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Genetic Susceptibility to Bortezomib-Induced Peripheral Neuroropathy : Replication of the Reported Candidate Susceptibility Loci

Campo, Chiara; da Silva Filho, Miguel Inacio LU ; Weinhold, Niels; Goldschmidt, Hartmut; Hemminki, Kari LU ; Merz, Maximilian and Försti, Asta LU (2017) In Neurochemical Research 42(3). p.925-931
Abstract

The introduction of proteasome inhibitors in the treatment of multiple myeloma (MM) patients has been a therapeutic success. Peripheral neuropathy (PNP) remains one of the most frequent side-effects experienced by patients who receive these novel agents. Recent investigations on the mechanisms of PNP in patients treated with bortezomib have suggested genetic susceptibility to neurotoxicity. We used data from a genome-wide association study conducted on 646 bortezomib-treated German MM patients to replicate the previously reported associations between single-nucleotide polymorphisms (SNPs) in candidate genes and PNP in MM patients, including 298 SNPs with a nominal significance (p value <0.05). Twelve associations were confirmed at a... (More)

The introduction of proteasome inhibitors in the treatment of multiple myeloma (MM) patients has been a therapeutic success. Peripheral neuropathy (PNP) remains one of the most frequent side-effects experienced by patients who receive these novel agents. Recent investigations on the mechanisms of PNP in patients treated with bortezomib have suggested genetic susceptibility to neurotoxicity. We used data from a genome-wide association study conducted on 646 bortezomib-treated German MM patients to replicate the previously reported associations between single-nucleotide polymorphisms (SNPs) in candidate genes and PNP in MM patients, including 298 SNPs with a nominal significance (p value <0.05). Twelve associations were confirmed at a significance level p value <0.05. The corresponding SNPs are located in genes involved in drug metabolism (ABCC1, ABCC6), development and function of the nervous system (POGZ, NFAT pathway, EDN1), modulation of immune responses (IL17RD, IL10RA) and the NF-κB signaling pathway (PSMB4, BTCR, F2). We systematically investigated functional consequences of those variants using several bioinformatics tools, such as HaploRegV4.1, RegulomeDB and UCSC Genome Browser. Expression quantitative trait loci (eQTL) data suggested that some of the identified SNPs might influence gene expression through a differential recruitment of transcription factors. In conclusion, we confirmed some of the recently reported associations between germline variation and PNP. Elucidating the mechanisms underlying these associations will contribute to the development of new strategies for the prevention or reduction of PNP.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Bortezomib, GWAS, Multiple myeloma, Neurotoxicity, Peripheral neuropathy
in
Neurochemical Research
volume
42
issue
3
pages
7 pages
publisher
Springer
external identifiers
  • scopus:84978869362
  • wos:000398044200019
ISSN
0364-3190
DOI
10.1007/s11064-016-2007-9
language
English
LU publication?
yes
id
3a8c29d5-7c5d-4cdd-aff1-421500c70512
date added to LUP
2017-01-12 12:21:59
date last changed
2018-08-26 04:51:21
@article{3a8c29d5-7c5d-4cdd-aff1-421500c70512,
  abstract     = {<p>The introduction of proteasome inhibitors in the treatment of multiple myeloma (MM) patients has been a therapeutic success. Peripheral neuropathy (PNP) remains one of the most frequent side-effects experienced by patients who receive these novel agents. Recent investigations on the mechanisms of PNP in patients treated with bortezomib have suggested genetic susceptibility to neurotoxicity. We used data from a genome-wide association study conducted on 646 bortezomib-treated German MM patients to replicate the previously reported associations between single-nucleotide polymorphisms (SNPs) in candidate genes and PNP in MM patients, including 298 SNPs with a nominal significance (p value &lt;0.05). Twelve associations were confirmed at a significance level p value &lt;0.05. The corresponding SNPs are located in genes involved in drug metabolism (ABCC1, ABCC6), development and function of the nervous system (POGZ, NFAT pathway, EDN1), modulation of immune responses (IL17RD, IL10RA) and the NF-κB signaling pathway (PSMB4, BTCR, F2). We systematically investigated functional consequences of those variants using several bioinformatics tools, such as HaploRegV4.1, RegulomeDB and UCSC Genome Browser. Expression quantitative trait loci (eQTL) data suggested that some of the identified SNPs might influence gene expression through a differential recruitment of transcription factors. In conclusion, we confirmed some of the recently reported associations between germline variation and PNP. Elucidating the mechanisms underlying these associations will contribute to the development of new strategies for the prevention or reduction of PNP.</p>},
  author       = {Campo, Chiara and da Silva Filho, Miguel Inacio and Weinhold, Niels and Goldschmidt, Hartmut and Hemminki, Kari and Merz, Maximilian and Försti, Asta},
  issn         = {0364-3190},
  keyword      = {Bortezomib,GWAS,Multiple myeloma,Neurotoxicity,Peripheral neuropathy},
  language     = {eng},
  number       = {3},
  pages        = {925--931},
  publisher    = {Springer},
  series       = {Neurochemical Research},
  title        = {Genetic Susceptibility to Bortezomib-Induced Peripheral Neuroropathy : Replication of the Reported Candidate Susceptibility Loci},
  url          = {http://dx.doi.org/10.1007/s11064-016-2007-9},
  volume       = {42},
  year         = {2017},
}