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

Genes & Immunity volume 13, pages 328–335 (2012)Cite this article

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Abstract

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.

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Acknowledgements

This work was supported by grants from the Canadian Institutes for Health Research (MOP74621), the Ontario Research Fund (RE01-061) and the Canadian Primary Biliary Cirrhosis Society (GMH and KAS), the US National Institutes of Health (RO1 DK80670), the American Gastroenterological Association and the AJ and Sigismunda Palumbo Charitable Trust (KNL) and Alliance for Lupus Research, the Center for the Study of Inflammatory Bowel Disease at MGH and the NIH (AI 064930, AI 076505 and AR 058481) to SP KAS holds the Sherman Family Chair in Genomic Medicine and a Canada Research Chair award. We thank the NHLBI GO Exome Sequencing Project and its ongoing studies, which produced and provided exome variant calls for comparison: the Lung GO Sequencing Project (HL-102923), the WHI Sequencing Project (HL-102924), the Broad GO Sequencing Project (HL-102925), the Seattle GO Sequencing Project (HL-102926) and the Heart GO Sequencing Project (HL-103010).

Author contributions: GMH, GX and KAS designed the study. GX, EL, YS, VC, SP and CIA performed the genotyping, variant expression/functional analysis and data analysis. GMH, BDJ, CC, ALM, PM, RPM, JAO, VAL, BB, HB, VL, CV, CL, KNL and KAS developed the clinical network and sample collection and processing framework required for case and control accrual. GMH, GX and KAS wrote the manuscript. GMH, GX, SP, CIA and KAS vouch for the data and its analysis/interpretation. GMH and KAS decided in agreement with all other authors to publish this paper.

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Authors and Affiliations

  1. Liver Centre, Toronto Western Hospital, Toronto, Ontario, Canada

    G M Hirschfield & C Coltescu

  2. Department of Medicine, University of Toronto, Toronto, Ontario, Canada

    G M Hirschfield & K A Siminovitch

  3. Mount Sinai Hospital, Samuel Lunenfeld Research Institute and Toronto General Research Institute, Toronto, Ontario, Canada

    G Xie, Y Sun & K A Siminovitch

  4. Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    E Lu & C I Amos

  5. Division of Gastroenterology and Hepatology, Center for Basic Research in Digestive Diseases, Mayo Clinic College of Medicine, Rochester, MN, USA

    B D Juran & K N Lazaridis

  6. Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    V Chellappa & S Pillai

  7. Department of Medicine, University of Alberta, Edmonton, Alberta, Canada

    A L Mason

  8. Liver Unit, Pomeranian Medical School, Szczecin, Poland

    P Milkiewicz

  9. Liver Unit, University of Calgary, Calgary, Alberta, Canada

    R P Myers

  10. Division of Liver Diseases, Mount Sinai School of Medicine, New York, NY, USA

    J A Odin

  11. Department of Gastroenterology, Virginia Commonwealth University, Richmond, VA, USA

    V A Luketic

  12. Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St Louis, MO, USA

    B Bacon

  13. Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA

    H Bodenheimer

  14. Centre of Gastroenterology and Dietetics, Vilnius University, Vilnius, Lithuania

    V Liakina

  15. Université de Montréal Hospital Centre, Saint-Luc Hospital, Montréal, Quebec, Canada

    C Vincent

  16. Center for Liver Diseases Division of Hepatology, University of Miami School of Medicine, Miami, FL, USA

    C Levy

  17. Departments of Immunology and Molecular Genetics, University of Toronto, Ontario, Canada

    K A Siminovitch

Authors
  1. G M Hirschfield
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  2. G Xie
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  3. E Lu
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  4. Y Sun
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  5. B D Juran
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  6. V Chellappa
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  7. C Coltescu
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  8. A L Mason
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  9. P Milkiewicz
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  10. R P Myers
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  11. J A Odin
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  12. V A Luketic
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  13. B Bacon
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  14. H Bodenheimer
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  15. V Liakina
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  16. C Vincent
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  17. C Levy
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  18. S Pillai
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  19. K N Lazaridis
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  20. C I Amos
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  21. K A Siminovitch
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Corresponding author

Correspondence to K A Siminovitch.

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Hirschfield, G., Xie, G., Lu, E. et al. Association of primary biliary cirrhosis with variants in the CLEC16A, SOCS1, SPIB and SIAE immunomodulatory genes. Genes Immun 13, 328–335 (2012). https://doi.org/10.1038/gene.2011.89

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  • DOI: https://doi.org/10.1038/gene.2011.89

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