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Classical HLA-DRB1 and DPB1 alleles account for HLA associations with primary biliary cirrhosis

Genes & Immunity volume 13, pages 461–468 (2012)Cite this article

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Abstract

Susceptibility to primary biliary cirrhosis (PBC) is strongly associated with human leukocyte antigen (HLA)-region polymorphisms. To determine if associations can be explained by classical HLA determinants, we studied Italian, 676 cases and 1440 controls, genotyped with dense single-nucleotide polymorphisms (SNPs) for which classical HLA alleles and amino acids were imputed. Although previous genome-wide association studies and our results show stronger SNP associations near DQB1, we demonstrate that the HLA signals can be attributed to classical DRB1 and DPB1 genes. Strong support for the predominant role of DRB1 is provided by our conditional analyses. We also demonstrate an independent association of DPB1. Specific HLA-DRB1 genes (*08, *11 and *14) account for most of the DRB1 association signal. Consistent with previous studies, DRB1*08 (P=1.59 × 10−11) was the strongest predisposing allele, whereas DRB1*11 (P=1.42 × 10−10) was protective. Additionally, DRB1*14 and the DPB1 association (DPB1*03:01; P=9.18 × 10−7) were predisposing risk alleles. No signal was observed in the HLA class 1 or class 3 regions. These findings better define the association of PBC with HLA and specifically support the role of classical HLA-DRB1 and DPB1 genes and alleles in susceptibility to PBC.

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Acknowledgements

This study was supported by NIH grants: R01 DK056839, R01DK091823, and K08AR055688 and HYPERGENES (European Network for Genetic-Epidemiological Studies HEALTH-F4-2007-201550).

Author information

Author notes

  1. Italian PBC Genetics Study Group members are listed in the appendix.

Authors and Affiliations

  1. Department of Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, Davis, CA, USA

    P Invernizzi, M E Gershwin & M F Seldin

  2. Department of Medicine, Center for Autoimmune Liver Diseases, IRCCS Istituto Clinico Humanitas, Milan, Italy

    P Invernizzi, A Lleo & M Podda

  3. Department of Biochemistry and Molecular Medicine, University of California at Davis, Davis, CA, USA

    M Ransom, R Kosoy, R Shigeta & M F Seldin

  4. Department of Medicine, Divisions of Genetics and Rheumatology, Brigham and Women’s Hospital, Boston, MA, USA

    S Raychaudhuri & P I W de Bakker

  5. Partners HealthCare Center for Personalized Genetic Medicine, Boston, MA, USA

    S Raychaudhuri

  6. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA

    S Raychaudhuri & P I W de Bakker

  7. Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany

    A Franke

  8. Division of Gastroenterology, IRCCS-CSS Hospital, San Giovanni Rotondo, Italy

    F Bossa

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

    C I Amos

  10. The Robert S Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY, USA,

    P K Gregersen

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

    K A Siminovitch

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

    K A Siminovitch

  13. Department of Medicine, Surgery and Dentistry, Università degli Studi di Milano, Milan, Italy

    D Cusi

  14. Genomics and Bioinformatics Unit, Fondazione Filarete, Milan, Italy

    D Cusi

  15. Department of Medical Genetics, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands

    P I W de Bakker

Authors
  1. P Invernizzi
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  2. M Ransom
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  3. S Raychaudhuri
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  4. R Kosoy
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  5. A Lleo
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  7. A Franke
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  8. F Bossa
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The Italian PBC Genetics Study Group

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Correspondence to M F Seldin.

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Supplementary Information accompanies the paper on Genes and Immunity website

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AppendixThe Italian PBC Genetic Study Group

