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

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...

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Main Authors: Ali, Mina (Author) , Ajore, Ram (Author) , Wihlborg, Anna-Karin (Author) , Niroula, Abhishek (Author) , Swaminathan, Bhairavi (Author) , Johnsson, Ellinor (Author) , Stephens, Owen W. (Author) , Morgan, Gareth (Author) , Meissner, Tobias (Author) , Turesson, Ingemar (Author) , Goldschmidt, Hartmut (Author) , Mellqvist, Ulf-Henrik (Author) , Gullberg, Urban (Author) , Hansson, Markus (Author) , Hemminki, Kari (Author) , Nahi, Hareth (Author) , Waage, Anders (Author) , Weinhold, Niels (Author) , Nilsson, Björn (Author)
Format: Article (Journal)
Language:English
Published: 25 April 2018
In: Nature Communications
Year: 2018, Volume: 9
ISSN:2041-1723
DOI:10.1038/s41467-018-04082-2
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41467-018-04082-2
Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41467-018-04082-2
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Author Notes:Mina Ali, Ram Ajore, Anna-Karin Wihlborg, Abhishek Niroula, Bhairavi Swaminathan, Ellinor Johnsson, Owen W Stephens, Gareth Morgan, Tobias Meissner, Ingemar Turesson, Hartmut Goldschmidt, Ulf-Henrik Mellqvist, Urban Gullberg, Markus Hansson, Kari Hemminki, Hareth Nahi, Anders Waage, Niels Weinhold & Björn Nilsson
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Summary: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 (Pcombined = 2.5 × 10−27; βcombined = −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.
Item Description:Gesehen am 01.07.2020
Physical Description:Online Resource
ISSN:2041-1723
DOI:10.1038/s41467-018-04082-2

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