Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma

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 () and Björn Nilsson ()
Additional contact information
Bhairavi Swaminathan: Hematology and Transfusion Medicine, Lund University
Guðmar Thorleifsson: deCODE genetics, Sturlugata 8
Magnus Jöud: Hematology and Transfusion Medicine, Lund University
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
Unnur Thorsteinsdóttir: deCODE genetics, Sturlugata 8
Björn Nilsson: Hematology and Transfusion Medicine, Lund University

Nature Communications, 2015, vol. 6, issue 1, 1-8

Abstract: 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).

Date: 2015
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DOI: 10.1038/ncomms8213

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