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Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus

Nature Genetics volume 40, pages 211–216 (2008)Cite this article

A Corrigendum to this article was published on 01 April 2008

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Abstract

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by production of autoantibodies and complex genetic inheritance1,2,3. In a genome-wide scan using 85,042 SNPs, we identified an association between SLE and a nonsynonymous substitution (rs10516487, R61H) in the B-cell scaffold protein with ankyrin repeats gene, BANK1. We replicated the association in four independent case-control sets (combined P = 3.7 × 10−10; OR = 1.38). We analyzed BANK1 cDNA and found two isoforms, one full-length and the other alternatively spliced and lacking exon 2 (Δ2), encoding a protein without a putative IP3R-binding domain. The transcripts were differentially expressed depending on a branch point–site SNP, rs17266594, in strong linkage disequilibrium (LD) with rs10516487. A third associated variant was found in the ankyrin domain (rs3733197, A383T). Our findings implicate BANK1 as a susceptibility gene for SLE, with variants affecting regulatory sites and key functional domains. The disease-associated variants could contribute to sustained B cell–receptor signaling and B-cell hyperactivity characteristic of this disease.

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Figure 1: Correlation of rs17266594 genotypes with differences in FL/Δ2 isoform ratio of BANK1.

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  • 27 March 2008

    In the version of this article initially published, the name of the 15th author was misspelled. The correct author name is Nadia Barizzone. Also, the affiliation of Javier Martin was incomplete. Dr. Martin is affiliated with Instituto de Biomedicina López-Neyra, Grenada 18100, Spain and Consejo Superior de Investigaciones Científicas (CSIC), Grenada 18100 Spain. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

The authors would like to express their gratitude to S. Lewén for help with purification of PBMCs and total RNA, H. Yin for help with the preparation of DNA samples and to the members of the Uppsala Genome Center for help with sequencing. We thank T. Bergström and L. Cavelier (Uppsala University) for providing RNA from chimpanzee spleen. We also thank A.I. Scollo, A.M. Perichon and M.C.R. Tenaglia (CEDIM, Diagnóstico Molecular y Forense SRL, Rosario, Argentina) for their help in DNA preparation of the Argentine samples and A. Voss for clinical help with the Danish samples. The authors would like to thank particularly the Lupus Patient Association of Asturias for their help in the collection of samples as well as all the patients for their contribution. The authors would also like to thank J.Osorio y Fortea (Pasteur Institut, Paris) for his contribution in the analyses that led to the identification of R61H early in this project.

This work has been supported in part by grants from the European CVDIMMUNE project from the European Commission LSHM-CT-2006-037227, Swedish Research Council for Medicine (12703), the Swedish Association against Rheumatism, the Magnus Bergwalls Foundation, the Gustaf V: 80th-year Jubilee Foundation, the Torsten and Ragnar Söderbergs Foundation and the Marcus Borsgtröms Foundation to M.E.A.-R. and by the Gurli and Edward Brunnbergs Foundation for rheumatologic research to S.V.K. M.E.A.-R. is supported by an award from the Knut and Alice Wallenberg Foundation through the Royal Swedish Academy of Sciences. This work was also partially supported by FISM, Regione Piemonte (CIPE), the Bundesministerium für Bildung und Forschung (BMBF) Kompetenznetz Rheuma C2.12, Germany and the Danish Rheumatism Association.

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Author notes

  1. Sergey V Kozyrev and Anna-Karin Abelson: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, 75185, Sweden

    Sergey V Kozyrev, Anna-Karin Abelson, Ammar Zaghlool, M V Prasad Linga Reddy & Marta E Alarcón-Riquelme

  2. Merck Serono, Chemin des Mines, Geneva, 12202, Switzerland

    Jerome Wojcik & Hadi Abderrahim

  3. Instituto de Biomedicina López-Neyra, Granada, 18100, Spain

    Elena Sanchez & Javier Martin

  4. Department of Medicine, Unit of Rheumatology, Karolinska University Hospital, Solna, 17176, Sweden

    Iva Gunnarsson & Elisabet Svenungsson

  5. Department of Rheumatology, University of Lund, Lund, 22200, Sweden

    Gunnar Sturfelt & Andreas Jönsen

  6. Department of Clinical Immunology and Microbiology, University of Lund, Lund, 22200, Sweden

    Lennart Truedsson

  7. Sanatorio Parque, Rosario, 2000, Argentina

    Bernardo A Pons-Estel

  8. Medical School Hannover, Hannover, 30625, Germany

    Torsten Witte

  9. Department of Medical Sciences and Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), University of Eastern Piedmont, Novara, 13100, Italy

    Sandra D'Alfonso & Nadia Barizzone

  10. Dipartimento di Scienze Mediche e Chirurgiche, Università Politecnica delle Marche, Ancona, 60121, Italy

    Maria Giovanna Danieli

  11. Department of Functional Biology, Hospital Universitario Central de Asturias, Universidad de Oviedo, Oviedo, 33006, Spain

    Carmen Gutierrez & Ana Suarez

  12. Department of Internal Medicine C, Section of Rheumatology, Odense University Hospital, Odense, 5000, Denmark

    Peter Junker & Helle Laustrup

  13. Departamento de Inmunología, Hospital Virgen del Rocío, Sevilla, 41013, Spain

    Maria Francisca González-Escribano

  14. Consejo Superior de Investigaciones Científicas (CSIC), Grenada , 18100, Spain

    Javier Martin

Authors
  1. Sergey V Kozyrev
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Contributions

M.E.A.-R., S.V.K. and H.A. designed the experiments. S.V.K., A.-K.A., J.W., A.Z., M.V.P.L.R. and E.S. performed the experiments. M.E.A.-R., S.V.K., A.-K.A., J.W. and H.A. performed the analyses. I.G., E.S., G.S., L.T., A.J., T.W., S.D., N.B., M.G.D., C.G., A.S., P.J., H.L., B.A.P.-E., M.F.G.-E. and J.M. and their multicenter collaborators provided the samples. M.E.A.-R., S.V.K. and A.-K.A. wrote the manuscript.

