title: Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma.
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).
authors.affiliation: Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, BMC B13, SE-221 84 Lund, Sweden.
authors.forename: Bhairavi
authors.initials: B
authors.lastname: Swaminathan
authors.affiliation: deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
authors.forename: Guðmar
authors.initials: G
authors.lastname: Thorleifsson
authors.affiliation: 1] Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, BMC B13, SE-221 84 Lund, Sweden [2] Clinical Immunology and Transfusion Medicine, Laboratory Medicine, Office of Medical Services, Akutgatan 8, SE-221 85 Lund, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Jöud
authors.affiliation: Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, BMC B13, SE-221 84 Lund, Sweden.
authors.forename: Mina
authors.initials: M
authors.lastname: Ali
authors.affiliation: Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, BMC B13, SE-221 84 Lund, Sweden.
authors.forename: Ellinor
authors.initials: E
authors.lastname: Johnsson
authors.affiliation: Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, BMC B13, SE-221 84 Lund, Sweden.
authors.forename: Ram
authors.initials: R
authors.lastname: Ajore
authors.affiliation: deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
authors.forename: Patrick
authors.identifier: 0000000171236123
authors.initials: P
authors.lastname: Sulem
authors.affiliation: Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, BMC B13, SE-221 84 Lund, Sweden.
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Halvarsson
authors.affiliation: The Laboratory in Mjodd, IS-109 Reykjavik, Iceland.
authors.forename: Guðmundur
authors.initials: G
authors.lastname: Eyjolfsson
authors.affiliation: Department of Hematology, Landspitali, The National University Hospital of Iceland, IS-101 Reykjavik, Iceland.
authors.forename: Vilhelmina
authors.initials: V
authors.lastname: Haraldsdottir
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Christina
authors.initials: C
authors.lastname: Hultman
authors.affiliation: Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Ingelsson
authors.affiliation: Faculty of Medicine, University of Iceland, IS-101 Reykjavik, Iceland.
authors.forename: Sigurður Y
authors.initials: SY
authors.lastname: Kristinsson
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Anna K
authors.initials: AK
authors.lastname: Kähler
authors.affiliation: Hematology Clinic, Skåne University Hospital, SE-221 85 Lund, Sweden.
authors.forename: Stig
authors.initials: S
authors.lastname: Lenhoff
authors.affiliation: deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
authors.forename: Gisli
authors.initials: G
authors.lastname: Masson
authors.affiliation: Section of Hematology, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden.
authors.forename: Ulf-Henrik
authors.initials: UH
authors.lastname: Mellqvist
authors.affiliation: Center for Hematology and Regenerative Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Robert
authors.initials: R
authors.lastname: Månsson
authors.affiliation: Department of Immunology, Pathology and Genetics, Uppsala University, Rudbeck Laboratory, SE-751 05 Uppsala, Sweden.
authors.forename: Sven
authors.initials: S
authors.lastname: Nelander
authors.affiliation: Department of Clinical Biochemistry, Landspitali, The National University Hospital of Iceland, IS-101 Reykjavik, Iceland.
authors.forename: Isleifur
authors.initials: I
authors.lastname: Olafsson
authors.affiliation: Department of Clinical Biochemistry, Akureyri Hospital, IS-600 Akureyri, Iceland.
authors.forename: Olof
authors.initials: O
authors.lastname: Sigurðardottir
authors.affiliation: Department of Hematology, Landspitali, The National University Hospital of Iceland, IS-101 Reykjavik, Iceland.
authors.forename: Hlif
authors.initials: H
authors.lastname: Steingrimsdóttir
authors.affiliation: Department of Haematology, University Hospital of Copenhagen at Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
authors.forename: Annette
authors.initials: A
authors.lastname: Vangsted
authors.affiliation: National Research Centre for the Working Environment, Lersø Parkallé 105, DK-2100 Copenhagen, Denmark.
authors.forename: Ulla
authors.initials: U
authors.lastname: Vogel
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Box 8905, N-7491 Trondheim, Norway.
authors.forename: Anders
authors.initials: A
authors.lastname: Waage
authors.affiliation: Center for Hematology and Regenerative Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Hareth
authors.initials: H
authors.lastname: Nahi
authors.affiliation: deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Gudbjartsson
authors.affiliation: deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
authors.forename: Thorunn
authors.initials: T
authors.lastname: Rafnar
authors.affiliation: Hematology Clinic, Skåne University Hospital, SE-221 85 Lund, Sweden.
authors.forename: Ingemar
authors.initials: I
authors.lastname: Turesson
authors.affiliation: Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, BMC B13, SE-221 84 Lund, Sweden.
authors.forename: Urban
authors.initials: U
authors.lastname: Gullberg
authors.affiliation: deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
authors.forename: Kári
authors.initials: K
authors.lastname: Stefánsson
authors.affiliation: 1] Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, BMC B13, SE-221 84 Lund, Sweden [2] Hematology Clinic, Skåne University Hospital, SE-221 85 Lund, Sweden.
authors.forename: Markus
authors.identifier: 0000000277154548
authors.initials: M
authors.lastname: Hansson
authors.affiliation: deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdóttir
authors.affiliation: 1] Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, BMC B13, SE-221 84 Lund, Sweden [2] Clinical Immunology and Transfusion Medicine, Laboratory Medicine, Office of Medical Services, Akutgatan 8, SE-221 85 Lund, Sweden [3] Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
authors.forename: Björn
authors.initials: B
authors.lastname: Nilsson
mesh_terms: D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood*; D007074:Immunoglobulin G / Q000097:blood*; D047908:Intracellular Signaling Peptides and Proteins; D016920:Meningitis, Bacterial / Q000235:genetics; D009101:Multiple Myeloma / Q000235:genetics*; D011506:Proteins / Q000235:genetics*; D035602:Transcriptional Elongation Factors / Q000235:genetics*
chemical_list: C447613:ELL2 protein, human; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C120296:TOM1 protein, human; D035602:Transcriptional Elongation Factors