Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma

Bhairavi Swaminathan; Gudmar Thorleifsson; Magnus Jöud; Mina Ali; Ellinor Johnsson; Ram Ajore; Patrick Sulem; Britt Marie Halvarsson; Gudmundur Eyjolfsson; Vilhelmina Haraldsdottir; Christina Hultman; Erik Ingelsson; Sigurdur Y. Kristinsson; Anna K. Kähler; Stig Lenhoff; Gisli Masson; Ulf Henrik Mellqvist; Robert Månsson; Sven Nelander; Isleifur Olafsson; Olof Sigurdardottir; Hlif Steingrimsdóttir; Annette Vangsted; Ulla Vogel; Anders Waage; Hareth Nahi; Daniel F. Gudbjartsson; Thorunn Rafnar; Ingemar Turesson; Urban Gullberg; Kári Stefánsson; Markus Hansson; Unnur Thorsteinsdóttir; Björn Nilsson

doi:10.1038/ncomms8213

Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma

Bhairavi Swaminathan, Gudmar Thorleifsson, Magnus Jöud, Mina Ali, Ellinor Johnsson, Ram Ajore, Patrick Sulem, Britt Marie Halvarsson, Gudmundur Eyjolfsson, Vilhelmina Haraldsdottir, Christina Hultman, Erik Ingelsson, Sigurdur Y. Kristinsson, Anna K. Kähler, Stig Lenhoff, Gisli Masson, Ulf Henrik Mellqvist, Robert Månsson, Sven Nelander, Isleifur OlafssonOlof Sigurdardottir, Hlif Steingrimsdóttir, Annette Vangsted, Ulla Vogel, Anders Waage, Hareth Nahi, Daniel F. Gudbjartsson, Thorunn Rafnar, Ingemar Turesson, Urban Gullberg, Kári Stefánsson, Markus Hansson, Unnur Thorsteinsdóttir^*, Björn Nilsson

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

45 Citations (Scopus)

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=9.6×10^-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).

Original language	English
Article number	7213
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8213
Publication status	Published - 26 May 2015

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Swaminathan, B., Thorleifsson, G., Jöud, M., Ali, M., Johnsson, E., Ajore, R., Sulem, P., Halvarsson, B. M., Eyjolfsson, G., Haraldsdottir, V., Hultman, C., Ingelsson, E., Kristinsson, S. Y., Kähler, A. K., Lenhoff, S., Masson, G., Mellqvist, U. H., Månsson, R., Nelander, S., ... Nilsson, B. (2015). Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma. Nature Communications, 6, [7213]. https://doi.org/10.1038/ncomms8213

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title = "Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma",

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=9.6×10-10). 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).",

author = "Bhairavi Swaminathan and Gudmar Thorleifsson and Magnus J{\"o}ud and Mina Ali and Ellinor Johnsson and Ram Ajore and Patrick Sulem and Halvarsson, {Britt Marie} and Gudmundur Eyjolfsson and Vilhelmina Haraldsdottir and Christina Hultman and Erik Ingelsson and Kristinsson, {Sigurdur Y.} and K{\"a}hler, {Anna K.} and Stig Lenhoff and Gisli Masson and Mellqvist, {Ulf Henrik} and Robert M{\aa}nsson and Sven Nelander and Isleifur Olafsson and Olof Sigurdardottir and Hlif Steingrimsd{\'o}ttir and Annette Vangsted and Ulla Vogel and Anders Waage and Hareth Nahi and Gudbjartsson, {Daniel F.} and Thorunn Rafnar and Ingemar Turesson and Urban Gullberg and K{\'a}ri Stef{\'a}nsson and Markus Hansson and Unnur Thorsteinsd{\'o}ttir and Bj{\"o}rn Nilsson",

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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, Sigurdardottir, 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 2015, 'Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma', Nature Communications, vol. 6, 7213. https://doi.org/10.1038/ncomms8213

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T1 - Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma

AU - Swaminathan, Bhairavi

AU - Thorleifsson, Gudmar

AU - Jöud, Magnus

AU - Ali, Mina

AU - Johnsson, Ellinor

AU - Ajore, Ram

AU - Sulem, Patrick

AU - Halvarsson, Britt Marie

AU - Eyjolfsson, Gudmundur

AU - Haraldsdottir, Vilhelmina

AU - Hultman, Christina

AU - Ingelsson, Erik

AU - Kristinsson, Sigurdur Y.

AU - Kähler, Anna K.

AU - Lenhoff, Stig

AU - Masson, Gisli

AU - Mellqvist, Ulf Henrik

AU - Månsson, Robert

AU - Nelander, Sven

AU - Olafsson, Isleifur

AU - Sigurdardottir, Olof

AU - Steingrimsdóttir, Hlif

AU - Vangsted, Annette

AU - Vogel, Ulla

AU - Waage, Anders

AU - Nahi, Hareth

AU - Gudbjartsson, Daniel F.

AU - Rafnar, Thorunn

AU - Turesson, Ingemar

AU - Gullberg, Urban

AU - Stefánsson, Kári

AU - Hansson, Markus

AU - Thorsteinsdóttir, Unnur

AU - Nilsson, Björn

PY - 2015/5/26

Y1 - 2015/5/26

N2 - 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=9.6×10-10). 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).

AB - 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=9.6×10-10). 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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U2 - 10.1038/ncomms8213

DO - 10.1038/ncomms8213

M3 - Article

C2 - 26007630

AN - SCOPUS:84930226491

SN - 2041-1723

VL - 6

JO - Nature Communications

JF - Nature Communications

M1 - 7213

ER -

Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma

Abstract

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