Wednesday, January 25, 2012

HLA and autoimmune disease association : a quick summary

Celiac disease :
  • CELIAC1 : heterodimers "DQ2" (DQA1*05-DQB1*02) or "DQ8" (DQA1*03-DQB1*03:02). Gradient of RR : DQB1*02/*02 or DQB1*02/*0302 > DQ2 > DQ8 > DQB1*02 (DQA1*05 negativo) >> DQ2/DQ8/DQB1*02 negative
  • DQ2/DQ8/DQB1*02 found in 30% of population => poor positive predictive value (1/30), very high negative predictive value
  • other predisposing genes : CELIAC2, CELIAC3/CTLA4, CELIAC4/MYO9B
  • the risks of celiac disease autoimmunity and celiac disease by the age of 5 years were 11% and 3%, respectively, among children with a single DR3–DQ2 haplotype, and 26% and 11%, respectively, among those with two copies (DR3–DQ2 homozygosity). In the adjusted model, the hazard ratios for celiac disease autoimmunity were 2.09 (95% confidence interval [CI], 1.70 to 2.56) among heterozygotes and 5.70 (95% CI, 4.66 to 6.97) among homozygotes, as compared with children who had the lowest-risk genotypes (DR4–DQ8 heterozygotes or homozygotes). Residence in Sweden was also independently associated with an increased risk of celiac disease autoimmunity (hazard ratio, 1.90; 95% CI, 1.61 to 2.25) (ref)
Type 1 diabetes mellitus :
  • haplotypes DRB1*03:01-DQA1*05:01-DQB1*02:01 or DRB1*04:01-DQA1*03:01-DQB1*03:02
  • RR in double heterozygotes = 20-40 > DR3 homozygotes  or DR4 homozygotes
  • odds ratio (OR) according to "diplotypes" (i.e. combinations of haplotypes) :

  • non DR-DQ HLA alleles predispose (A*24, B*39, B*18) or protect (B*27, A*01, A*11, A*31) (typing not recommended)
  • other genes : INS/IDDM2 VNTR, PTPN22/Lyp, CTLA4, IL2RA, IFIH1, CLEC16A, PTPN2, CYP27B1
Rheumatoid arthritis  :
  • prevalence = 0.5-1% worldwide (commonest autoimmune disease); M:F ratio 1:3
  • position 70-74 in HVR3 of HLA-DRB1 alleles : predisposing shared epitope (*01:01, *01:02, *04:01, *10:01, *14:02)) or   protective (*01:03, *04:02, *11:02, *11:03, *13:01, *13:02)
  • DRB1*03 correlates with lack of anti-CCP autoAb
  • other predisposing genes :  PTPN22/Lyp C1858T,  CTLA4, PADI4, MIF, TRAF1-C5, 6q23
Juvenile idiopathic arthritis (JIA) :
  • A*02 predisposes to early-onset JIA
  • B27 predisposes to enthesitis-associated JIA
  • DRB1*01, *08, *11, *13, DPB1*02 and DQB1*04 predispose to oliogoarticular JIA, while DRB1*04 and *07 protect from it
  • DRB1*08 and DPB1*03 predispose to polyarticular RF-negative JIA
  • DRB1*04, DQA1*03 and  DQB1*03 predispose to polyarticular RF-positive JIA
  • DRB1*01 and DQA1*0101 predispose to psoriatic JIA
  • non-HLA genes : TNFA-857A/G, MIF, SLC11A1, PTPN22
Ankylosing spondylitis / Bechterew disease and reactive arthritis :
  • all B27 alleles other than *27:06 (Sardinia) and *27:09 (South-East Asia) (OR > 100; PPV : 5%), B60 (OR 3.6), and DRB1*01
  • non-HLA genes : IL-1 family, CYP2D6, CARD15/NOD2, ANKH, ARTS1 and IL23R.
Uveitis :
  • acute anterior uveitis : B27 (expecially HLA-B*2705)
  • Behçet disease : B51
  • birdshot-like chorioretinopathy : A29 (RR = 50-250)
  • glaucomacyclitic crisis (Posner-Schlossman syndrome) : B54
  • pars-planitis : DR15
  • juvenile arthritis-related uveitis : DPB1*0202
  • tubulointerstitial nephritis and uveitis : DRB1*01:02 and DQA1*01
  • Vogt-Koyanagi-Harada syndrome : DR1 and DR4 in Caucasians and DRB1*04:05 in Asia
Behçet disease : B*510101 (RR = 6-10)
Multiple sclerosis :
  • "HLA-DR15" haplotype :
  1. DRB1*15:01, DRB5*01:01, DQA1*01:02, DQB1*06:02) and B18 (OR 2.6 or OR 6.2)
  2. DRB1*03:01 (OR = 1.4)
  • HLA-A*02:01; B*44:02; C*05:01 is a protective haplotype (OR : 0.2)
Myasthenia gravis : B8, B7, DR3 in Caucasians
  • DR9, DR13, DQ3, B12 and A10 in Japanese
  • HLA-DRB1*16,-DRB1*14 and -DQB1*05 with MuSK-MG (ref)
  • HLA A1-B8-DR3 haplotype in female patients with thymus hyperplasia and early onset MG, while HLA B7-DR2 haplotype was found in late onset MG (ref1, ref2). HLA-DQB polymorphism has also been linked to MG in earlier studies (ref). More recently, associations betweenHLA-DRB1*14, HLA-DRB1*16 and DQ5 have been observed with the small MuSK-MG subgroup in two different studies (ref1, ref2).
Löfgren's syndrome : DRB1*03

