Association of primary biliary cirrhosis with variants in the CLEC16A, SOCS1, SPIB and SIAE immunomodulatory genes

Genes Immun. 2012 Jun;13(4):328-35. doi: 10.1038/gene.2011.89. Epub 2012 Jan 19.


We fine mapped two primary biliary cirrhosis (PBC) risk loci, CLEC16A (C-type lectin domain family 16 member A)-suppressor of cytokine signaling 1 (SOCS1) and Spi-B protein (SPIB) and sequenced a locus, sialic acid acetylesterase (SIAE), proposed to harbor autoimmunity-associated mutations. In all, 1450 PBC cases and 2957 healthy controls were genotyped for 84 single-nucleotide polymorphisms (SNPs) across the CLEC16A-SOCS1 and SPIB loci. All 10 exons of the SIAE gene were resequenced in 381 cases and point substitutions of unknown significance assayed for activity and secretion. Fine mapping identified 26 SNPs across the CLEC16A-SOCS1 and 11 SNPs across the SPIB locus with significant association to PBC, the strongest signals at the CLEC16A-SOCS1 locus emanating from a SOCS1 intergenic SNP (rs243325; P=9.91 × 10(-9)) and at the SPIB locus from a SPIB intronic SNP (rs34944112; P=3.65 × 10(-9)). Among the associated SNPs at the CLEC16A-SOCS1 locus, two within the CLEC16A gene as well as one SOCS1 SNP (rs243325) remained significant after conditional logistic regression and contributed independently to risk. Sequencing of the SIAE gene and functional assays of newly identified variants revealed six patients with functional non-synonymous SIAE mutations (Fisher's P=9 × 10(-4) vs controls) We demonstrate independent effects on risk of PBC for CLEC16A, SOCS1 and SPIB variants, while identifying functionally defective SIAE variants as potential factors in risk for PBC.

Publication types

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

MeSH terms

  • Acetylesterase / genetics*
  • Acetylesterase / metabolism
  • Alleles
  • Case-Control Studies
  • Chromosome Mapping / methods
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Enzyme Assays
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Haplotypes
  • Humans
  • Lectins, C-Type / genetics*
  • Lectins, C-Type / metabolism
  • Liver Cirrhosis, Biliary / genetics*
  • Liver Cirrhosis, Biliary / immunology
  • Liver Cirrhosis, Biliary / metabolism
  • Logistic Models
  • Monosaccharide Transport Proteins / genetics*
  • Monosaccharide Transport Proteins / metabolism
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins / genetics*
  • Suppressor of Cytokine Signaling Proteins / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism


  • CLEC16A protein, human
  • DNA-Binding Proteins
  • Lectins, C-Type
  • Monosaccharide Transport Proteins
  • SOCS1 protein, human
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Transcription Factors
  • SPIB protein, human
  • Acetylesterase
  • sialate O-acetylesterase