The multiple myeloma risk allele at 5q15 lowers ELL2 expression and increases ribosomal gene expression
(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.
(Less)
- author
- organization
-
- Hematogenomics (research group)
- Division of Hematology and Transfusion Medicine
- Myeloma research group (research group)
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
- Transcriptional mechanisms for the Wilms’ tumor gene 1 (WT1) oncoprotein (research group)
- Family Medicine and Clinical Epidemiology (research group)
- EpiHealth: Epidemiology for Health
- publishing date
- 2018-12-01
- 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
- 2024-09-02 20:06:15
@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}}, }