Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma

By Bhairavi Swaminathan, G. Thorleifsson, Magnus Jöud, Mina Ali, E. Johnsson, Ram Ajore, P. Sulem, Britta Halvarsson, G. Eyjolfsson, V. Haraldsdóttir and 24 more. Nature Communications, 2015

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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.

Subfields: Cell Biology, Hematology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/676590c01a12bae9892cebc9d135bc0d2c07b285