transplantation 1
• DRB1*0401 is associated with older age at presentation, concurrent autoimmune diseases, and better response to corticosteroids 1
• Type 2 AIH is associated with DRB1*07:01 1
• HLA-DRB1*04:01 is associated with concurrent autoimmune diseases in AIH patients (42% in those ≥60 years versus 13% in those ≤30 years) 1

Other Autoimmune Diseases

Systemic Lupus Erythematosus (SLE):

• DRB1*03 is associated with SLE (OR = 2.49) 6
• HLA-DRB1*13 is protective (18.3% versus 29.8% in controls) 6

Psoriasis and Psoriatic Arthritis:

• DRB1*07 is associated with psoriasis/psoriatic arthritis (OR = 1.79) 6
• HLA-DRB1*13 is protective (19.3% versus 29.8% in controls) 6

Systemic Sclerosis:

• DRB101 (OR = 2.28) and DRB108 (OR = 3.01) are associated with systemic sclerosis 6
• HLA-DRB1*13 is protective (11.9% versus 29.8% in controls) 6

Myasthenia Gravis:

• DRB1*03 is associated with myasthenia gravis (OR = 2.98) 6

Aspirin-Exacerbated Respiratory Disease (AERD):

• HLA-DPB1 (class II gene) is the strongest predictor for AERD in Korean populations 1

Clinical Implications

Important Caveats:

• Routine HLA-DRB1 typing is NOT recommended for clinical diagnosis or management of type 1 diabetes or most autoimmune diseases 1
• HLA typing is primarily useful for research studies, risk stratification in clinical trials, and classification of uncertain diabetes cases 1
• HLA-DRB1*13 appears to confer broad protection across multiple autoimmune diseases, possibly through more efficient antigen presentation favoring clonal deletion during thymic selection 6
• The association between HLA-DRB1 and disease severity varies: in RA, certain alleles predict both susceptibility and severity, while in type 1 diabetes, HLA genes primarily affect susceptibility rather than progression after autoimmunity develops 1, 3