Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population

Am J Hum Genet. 2012 Oct 5;91(4):721-8. doi: 10.1016/j.ajhg.2012.08.010. Epub 2012 Sep 20.

Abstract

For the identification of susceptibility loci for primary biliary cirrhosis (PBC), a genome-wide association study (GWAS) was performed in 963 Japanese individuals (487 PBC cases and 476 healthy controls) and in a subsequent replication study that included 1,402 other Japanese individuals (787 cases and 615 controls). In addition to the most significant susceptibility region, human leukocyte antigen (HLA), we identified two significant susceptibility loci, TNFSF15 (rs4979462) and POU2AF1 (rs4938534) (combined odds ratio [OR] = 1.56, p = 2.84 × 10(-14) for rs4979462, and combined OR = 1.39, p = 2.38 × 10(-8) for rs4938534). Among 21 non-HLA susceptibility loci for PBC identified in GWASs of individuals of European descent, three loci (IL7R, IKZF3, and CD80) showed significant associations (combined p = 3.66 × 10(-8), 3.66 × 10(-9), and 3.04 × 10(-9), respectively) and STAT4 and NFKB1 loci showed suggestive association with PBC (combined p = 1.11 × 10(-6) and 1.42 × 10(-7), respectively) in the Japanese population. These observations indicated the existence of ethnic differences in genetic susceptibility loci to PBC and the importance of TNF signaling and B cell differentiation for the development of PBC in individuals of European descent and Japanese individuals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Asian Continental Ancestry Group
  • B-Lymphocytes
  • Case-Control Studies
  • Cell Differentiation / genetics
  • European Continental Ancestry Group / genetics
  • Female
  • Genetic Loci / genetics
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study / methods
  • HLA Antigens / genetics
  • Humans
  • Liver Cirrhosis, Biliary / genetics*
  • Male
  • Middle Aged
  • NF-kappa B p50 Subunit / genetics
  • Polymorphism, Genetic
  • STAT4 Transcription Factor / genetics
  • Trans-Activators / genetics*
  • Tumor Necrosis Factor Ligand Superfamily Member 15 / genetics*
  • Tumor Necrosis Factor-alpha / genetics
  • Young Adult

Substances

  • HLA Antigens
  • NF-kappa B p50 Subunit
  • NFKB1 protein, human
  • POU2AF1 protein, human
  • STAT4 Transcription Factor
  • TNF protein, human
  • TNFSF15 protein, human
  • Trans-Activators
  • Tumor Necrosis Factor Ligand Superfamily Member 15
  • Tumor Necrosis Factor-alpha