Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma.

Bhairavi Swaminathan; Guðmar Thorleifsson; Magnus Jöud; Mina Ali; Ellinor Johnsson; Ram Ajore; Patrick Sulem; Britt-Marie Halvarsson; Guðmundur Eyjolfsson; Vilhelmina Haraldsdottir; Christina Hultman; Erik Ingelsson; Sigurður Y Kristinsson; Anna K Kähler; Stig Lenhoff; Gisli Masson; Ulf-Henrik Mellqvist; Robert Månsson; Sven Nelander; Isleifur Olafsson; Olof Sigurðardottir; 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, Guðmar Thorleifsson, Magnus Jöud, Mina Ali, Ellinor Johnsson, Ram Ajore, Patrick Sulem, Britt-Marie Halvarsson, Guðmundur Eyjolfsson, Vilhelmina Haraldsdottir, Christina Hultman, Erik Ingelsson, Sigurður Y Kristinsson, Anna K Kähler, Stig Lenhoff, Gisli Masson, Ulf-Henrik Mellqvist, Robert Månsson, Sven Nelander, Isleifur OlafssonOlof Sigurðardottir, 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

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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 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).

Original language	English
Article number	7213
Pages (from-to)	1-8
Journal	Nature Communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms8213
Publication status	Published - 2015

Subject classification (UKÄ)

Hematology

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10.1038/ncomms8213Licence: CC BY

NPG_Swaminathan_et_al

http://www.ncbi.nlm.nih.gov/pubmed/26007630?dopt=Abstract

2 Doctoral Thesis (compilation)

Genetic Predisposition to Sporadic and Familial Multiple Myeloma
Halvarsson, B-M., 2022, Lund: Lund University, Faculty of Medicine. 99 p.
Research output: Thesis › Doctoral Thesis (compilation)

Open Access
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Identification and characterization of DNA sequence variants associated with multiple myeloma
Ali, M., 2018, Lund: Lund University: Faculty of Medicine. 49 p.
Research output: Thesis › Doctoral Thesis (compilation)

1 Active

Genetic predisposition for multiple myeloma
Nilsson, B., Pertesi, M., Ajore, R., Wihlborg, A., Duran Lozano, L., Cafaro, C., Johnsson, E., Hansson, M., Halvarsson, B. & Niroula, A.
2011/01/03 → …
Project: Research

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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, 1-8. [7213]. https://doi.org/10.1038/ncomms8213

@article{49d76660acbb4abbaf1425044a6ee936,

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 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).",

author = "Bhairavi Swaminathan and Gu{\dh}mar Thorleifsson and Magnus J{\"o}ud and Mina Ali and Ellinor Johnsson and Ram Ajore and Patrick Sulem and Britt-Marie Halvarsson and Gu{\dh}mundur Eyjolfsson and Vilhelmina Haraldsdottir and Christina Hultman and Erik Ingelsson and Kristinsson, {Sigur{\dh}ur Y} and K{\"a}hler, {Anna K} and Stig Lenhoff and Gisli Masson and Ulf-Henrik Mellqvist and Robert M{\aa}nsson and Sven Nelander and Isleifur Olafsson and Olof Sigur{\dh}ardottir 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",

year = "2015",

doi = "10.1038/ncomms8213",

language = "English",

volume = "6",

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journal = "Nature Communications",

issn = "2041-1723",

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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, SY, Kähler, AK, Lenhoff, S, Masson, G, Mellqvist, U-H, 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 2015, 'Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma.', Nature Communications, vol. 6, 7213, pp. 1-8. https://doi.org/10.1038/ncomms8213

TY - JOUR

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

AU - Swaminathan, Bhairavi

AU - Thorleifsson, Guðmar

AU - Jöud, Magnus

AU - Ali, Mina

AU - Johnsson, Ellinor

AU - Ajore, Ram

AU - Sulem, Patrick

AU - Halvarsson, Britt-Marie

AU - Eyjolfsson, Guðmundur

AU - Haraldsdottir, Vilhelmina

AU - Hultman, Christina

AU - Ingelsson, Erik

AU - Kristinsson, Sigurður 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 - Sigurðardottir, 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

Y1 - 2015

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 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).

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 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).

U2 - 10.1038/ncomms8213

DO - 10.1038/ncomms8213

M3 - Article

C2 - 26007630

SN - 2041-1723

VL - 6

SP - 1

EP - 8

JO - Nature Communications

JF - Nature Communications

M1 - 7213

ER -

Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma.

Abstract

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Research output

Genetic Predisposition to Sporadic and Familial Multiple Myeloma

Identification and characterization of DNA sequence variants associated with multiple myeloma

Projects

Genetic predisposition for multiple myeloma

Cite this