Primary biliary cirrhosis associated with HLA, IL12A, and IL12RB2 variants

N Engl J Med. 2009 Jun 11;360(24):2544-55. doi: 10.1056/NEJMoa0810440. Epub 2009 May 20.


Background: Primary biliary cirrhosis is a chronic granulomatous cholangitis, characteristically associated with antimitochondrial antibodies. Twin and family aggregation data suggest that there is a significant genetic predisposition to primary biliary cirrhosis, but the susceptibility loci are unknown.

Methods: To identify genetic loci conferring a risk for primary biliary cirrhosis, we carried out a genomewide association analysis in which DNA samples from 2072 Canadian and U.S. subjects (536 patients with primary biliary cirrhosis and 1536 controls) were genotyped for more than 300,000 single-nucleotide polymorphisms (SNPs). Sixteen of the SNPs most strongly associated with primary biliary cirrhosis were genotyped in two independent replication sets. We carried out fine-mapping studies across three loci associated with primary biliary cirrhosis.

Results: We found significant associations between primary biliary cirrhosis and 13 loci across the HLA class II region; the HLA-DQB1 locus (encoding the major histocompatibility complex class II, DQ beta chain 1) had the strongest association (P=1.78x10(-19); odds ratio for patients vs. controls, 1.75). Primary biliary cirrhosis was also significantly and reproducibly associated with two SNPs at the IL12A locus (encoding interleukin-12alpha), rs6441286 (P=2.42x10(-14); odds ratio, 1.54) and rs574808 (P=1.88x10(-13); odds ratio, 1.54), and one SNP at the IL12RB2 locus (encoding interleukin-12 receptor beta2), rs3790567 (P=2.76x10(-11); odds ratio, 1.51). Fine-mapping analysis showed that a five-allele haplotype in the 3' flank of IL12A was significantly associated with primary biliary cirrhosis (P=1.15x10(-34)). We found a modest genomewide association (P<5.0x10(-5)) with the risk of disease for SNPs at the STAT4 locus (encoding signal transducer and activator of transcription 4) and the CTLA4 locus (encoding cytotoxic T-lymphocyte-associated protein 4) and 10 other loci.

Conclusions: Our data show significant associations between primary biliary cirrhosis and common genetic variants at the HLA class II, IL12A, and IL12RB2 loci and suggest that the interleukin-12 immunoregulatory signaling axis is relevant to the pathophysiology of primary biliary cirrhosis. ( number, NCT00242125.)

Publication types

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

MeSH terms

  • Genes, MHC Class II*
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • HLA Antigens / genetics
  • HLA-DQ Antigens / genetics*
  • HLA-DQ beta-Chains
  • Humans
  • Interleukin-12 Receptor beta 2 Subunit / genetics*
  • Interleukin-12 Subunit p35 / genetics*
  • Interleukin-23 / genetics
  • Liver Cirrhosis, Biliary / genetics*
  • Polymorphism, Single Nucleotide
  • Receptors, Interleukin-12 / genetics


  • HLA Antigens
  • HLA-DQ Antigens
  • HLA-DQ beta-Chains
  • HLA-DQB1 antigen
  • Interleukin-12 Receptor beta 2 Subunit
  • Interleukin-12 Subunit p35
  • Interleukin-23
  • Receptors, Interleukin-12

Associated data