Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma

B. Swaminathan; G. Thorleifsson; M. Joud; M. Ali; E. Johnsson; R. Ajore; P. Sulem; B.M. Halvarsson; G. Eyjolfsson; V. Haraldsdottir; C. Hultman; E. Ingelsson; S.Y. Kristinsson; A.K. Kahler; S. Lenhoff; G. Masson; U.H. Mellqvist; R. Mansson; S. Nelander; I. Olafsson; O. Sigurethardottir; H. Steingrimsdottir; A.J. Vangsted; Ulla Birgitte Vogel; A. Waage; H. Nahi; D.F. Gudbjartsson; T. Rafnar; I. Turesson; U. Gullberg; K. Stefansson; M. Hansson; U. Thorsteinsdottir; B. Nilsson

doi:10.1038/ncomms8213

Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma

B. Swaminathan
, G. Thorleifsson
, M. Joud
, M. Ali
, E. Johnsson
, R. Ajore
, P. Sulem
, B.M. Halvarsson
, G. Eyjolfsson
, V. Haraldsdottir
, C. Hultman
, E. Ingelsson
, S.Y. Kristinsson
, A.K. Kahler
, S. Lenhoff
, G. Masson
, U.H. Mellqvist
, R. Mansson
, S. Nelander
, I. Olafsson

O. Sigurethardottir, H. Steingrimsdottir, A.J. Vangsted, Ulla Birgitte Vogel, A. Waage, H. Nahi, D.F. Gudbjartsson, T. Rafnar, I. Turesson, U. Gullberg, K. Stefansson, M. Hansson, U. Thorsteinsdottir, B. Nilsson

Kemi og mikrobiologi

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Abstract

[Open access] 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 x 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 x 10(-9) and P=6.4 x 10(-3), respectively) and, potentially, with an increased risk of bacterial meningitis (OR=1.30; P=0.0024)

Originalsprog	Engelsk
Tidsskrift	Nature Communications
Vol/bind	6
Sider (fra-til)	7213-
ISSN	2041-1723
DOI	https://doi.org/10.1038/ncomms8213
Status	Udgivet - 2015

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10.1038/ncomms8213

Citationsformater

Swaminathan, B., Thorleifsson, G., Joud, M., Ali, M., Johnsson, E., Ajore, R., Sulem, P., Halvarsson, B. M., Eyjolfsson, G., Haraldsdottir, V., Hultman, C., Ingelsson, E., Kristinsson, S. Y., Kahler, A. K., Lenhoff, S., Masson, G., Mellqvist, U. H., Mansson, 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

@article{14fb49f5a4934c8396283f11b8b89397,

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

abstract = "[Open access] 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 x 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 x 10(-9) and P=6.4 x 10(-3), respectively) and, potentially, with an increased risk of bacterial meningitis (OR=1.30; P=0.0024)",

author = "B. Swaminathan and G. Thorleifsson and M. Joud and M. Ali and E. Johnsson and R. Ajore and P. Sulem and B.M. Halvarsson and G. Eyjolfsson and V. Haraldsdottir and C. Hultman and E. Ingelsson and S.Y. Kristinsson and A.K. Kahler and S. Lenhoff and G. Masson and U.H. Mellqvist and R. Mansson and S. Nelander and I. Olafsson and O. Sigurethardottir and H. Steingrimsdottir and A.J. Vangsted and Vogel, \{Ulla Birgitte\} and A. Waage and H. Nahi and D.F. Gudbjartsson and T. Rafnar and I. Turesson and U. Gullberg and K. Stefansson and M. Hansson and U. Thorsteinsdottir and B. Nilsson",

note = "SUBMISSIONYEAR:2015",

year = "2015",

doi = "10.1038/ncomms8213",

language = "English",

volume = "6",

pages = "7213--",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Swaminathan, B, Thorleifsson, G, Joud, M, Ali, M, Johnsson, E, Ajore, R, Sulem, P, Halvarsson, BM, Eyjolfsson, G, Haraldsdottir, V, Hultman, C, Ingelsson, E, Kristinsson, SY, Kahler, AK, Lenhoff, S, Masson, G, Mellqvist, UH, Mansson, R, Nelander, S, Olafsson, I, Sigurethardottir, O, Steingrimsdottir, H, Vangsted, AJ, Vogel, UB, Waage, A, Nahi, H, Gudbjartsson, DF, Rafnar, T, Turesson, I, Gullberg, U, Stefansson, K, Hansson, M, Thorsteinsdottir, U & Nilsson, B 2015, 'Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma', Nature Communications, bind 6, s. 7213-. https://doi.org/10.1038/ncomms8213

TY - JOUR

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

AU - Swaminathan, B.

AU - Thorleifsson, G.

AU - Joud, M.

AU - Ali, M.

AU - Johnsson, E.

AU - Ajore, R.

AU - Sulem, P.

AU - Halvarsson, B.M.

AU - Eyjolfsson, G.

AU - Haraldsdottir, V.

AU - Hultman, C.

AU - Ingelsson, E.

AU - Kristinsson, S.Y.

AU - Kahler, A.K.

AU - Lenhoff, S.

AU - Masson, G.

AU - Mellqvist, U.H.

AU - Mansson, R.

AU - Nelander, S.

AU - Olafsson, I.

AU - Sigurethardottir, O.

AU - Steingrimsdottir, H.

AU - Vangsted, A.J.

AU - Vogel, Ulla Birgitte

AU - Waage, A.

AU - Nahi, H.

AU - Gudbjartsson, D.F.

AU - Rafnar, T.

AU - Turesson, I.

AU - Gullberg, U.

AU - Stefansson, K.

AU - Hansson, M.

AU - Thorsteinsdottir, U.

AU - Nilsson, B.

N1 - SUBMISSIONYEAR:2015

PY - 2015

Y1 - 2015

N2 - [Open access] 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 x 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 x 10(-9) and P=6.4 x 10(-3), respectively) and, potentially, with an increased risk of bacterial meningitis (OR=1.30; P=0.0024)

AB - [Open access] 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 x 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 x 10(-9) and P=6.4 x 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 - Journal article

SN - 2041-1723

VL - 6

SP - 7213-

JO - Nature Communications

JF - Nature Communications

ER -

Variants in ELL2 influencing immunoglobulin levels associate with multiple myeloma

Abstract

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