Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma

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 genomewide association study in the No...

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Main Authors: Swaminathan, Bhairavi, Thorleifsson, Gudmar, Jöud, Magnus, Ali, Mina, Johnsson, Ellinor, Ajore, Ram, Sulem, Patrick, Halvarsson, Britt-Marie, Eyjolfsson, Gudmundur I, Haraldsdottir, Vilhelmina, Hultman, Christina, Ingelsson, Erik, Kristinsson, Sigurdur Y, Kähler, Anna Katarina, Lenhoff, Stig, Masson, Gisli, Mellqvist, Ulf-Henrik, Månsson, Robert, Nelander, Sven, Olafsson, Isleifur, Sigurdardóttir, Olöf Gudrun, Steingrimsdottir, Hlif, Vangsted, Annette, Vogel, Ulla, Waage, Anders, Nahi, Hareth, Gudbjartsson, Daniel F, Rafnar, Thorunn, Turesson, Ingemar, Gullberg, Urban, Stefansson, Kari, Hansson, Markus, Thorsteinsdottir, Unnur, Nilsson, Björn
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Language:English
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Summary: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 genomewide association study in the Nordic region identifying a novel MM risk locus at ELL2 (rs56219066T; odds ratio (OR)=1.25; P=9.6 x10 -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=8.6x 10- 9 and P=6.4x 10- 3, respectively) and, potentially, with an increased risk of bacterial meningitis (OR=1.30; P=0.0024).