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Nature Research, Nature Communications, 1(6), 2015

DOI: 10.1038/ncomms8213

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Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma

This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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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 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). ; (c)2015 Macmillan Publishers Limited. All rights reserved. Creative Commons Attribution License 4.0.