Takayasu's arteritis : B*52
  • DQA1*01:02-DQB1*06:02 haplotype (in combination with DRB1*15:01 in Caucasians); more severe in homozygous
  • DQB1*03:01 worsens
  • DQB1*05:01 and *06:01 protect
  • non-HLA genes : hypocretin/orexin
Psoriasis :
  • B13, B57, B37, B39, C*06:02 (RR = 2-5 in homozygous), DR7 and DR4
  • psoriatic arthritis : B27 (interphalangeal), B38 and B39 (peripheral joints), DR4 (symmetric) and DR7
Fetal neonatal alloimmune thrombocytopenia (FNAIT) :  the immune-dominant antigen leading to severe FNAIT is the human PLT antigen (HPA)-1, whose polymorphism constitutes an epitope for human leukocyte antigens (HLAs) DRB3*0101 and DRB4*01:01

Moyamoya angiopathy (MMA) : HLA-DRB1*03, DRB1*13

Parkinson's disease (PD) : HLA-DRB1*04

Primary biliary cirrhosis (PBC) :
  • HLA-DRB1*08 (P=1.59 × 10−11), HLA-DRB1*14, and  the DPB1 association (DPB1*03:01; P=9.18 × 10−7) are predisposing risk alleles
  • HLA-DRB1*11 is protective (P=1.42 × 10−10) (ref)
ANCA-associated vasculitis (AAV) : HLA-DRB1*0405 might be an independent risk factor for the poor response to treatment and the deterioration of renal function, whereas DPB1*0402 might be an independent risk factor for all-cause mortality (ref).

Immune-mediated bone marrow aplasia : HLA-DR15 allele in patients with MDS appeared to be associated with a good response to immune-suppressive therapy, suggesting that this allele may be a specific predisposing factor for the development of immunemediated bone marrow failure (ref). Secondary graft failure rate at 2 years was lower in patients who were HLA DR15+ (hazard ratio = 0.46, P = .01) (ref).

Chronic beryllium disease (CBD) / beryllium sensitization (BeS) : HLA-DPB1 alleles with a glutamic acid residue at position 69 (E69). Results suggest that the less-frequent E69 variants (non-*0201/*0202 alleles) might be associated with greater risk of CBD (ref).

Acute lymphoblastic leukemia (ALL) : HLA-DPB1*01:01 (ref).

Pemphigus vulgaris : DRB1*04–DQB1*03 or HLA-DRB1*14–DQB1*05 (ref)

Endemic pemphigus foliaceus (EPF) : rs3087456 in the CIITA gene promoter is associated with susceptibility (OR =2.6 and OR=2 for genotypes G/G and G/A)

Autoimmune thrombotic thrombocytopenic purpura (TTP) : DRB1*11 (ref)

Insulin autoimmune syndrome (IAS) / Hirata disease : HLA DRB1*04:06 (expecially in Japanese) and DRB1*04:03 (expecially in Caucasians) (ref)

Idiopathic membranous nephropathy (IMN) : HLA-DQA1 (ref) Print this post

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