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Genetic Predisposition to Multiple Myeloma at 5q15 Is Mediated by an ELL2 Enhancer Polymorphism

Genetic Predisposition to Multiple Myeloma at 5q15 Is Mediated by an ELL2 Enhancer Polymorphism
Genetic Predisposition to Multiple Myeloma at 5q15 Is Mediated by an ELL2 Enhancer Polymorphism

Multiple myeloma (MM) is a malignancy of plasma cells. Genome-wide association studies have shown that variation at 5q15 influences MM risk. Here, we have sought to decipher the causal variant at 5q15 and the mechanism by which it influences tumorigenesis. We show that rs6877329 G > C resides in a predicted enhancer element that physically interacts with the transcription start site of ELL2. The rs6877329-C risk allele is associated with reduced enhancer activity and lowered ELL2 expression. Since ELL2 is critical to the B cell differentiation process, reduced ELL2 expression is consistent with inherited genetic variation contributing to arrest of plasma cell development, facilitating MM clonal expansion. These data provide evidence for a biological mechanism underlying a hereditary risk of MM at 5q15.

Alleles, Chromosomes, Human, Pair 5, Diploidy, Enhancer Elements, Genetic, Epigenesis, Genetic, Epigenomics, Genetic Loci, Genetic Predisposition to Disease, Humans, Multiple Myeloma, Nuclear Proteins, Physical Chromosome Mapping, Polymorphism, Single Nucleotide, Prognosis, Protein Binding, Risk Factors, Transcription Elongation, Genetic, Transcriptional Elongation Factors, Unfolded Protein Response, Journal Article
2211-1247
2556-2564
Li, Ni
b047d2c1-98de-4d16-b44e-057b032ab898
Johnson, David C.
37fc5be7-f918-4646-9224-136f3a0ef557
Weinhold, Niels
ba9220dd-e751-4b3a-a519-e3787752a083
Kimber, Scott
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Dobbins, Sara E
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Mitchell, Jonathan S
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Kinnersley, Ben
60b20abb-8a16-48c8-b4bc-e7d25ddb2af2
Sud, Amit
fcd5d252-8f84-40c5-a2b8-dad5fc301c17
Law, Philip J
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Orlando, Giulia
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Scales, Matthew
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Wardell, Christopher P
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Försti, Asta
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Hoang, Phuc H
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Went, Molly
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Holroyd, Amy
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Hariri, Fadi
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Pastinen, Tomi
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Meissner, Tobias
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Goldschmidt, Hartmut
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Hemminki, Kari
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Morgan, Gareth J
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Kaiser, Martin
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Houlston, Richard S
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Li, Ni
b047d2c1-98de-4d16-b44e-057b032ab898
Johnson, David C.
37fc5be7-f918-4646-9224-136f3a0ef557
Weinhold, Niels
ba9220dd-e751-4b3a-a519-e3787752a083
Kimber, Scott
912df707-c67a-42eb-8f6d-5395e7397d38
Dobbins, Sara E
587028e6-a073-4f99-a62c-6012ce4ac1e5
Mitchell, Jonathan S
4e16747a-68e0-4660-b540-8b0af8f7855b
Kinnersley, Ben
60b20abb-8a16-48c8-b4bc-e7d25ddb2af2
Sud, Amit
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Law, Philip J
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Orlando, Giulia
1e716170-59cd-4553-80d3-78ad472bd192
Scales, Matthew
987e1cec-816e-4111-93e0-d9e76bb6b4de
Wardell, Christopher P
0d498cee-324b-457c-adff-7193c16cf2d5
Försti, Asta
50654f61-4eda-4eba-944b-041026370190
Hoang, Phuc H
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Went, Molly
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Holroyd, Amy
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Hariri, Fadi
1cdd0e97-176e-467c-b766-7d26a993e9db
Pastinen, Tomi
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Meissner, Tobias
05292b80-8165-49ae-9fcb-bc9bcb926ce7
Goldschmidt, Hartmut
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Hemminki, Kari
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Morgan, Gareth J
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Kaiser, Martin
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Houlston, Richard S
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Li, Ni, Johnson, David C., Weinhold, Niels, Kimber, Scott, Dobbins, Sara E, Mitchell, Jonathan S, Kinnersley, Ben, Sud, Amit, Law, Philip J, Orlando, Giulia, Scales, Matthew, Wardell, Christopher P, Försti, Asta, Hoang, Phuc H, Went, Molly, Holroyd, Amy, Hariri, Fadi, Pastinen, Tomi, Meissner, Tobias, Goldschmidt, Hartmut, Hemminki, Kari, Morgan, Gareth J, Kaiser, Martin and Houlston, Richard S (2017) Genetic Predisposition to Multiple Myeloma at 5q15 Is Mediated by an ELL2 Enhancer Polymorphism. Cell Reports, 20 (11), 2556-2564. (doi:10.1016/j.celrep.2017.08.062).

Record type: Article

Abstract

Multiple myeloma (MM) is a malignancy of plasma cells. Genome-wide association studies have shown that variation at 5q15 influences MM risk. Here, we have sought to decipher the causal variant at 5q15 and the mechanism by which it influences tumorigenesis. We show that rs6877329 G > C resides in a predicted enhancer element that physically interacts with the transcription start site of ELL2. The rs6877329-C risk allele is associated with reduced enhancer activity and lowered ELL2 expression. Since ELL2 is critical to the B cell differentiation process, reduced ELL2 expression is consistent with inherited genetic variation contributing to arrest of plasma cell development, facilitating MM clonal expansion. These data provide evidence for a biological mechanism underlying a hereditary risk of MM at 5q15.

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Published date: 12 September 2017
Keywords: Alleles, Chromosomes, Human, Pair 5, Diploidy, Enhancer Elements, Genetic, Epigenesis, Genetic, Epigenomics, Genetic Loci, Genetic Predisposition to Disease, Humans, Multiple Myeloma, Nuclear Proteins, Physical Chromosome Mapping, Polymorphism, Single Nucleotide, Prognosis, Protein Binding, Risk Factors, Transcription Elongation, Genetic, Transcriptional Elongation Factors, Unfolded Protein Response, Journal Article

Identifiers

Local EPrints ID: 429890
URI: http://eprints.soton.ac.uk/id/eprint/429890
DOI: doi:10.1016/j.celrep.2017.08.062
ISSN: 2211-1247
PURE UUID: d9de17d1-d977-471a-b4e7-b3403f30e384

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Date deposited: 08 Apr 2019 16:30
Last modified: 16 Mar 2024 00:20

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Contributors

Author: Ni Li
Author: David C. Johnson
Author: Niels Weinhold
Author: Scott Kimber
Author: Sara E Dobbins
Author: Jonathan S Mitchell
Author: Ben Kinnersley
Author: Amit Sud
Author: Philip J Law
Author: Giulia Orlando
Author: Matthew Scales
Author: Christopher P Wardell
Author: Asta Försti
Author: Phuc H Hoang
Author: Molly Went
Author: Amy Holroyd
Author: Fadi Hariri
Author: Tomi Pastinen
Author: Tobias Meissner
Author: Hartmut Goldschmidt
Author: Kari Hemminki
Author: Gareth J Morgan
Author: Martin Kaiser
Author: Richard S Houlston

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