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Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma.

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Author

  • Bhairavi Swaminathan
  • Guðmar Thorleifsson
  • Magnus Jöud
  • Mina Ali
  • Ellinor Johnsson
  • Ram Ajore
  • Patrick Sulem
  • Britt-Marie Halvarsson
  • Guðmundur Eyjolfsson
  • Vilhelmina Haraldsdottir
  • Christina Hultman
  • Erik Ingelsson
  • Sigurður Y Kristinsson
  • Anna K Kähler
  • Stig Lenhoff
  • Gisli Masson
  • Ulf-Henrik Mellqvist
  • Robert Månsson
  • Sven Nelander
  • Isleifur Olafsson
  • Olof Sigurðardottir
  • Hlif Steingrimsdóttir
  • Annette Vangsted
  • Ulla Vogel
  • Anders Waage
  • Hareth Nahi
  • Daniel F Gudbjartsson
  • Thorunn Rafnar
  • Ingemar Turesson
  • Urban Gullberg
  • Kári Stefánsson
  • Markus Hansson
  • Unnur Thorsteinsdóttir
  • Björn Nilsson
Show all

Summary, in English

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).

Department/s

Publishing year

2015

Language

English

Pages

1-8

Publication/Series

Nature Communications

Volume

6

Document type

Journal article

Publisher

Nature Publishing Group

Topic

  • Hematology

Status

Published

Project

  • Genetic predisposition for multiple myeloma

Research group

  • Hematogenomics
  • Myeloma research group

ISBN/ISSN/Other

  • ISSN: 2041-1723