Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma
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
Journal article, Peer reviewed
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Original versionNature Communications 2015, 6 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 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).