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The multiple myeloma risk allele at 5q15 lowers ELL2 expression and increases ribosomal gene expression

Ali, Mina LU ; Ajore, Ram LU ; Wihlborg, Anna Karin LU ; Niroula, Abhishek LU ; Swaminathan, Bhairavi LU ; Johnsson, Ellinor LU ; Stephens, Owen W. ; Morgan, Gareth ; Meissner, Tobias and Turesson, Ingemar LU , et al. (2018) In Nature Communications 9(1).
Abstract

Recently, we identified ELL2 as a susceptibility gene for multiple myeloma (MM). To understand its mechanism of action, we performed expression quantitative trait locus analysis in CD138+ plasma cells from 1630 MM patients from four populations. We show that the MM risk allele lowers ELL2 expression in these cells (P combined = 2.5 × 10-27; β combined = -0.24 SD), but not in peripheral blood or other tissues. Consistent with this, several variants representing the MM risk allele map to regulatory genomic regions, and three yield reduced transcriptional activity in plasmocytoma cell lines. One of these (rs3777189-C) co-locates with the best-supported lead variants for ELL2 expression and MM... (More)

Recently, we identified ELL2 as a susceptibility gene for multiple myeloma (MM). To understand its mechanism of action, we performed expression quantitative trait locus analysis in CD138+ plasma cells from 1630 MM patients from four populations. We show that the MM risk allele lowers ELL2 expression in these cells (P combined = 2.5 × 10-27; β combined = -0.24 SD), but not in peripheral blood or other tissues. Consistent with this, several variants representing the MM risk allele map to regulatory genomic regions, and three yield reduced transcriptional activity in plasmocytoma cell lines. One of these (rs3777189-C) co-locates with the best-supported lead variants for ELL2 expression and MM risk, and reduces binding of MAFF/G/K family transcription factors. Moreover, further analysis reveals that the MM risk allele associates with upregulation of gene sets related to ribosome biogenesis, and knockout/knockdown and rescue experiments in plasmocytoma cell lines support a cause-effect relationship. Our results provide mechanistic insight into MM predisposition.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
9
issue
1
article number
1649
publisher
Nature Publishing Group
external identifiers
  • pmid:29695719
  • scopus:85046094111
ISSN
2041-1723
DOI
10.1038/s41467-018-04082-2
project
Genetic predisposition for multiple myeloma
language
English
LU publication?
yes
id
60969839-f43a-4be0-aaa1-c1b4599e1ba7
date added to LUP
2018-05-07 13:02:44
date last changed
2021-04-13 03:13:20
@article{60969839-f43a-4be0-aaa1-c1b4599e1ba7,
  abstract     = {<p>Recently, we identified ELL2 as a susceptibility gene for multiple myeloma (MM). To understand its mechanism of action, we performed expression quantitative trait locus analysis in CD138<sup>+</sup> plasma cells from 1630 MM patients from four populations. We show that the MM risk allele lowers ELL2 expression in these cells (P <sub>combined</sub> = 2.5 × 10<sup>-27</sup>; β <sub>combined</sub> = -0.24 SD), but not in peripheral blood or other tissues. Consistent with this, several variants representing the MM risk allele map to regulatory genomic regions, and three yield reduced transcriptional activity in plasmocytoma cell lines. One of these (rs3777189-C) co-locates with the best-supported lead variants for ELL2 expression and MM risk, and reduces binding of MAFF/G/K family transcription factors. Moreover, further analysis reveals that the MM risk allele associates with upregulation of gene sets related to ribosome biogenesis, and knockout/knockdown and rescue experiments in plasmocytoma cell lines support a cause-effect relationship. Our results provide mechanistic insight into MM predisposition.</p>},
  author       = {Ali, Mina and Ajore, Ram and Wihlborg, Anna Karin and Niroula, Abhishek and Swaminathan, Bhairavi and Johnsson, Ellinor and Stephens, Owen W. and Morgan, Gareth and Meissner, Tobias and Turesson, Ingemar and Goldschmidt, Hartmut and Mellqvist, Ulf Henrik and Gullberg, Urban and Hansson, Markus and Hemminki, Kari and Nahi, Hareth and Waage, Anders and Weinhold, Niels and Nilsson, Björn},
  issn         = {2041-1723},
  language     = {eng},
  month        = {12},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {The multiple myeloma risk allele at 5q15 lowers ELL2 expression and increases ribosomal gene expression},
  url          = {http://dx.doi.org/10.1038/s41467-018-04082-2},
  doi          = {10.1038/s41467-018-04082-2},
  volume       = {9},
  year         = {2018},
}