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Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma.
Swaminathan, Bhairavi; Thorleifsson, Guðmar; Jöud, Magnus; Ali, Mina; Johnsson, Ellinor; Ajore, Ram; Sulem, Patrick; Halvarsson, Britt-Marie; Eyjolfsson, Guðmundur; Haraldsdottir, Vilhelmina; Hultman, Christina; Ingelsson, Erik; Kristinsson, Sigurður Y; Kähler, Anna K; Lenhoff, Stig; Masson, Gisli; Mellqvist, Ulf-Henrik; Månsson, Robert; Nelander, Sven; Olafsson, Isleifur; Sigurðardottir, Olof; Steingrimsdóttir, Hlif; Vangsted, Annette; Vogel, Ulla; Waage, Anders; Nahi, Hareth; Gudbjartsson, Daniel F; Rafnar, Thorunn; Turesson, Ingemar; Gullberg, Urban; Stefánsson, Kári; Hansson, Markus; Thorsteinsdóttir, Unnur; Nilsson, Björn.
Afiliación
  • Swaminathan B; Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, BMC B13, SE-221 84 Lund, Sweden.
  • Thorleifsson G; deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
  • Jöud M; 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.
  • Ali M; Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, BMC B13, SE-221 84 Lund, Sweden.
  • Johnsson E; Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, BMC B13, SE-221 84 Lund, Sweden.
  • Ajore R; Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, BMC B13, SE-221 84 Lund, Sweden.
  • Sulem P; deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
  • Halvarsson BM; Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, BMC B13, SE-221 84 Lund, Sweden.
  • Eyjolfsson G; The Laboratory in Mjodd, IS-109 Reykjavik, Iceland.
  • Haraldsdottir V; Department of Hematology, Landspitali, The National University Hospital of Iceland, IS-101 Reykjavik, Iceland.
  • Hultman C; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
  • Ingelsson E; Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.
  • Kristinsson SY; Faculty of Medicine, University of Iceland, IS-101 Reykjavik, Iceland.
  • Kähler AK; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
  • Lenhoff S; Hematology Clinic, Skåne University Hospital, SE-221 85 Lund, Sweden.
  • Masson G; deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
  • Mellqvist UH; Section of Hematology, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden.
  • Månsson R; Center for Hematology and Regenerative Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
  • Nelander S; Department of Immunology, Pathology and Genetics, Uppsala University, Rudbeck Laboratory, SE-751 05 Uppsala, Sweden.
  • Olafsson I; Department of Clinical Biochemistry, Landspitali, The National University Hospital of Iceland, IS-101 Reykjavik, Iceland.
  • Sigurðardottir O; Department of Clinical Biochemistry, Akureyri Hospital, IS-600 Akureyri, Iceland.
  • Steingrimsdóttir H; Department of Hematology, Landspitali, The National University Hospital of Iceland, IS-101 Reykjavik, Iceland.
  • Vangsted A; Department of Haematology, University Hospital of Copenhagen at Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
  • Vogel U; National Research Centre for the Working Environment, Lersø Parkallé 105, DK-2100 Copenhagen, Denmark.
  • Waage A; Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Box 8905, N-7491 Trondheim, Norway.
  • Nahi H; Center for Hematology and Regenerative Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
  • Gudbjartsson DF; deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
  • Rafnar T; deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
  • Turesson I; Hematology Clinic, Skåne University Hospital, SE-221 85 Lund, Sweden.
  • Gullberg U; Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, BMC B13, SE-221 84 Lund, Sweden.
  • Stefánsson K; deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
  • Hansson M; 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.
  • Thorsteinsdóttir U; deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.
  • Nilsson B; 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,
Nat Commun ; 6: 7213, 2015 May 26.
Article en En | MEDLINE | ID: mdl-26007630
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).
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Contexto en salud: 3_ND / 4_TD Problema de salud: 3_zoonosis / 4_meningitis Asunto principal: Inmunoglobulina A / Inmunoglobulina G / Proteínas / Factores de Elongación Transcripcional / Mieloma Múltiple Tipo de estudio: Clinical_trials / Prognostic_studies / Risk_factors_studies / Systematic_reviews Límite: Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2015 Tipo del documento: Article País de afiliación: Suecia
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Contexto en salud: 3_ND / 4_TD Problema de salud: 3_zoonosis / 4_meningitis Asunto principal: Inmunoglobulina A / Inmunoglobulina G / Proteínas / Factores de Elongación Transcripcional / Mieloma Múltiple Tipo de estudio: Clinical_trials / Prognostic_studies / Risk_factors_studies / Systematic_reviews Límite: Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2015 Tipo del documento: Article País de afiliación: Suecia