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Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis

Nature Genetics volume 42, pages 655–657 (2010)Cite this article

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Abstract

We genotyped individuals with primary biliary cirrhosis and unaffected controls for suggestive risk loci (genome-wide association P < 1 × 10−4) identified in a previous genome-wide association study. Combined analysis of the genome-wide association and replication datasets identified IRF5-TNPO3 (combined P = 8.66 × 10−13), 17q12-21 (combined P = 3.50 × 10−13) and MMEL1 (combined P = 3.15 × 10−8) as new primary biliary cirrhosis susceptibility loci. Fine-mapping studies showed that a single variant accounts for the IRF5-TNPO3 association. As these loci are implicated in other autoimmune conditions, these findings confirm genetic overlap among such diseases.

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Figure 1: Association plots for the IRF5-TNPO3, 17q12-21 and MMEL1 loci.

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Acknowledgements

This research was supported by grants from the Canadian Institutes for Health Research (MOP 74621), the Ontario Research Fund (RE01-061), the Canadian Primary Biliary Cirrhosis Society, the Canadian Foundation for Innovation, the Ben and Hilda Katz Charitable Foundation, the US National Institutes of Health (K23 DK68290, RO3 DK78527 and RO1 DK80670), the American Gastroenterological Association and the A.J. and Sigismunda Palumbo Charitable Trust. K.A.S. is a recipient of a Canada Research Chair award. We thank all the study subjects and supporting physicians as well as the technical staff of the University Health Network Analytical Genetics Technology Centre for their assistance in this research.

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Authors and Affiliations

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

    Gideon M Hirschfield, Catalina Coltescu & E Jenny Heathcote

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

    Gideon M Hirschfield, Xiangdong Liu, Yan Lu, Chun Xu, Jinyi Zhang, E Jenny Heathcote & Katherine A Siminovitch

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

    Xiangdong Liu, Yan Lu, Chun Xu, Jinyi Zhang & Katherine A Siminovitch

  4. Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

    Younghun Han, Ivan P Gorlov, Yue Lu, Wei Chen & Christopher I Amos

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

    Brian D Juran & Konstantinos N Lazaridis

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

    Andrew L Mason

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

    Piotr Milkiewicz

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

    Robert P Myers

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

    Joseph A Odin

  10. Department of Gastroenterology, Virginia Commonwealth University, Richmond, Virginia, USA

    Velimir A Luketic

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

    Danute Speiciene

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

    Catherine Vincent

  13. Division of Gastroenterology, Department of Medicine, Hepatology and Nutrition, University of Florida, Gainesville, Florida, USA

    Cynthia Levy

  14. Feinstein Institute for Medical Research, North Shore Long Island Jewish Health System, Manhasset, New York, USA

    Peter K Gregersen

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

    Katherine A Siminovitch

Authors
  1. Gideon M Hirschfield
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  2. Xiangdong Liu
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  3. Younghun Han
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  4. Ivan P Gorlov
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  5. Yan Lu
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  7. Yue Lu
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  8. Wei Chen
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  9. Brian D Juran
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  10. Catalina Coltescu
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  11. Andrew L Mason
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  12. Piotr Milkiewicz
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  13. Robert P Myers
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  14. Joseph A Odin
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  15. Velimir A Luketic
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  16. Danute Speiciene
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  17. Catherine Vincent
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  18. Cynthia Levy
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  19. Peter K Gregersen
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  20. Jinyi Zhang
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  21. E Jenny Heathcote
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  22. Konstantinos N Lazaridis
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  23. Christopher I Amos
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  24. Katherine A Siminovitch
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Contributions

G.M.H., X.L., C.I.A. and K.A.S. designed the study. X.L., Y.H., I.P.G., Y.L., C.X., Y.L., W.C., J.Z. and C.I.A. performed the genotyping and data analysis. G.M.H., B.D.J., C.C., A.L.M., P.M., R.P.M., J.A.O., V.A.L., D.S., C.V., C.L., P.K.G., E.J.H., K.N.L. and K.A.S. developed the clinical network and sample collection and processing framework required for case and control accrual. G.M.H., C.I.A. and K.A.S. wrote the manuscript. G.M.H., X.L., C.I.A. and K.A.S. vouch for the data and its analysis. G.M.H., C.I.A. and K.A.S. (the senior and corresponding author) decided in agreement with all other authors to publish this paper.

Corresponding author

Correspondence to Katherine A Siminovitch.

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Competing interests

G.M.H. reports receiving lecture and consultancy fees from Axcan Pharma and A.L.M. received grant support from Novartis and Schering-Plough. J.H. reports receiving lecture fees and grant support from Axcan Pharma.

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Supplementary Figures 1 and 2, Supplementary Tables 1–6 and Supplementary Methods (PDF 1209 kb)

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Hirschfield, G., Liu, X., Han, Y. et al. Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis. Nat Genet 42, 655–657 (2010). https://doi.org/10.1038/ng.631

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