Swaminathan B, Thorleifsson G, Jöud M, Ali M, Johnsson E, Ajore R, Sulem P, Halvarsson BM, Eyjolfsson G, Haraldsdottir V, Hultman C, Ingelsson E, Kristinsson SY, Kähler AK, Lenhoff S, Masson G, Mellqvist UH, Månsson R, Nelander S, Olafsson I, Sigurðardottir O, Steingrimsdóttir H, Vangsted A, Vogel U, Waage A, Nahi H, Gudbjartsson DF, Rafnar T, Turesson I, Gullberg U, Stefánsson K, Hansson M, Thorsteinsdóttir U, Nilsson B
Nat Commun 6 (-) 7213 [2015-05-26; online 2015-05-26]
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).
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