The Argentine Collaborative Group participants are:

Hugo R. Scherbarth, Pilar C. Marino and Estela L. Motta (Servicio de Reumatología, Hospital Interzonal General de Agudos 'Dr. Oscar Alende', Mar del Plata, Argentina), Susana Gamron, Cristina Drenkard and Emilia Menso (Servicio de Reumatología de la UHMI 1, Hospital Nacional de Clínicas, Universidad Nacional de Córdoba, Córdoba, Argentina), Alberto Allievi and Guillermo A. Tate (Organización Médica de Investigación, Buenos Aires, Argentina), Jose L. Presas (Hospital General de Agudos Dr. Juán A. Fernandez, Buenos Aires, Argentina), Simon A. Palatnik, Marcelo Abdala and Mariela Bearzotti (Facultad de Ciencias Medicas, Universidad Nacional de Rosario y Hospital Provincial del Centenario, Rosario, Argentina), Alejandro Alvarellos, Francisco Caeiro and Ana Bertoli (Servicio de Reumatología, Hospital Privado, Centro Medico de Córdoba, Córdoba, Argentina), Sergio Paira and Susana Roverano (Hospital José M. Cullen, Santa Fe, Argentina), Cesar E. Graf and Estela Bertero (Hospital San Martín, Paraná, Argentina), Cesar Caprarulo and Griselda Buchanan (Hospital Felipe Heras, Concordia, Entre Ríos, Argentina), Carolina Guillerón, Sebastian Grimaudo and Jorge Manni (Departamento de Inmunología, Instituto de Investigaciones Médicas 'Alfredo Lanari', Buenos Aires, Argentina), Luis J. Catoggio, Enrique R. Soriano and Carlos D. Santos (Sección Reumatología, Servicio de Clínica Medica, Hospital Italiano de Buenos Aires y Fundación Dr. Pedro M. Catoggio para el Progreso de la Reumatología, Buenos Aires, Argentina), Cristina Prigione, Fernando A. Ramos and Sandra M. Navarro (Servicio de Reumatología, Hospital Provincial de Rosario, Rosario, Argentina), Guillermo A. Berbotto, Marisa Jorfen and Elisa J. Romero (Servicio de Reumatología Hospital Escuela Eva Perón, Granadero Baigorria, Rosario, Argentina), Mercedes A. Garcia, Juan C. Marcos and Ana I. Marcos (Servicio de Reumatología, Hospital Interzonal General de Agudos General San Martín, La Plata, Buenos Aires, Argentina), Carlos E. Perandones and Alicia Eimon (Centro de Educación Médica e Investigaciones Clínicas (CEMIC), Buenos Aires, Argentina), and Cristina G. Battagliotti (Hospital de Niños Dr. Orlando Alassia, Santa Fe, Argentina). B.A.P.-E. is coordinator of the Argentine Collaborative Group.

The German Collaborative Group participants are:

K. Armadi-Simab and Wolfgang L. Gross (Abteilung Rheumatologie, University Hospital of Schleswig-Holstein, Campus Luebeck, Rheumaklinik Bad Bramstedt, Luebeck, Germany), Erika Gromnica-Ihle (Rheumaklinik Berlin-Buch, Berlin, Germany), Hans-Hartmut Peter (Medizinische Universitaetsklinik, Abteilung Rheumatologie und Klinische Immunologie, Freiburg, Germany), Karin Manger (Medizinische Klinik III derFAU Erlangen-Nuernberg, Erlangen, Germany), Sebastian Schnarr and Henning Zeidler (Abteilung Rheumatologie, Medizinische Hochschule Hannover, Hannover, Germany) and Reinhold E. Schmidt (Abteilung Klinische Immunologie, Medizinische Hochschule Hannover, Hannover, Germany).

The Spanish Collaborative Group participants are:

Norberto Ortego (Servicio Medicina Interna, Hospital Clínico San Cecilio, Granada, Spain), Enrique de Ramón (Servicio de Medicina Interna, Hospital Carlos Haya, Malaga, Spain), Juan Jiménez-Alonso (Servicio de Medicina Interna, Hospital Virgen de las Nieves, Granada, Spain), Julio Sánchez-Román (Servico de Medicina Interna, Hospital Virgen del Rocio, Sevilla, Spain) and Miguel Angel López-Nevot (Servicio de Inmunología, Hospital Virgen de las Nieves, Granada, Spain).

The Italian Collaborative participants are:

Gian Domenico Sebastiani (U.O.C. di Reumatologia Ospedale San Camillo, Roma, Italy), Enrica Bozzolo (IRCCS San Raffaele Hospital, Milan, Italy), Mauro Galeazzi (Siena University, Siena, Italy), Sergio Migliaresi (Rheumatology Unit Second University of Naples, Naples, Italy). Also we would like to thank Armando Gabrielli, Clinica Medica di Scienze Mediche e Chirurgiche, Universitá Politecnica delle Marche.

Corresponding author

Correspondence to Marta E Alarcón-Riquelme.

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Competing interests

Jerome Wojcik and Hadi Abderrahim are employees of Merck Serono Inc. Merck Serono Inc. performed and financed the 100K Affymetrix microarray SNP genotyping.

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Kozyrev, S., Abelson, AK., Wojcik, J. et al. Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. Nat Genet 40, 211–216 (2008). https://doi.org/10.1038/ng.79

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