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Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma

Author

Listed:
  • Bhairavi Swaminathan

    (Hematology and Transfusion Medicine, Lund University)

  • Guðmar Thorleifsson

    (deCODE genetics, Sturlugata 8)

  • Magnus Jöud

    (Hematology and Transfusion Medicine, Lund University
    Clinical Immunology and Transfusion Medicine, Laboratory Medicine, Office of Medical Services)

  • Mina Ali

    (Hematology and Transfusion Medicine, Lund University)

  • Ellinor Johnsson

    (Hematology and Transfusion Medicine, Lund University)

  • Ram Ajore

    (Hematology and Transfusion Medicine, Lund University)

  • Patrick Sulem

    (deCODE genetics, Sturlugata 8)

  • Britt-Marie Halvarsson

    (Hematology and Transfusion Medicine, Lund University)

  • Guðmundur Eyjolfsson

    (The Laboratory in Mjodd)

  • Vilhelmina Haraldsdottir

    (Landspitali, The National University Hospital of Iceland)

  • Christina Hultman

    (Karolinska Institutet)

  • Erik Ingelsson

    (Molecular Epidemiology and Science for Life Laboratory, Uppsala University)

  • Sigurður Y. Kristinsson

    (Faculty of Medicine, University of Iceland)

  • Anna K. Kähler

    (Karolinska Institutet)

  • Stig Lenhoff

    (Hematology Clinic, Skåne University Hospital)

  • Gisli Masson

    (deCODE genetics, Sturlugata 8)

  • Ulf-Henrik Mellqvist

    (Section of Hematology, Sahlgrenska University Hospital)

  • Robert Månsson

    (Center for Hematology and Regenerative Medicine, Karolinska Institutet)

  • Sven Nelander

    (Pathology and Genetics, Uppsala University, Rudbeck Laboratory)

  • Isleifur Olafsson

    (Landspitali, The National University Hospital of Iceland)

  • Olof Sigurðardottir

    (Akureyri Hospital)

  • Hlif Steingrimsdóttir

    (Landspitali, The National University Hospital of Iceland)

  • Annette Vangsted

    (University Hospital of Copenhagen at Rigshospitalet)

  • Ulla Vogel

    (National Research Centre for the Working Environment, Lersø Parkallé 105)

  • Anders Waage

    (Norwegian University of Science and Technology)

  • Hareth Nahi

    (Center for Hematology and Regenerative Medicine, Karolinska Institutet)

  • Daniel F. Gudbjartsson

    (deCODE genetics, Sturlugata 8)

  • Thorunn Rafnar

    (deCODE genetics, Sturlugata 8)

  • Ingemar Turesson

    (Hematology Clinic, Skåne University Hospital)

  • Urban Gullberg

    (Hematology and Transfusion Medicine, Lund University)

  • Kári Stefánsson

    (deCODE genetics, Sturlugata 8)

  • Markus Hansson

    (Hematology and Transfusion Medicine, Lund University
    Hematology Clinic, Skåne University Hospital)

  • Unnur Thorsteinsdóttir

    (deCODE genetics, Sturlugata 8)

  • Björn Nilsson

    (Hematology and Transfusion Medicine, Lund University
    Clinical Immunology and Transfusion Medicine, Laboratory Medicine, Office of Medical Services
    Broad Institute, 7 Cambridge Center)

Abstract

Multiple myeloma (MM) is characterized by an uninhibited, clonal growth of plasma cells. While first-degree relatives of patients with MM show an increased risk of MM, the genetic basis of inherited MM susceptibility is incompletely understood. Here we report a genome-wide association study in the Nordic region identifying a novel MM risk locus at ELL2 (rs56219066T; odds ratio (OR)=1.25; P=9.6 × 10−10). This gene encodes a stoichiometrically limiting component of the super-elongation complex that drives secretory-specific immunoglobulin mRNA production and transcriptional regulation in plasma cells. We find that the MM risk allele harbours a Thr298Ala missense variant in an ELL2 domain required for transcription elongation. Consistent with a hypomorphic effect, we find that the MM risk allele also associates with reduced levels of immunoglobulin A (IgA) and G (IgG) in healthy subjects (P=8.6 × 10−9 and P=6.4 × 10−3, respectively) and, potentially, with an increased risk of bacterial meningitis (OR=1.30; P=0.0024).

Suggested Citation

  • Bhairavi Swaminathan & Guðmar Thorleifsson & Magnus Jöud & Mina Ali & Ellinor Johnsson & Ram Ajore & Patrick Sulem & Britt-Marie Halvarsson & Guðmundur Eyjolfsson & Vilhelmina Haraldsdottir & Christin, 2015. "Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma," Nature Communications, Nature, vol. 6(1), pages 1-8, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8213
    DOI: 10.1038/ncomms8213
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    Cited by:

    1. Molly Went & Laura Duran-Lozano & Gisli H. Halldorsson & Andrea Gunnell & Nerea Ugidos-Damboriena & Philip Law & Ludvig Ekdahl & Amit Sud & Gudmar Thorleifsson & Malte Thodberg & Thorunn Olafsdottir &, 2024. "Deciphering the genetics and mechanisms of predisposition to multiple myeloma," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Lili Liu & Atlas Khan & Elena Sanchez-Rodriguez & Francesca Zanoni & Yifu Li & Nicholas Steers & Olivia Balderes & Junying Zhang & Priya Krithivasan & Robert A. LeDesma & Clara Fischman & Scott J. Heb, 2022. "Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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