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Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma

2015; Nature Portfolio; Volume: 6; Issue: 1 Linguagem: Inglês

10.1038/ncomms8213

2041-1723

Bhairavi Swaminathan, Guðmar Þorleifsson, Magnus Jöud, Mina Ali, Ellinor Johnsson, Ram Ajore, Patrick Sulem, Britt-Marie Halvarsson, Guðmundur I. Eyjólfsson, Vilhelmína Haraldsdóttir, Christina M. Hultman, Erik Ingelsson, Sigurður Y. Kristinsson, Anna K. Kähler, Stig Lenhoff, Gísli Másson, Ulf‐Henrik Mellqvist, Robert Månsson, Sven Nelander, Ísleifur Ólafsson, Ólöf Sigurðardóttir, Hlíf Steingrímsdóttir, Annette Juul Vangsted, Ulla Vogel, Anders Waage, Hareth Nahi, Daníel F. Guðbjartsson, Þórunn Rafnar, Ingemar Turesson, Urban Gullberg, Kári Stéfansson, Markus Hansson, Unnur Þorsteinsdóttir, Björn Nilsson,

Peptidase Inhibition and Analysis

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).