Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma

• Published in: Nature communications Vol. 6; no. 1; p. 7213
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26.05.2015; Nature Publishing Group; Nature Pub. Group
• Subjects: 631/208/205/2138; 631/208/457; 692/699/67/1990/804; Clinical Medicine; Genetic Predisposition to Disease; Genome-Wide Association Study; Hematologi; Hematology; Humanities and Social Sciences; Humans; Immunoglobulin A - blood; Immunoglobulin G - blood; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap; Meningitis, Bacterial - genetics; multidisciplinary; Multiple myeloma; Multiple Myeloma - genetics; Proteins - genetics; Science; Science (multidisciplinary); Transcriptional Elongation Factors - genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms8213

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). Multiple myeloma is an incurable and fatal disease characterized by uninhibited growth of plasma cells in the bone marrow. Here, Swaminathan et al. conduct a genome-wide association study and identify a novel risk locus at ELL2 , which encodes a key component of the super-elongation complex.