AppendixThe Italian PBC Genetic Study Group

Piero L. Almasio (Gastroenterology and Hepatology Unit, Di.Bi.M.I.S., University of Palermo, Palermo), Domenico Alvaro (Department of Medico-Surgical Sciences and Biotechnologies, Fondazione Eleonora Lorillard Spencer Cenci, University Sapienza of Rome, Rome), Pietro Andreone (Dipartimento di Medicina Clinica, Università di Bologna, Bologna), Angelo Andriulli (IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo), Cristina Barlassina (Department of Medicine, Surgery and Dentistry, Università degli Studi di Milano, Milan), Antonio Benedetti (Università Politecnica delle Marche, Ancona), Francesca Bernuzzi (Center for Autoimmune Liver Diseases, IRCCS Istituto Clinico Humanitas, Rozzano), Ilaria Bianchi (Center for Autoimmune Liver Diseases, IRCCS Istituto Clinico Humanitas, Rozzano), MariaConsiglia Bragazzi (Department of Medico-Surgical Sciences and Biotechnologies, Fondazione Eleonora Lorillard Spencer Cenci, University Sapienza of Rome, Rome), Maurizia Brunetto (Azienda Ospedaliera Universitaria Pisana, Pisa), Savino Bruno (Department of Internal Medicine, Ospedale Fatebene Fratelli e Oftalmico, Milan), Lisa Caliari (Center for Autoimmune Liver Diseases, IRCCS Istituto Clinico Humanitas, Rozzano), Giovanni Casella (Medical Department, Desio Hospital, Desio), Fabiola Civardi (Center for Autoimmune Liver Diseases, IRCCS Istituto Clinico Humanitas, Rozzano IRCCS Istituto Clinico Humanitas, Rozzano), Barbara Coco (Azienda Ospedaliera Universitaria Pisana, Pisa), Agostino Colli (Department of Internal Medicine, AO Provincia di Lecco, Lecco), Massimo Colombo (Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan), Silvia Colombo (Treviglio Hospital, Treviglio), Carmela Cursaro (Dipartimento di Medicina Clinica, Università di Bologna, Bologna), Lory Saveria Croce (University of Trieste and Fondazione Italiana Fegato (FIF), Trieste), Andrea Crosignani (San Paolo Hospital Medical School, Università di Milano, Milan), Francesca Donato (Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan), Luca Fabris (University of Padova, Padova), Carlo Ferrari (Azienda Ospedaliero-Universitaria di Parma, Parma), Annarosa Floreani (Dept. of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova), Andrea Galli (University of Florence, Florence), Ignazio Grattagliano (Italian College of General Practicioners, ASL Bari), Roberta Lazzari (Department of Surgical, Oncological and Gastroenterological SciencesUniversity of Padova, Padova), Fabio Macaluso (Gastroenterology & Hepatology Unit, Di.Bi.M.I.S., University of Palermo, Palermo), Fabio Marra (University of Florence, Florence), Marco Marzioni (Università Politecnica delle Marche, Ancona), Alberto Mattalia (Santa Croce Carle Hospital, Cuneo), Renzo Montanari (Ospedale di Negrar, Verona), Lorenzo Morini (Magenta Hospital, Magenta), Filomena Morisco (University of Naples, Federico II, Naples), Luca Moroni (Center for Autoimmune Liver Diseases, IRCCS Istituto Clinico Humanitas, Rozzano), Luigi Muratori (Department of Clinical Medicine, University of Bologna, Bologna), Paolo Muratori (Department of Clinical Medicine, University of Bologna, Bologna), Grazia Niro (IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo), Antonio Picciotto (University of Genoa, Genoa), Piero Portincasa (Department of Interdisciplinary Medicine, University Medical School, Bari), Daniele Prati (Ospedale Alessandro Manzoni, Lecco, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan), Cleofe Prisco (Ospedale Niguarda, Milan), Floriano Rosina (Division of Gastroenterology & Hepatology, Center for Predictive Medicine, Gradenigo Hospital, Turin), Sonia Rossi (Department of Internal Medicine, Ospedale Fatebene Fratelli e Oftalmico, Milan), Carlo Selmi (IRCCS Istituto Clinico Humanitas, Rozzano), Giancarlo Spinzi (Azienda Ospedaliera Valduce, Como), Mario Strazzabosco (Yale University, New Haven, Connecticut 06511, USA and University of Milan-Bicocca, Monza), Sonia Tarallo (Division of Gastroenterology and Hepatology, Center for Predictive Medicine, Gradenigo Hospital, Turin), Claudio Tiribelli (University of Trieste and Fondazione Italiana Fegato (FIF), Trieste), Pierluigi Toniutto (University of Udine, Udine), Maria Vinci (Ospedale Niguarda, Milan), Massimo Zuin (San Paolo Hospital Medical School, Università di Milano, Milan).

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Invernizzi, P., Ransom, M., Raychaudhuri, S. et al. Classical HLA-DRB1 and DPB1 alleles account for HLA associations with primary biliary cirrhosis. Genes Immun 13, 461–468 (2012). https://doi.org/10.1038/gene.2012.17

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