GEO Logo
   NCBI > GEO > Accession DisplayHelp Not logged in | LoginHelp
GEO help: Mouse over screen elements for information.
Series GSE66903 Query DataSets for GSE66903
Status Public on Jun 01, 2016
Title Genome wide association study on neuropathy in multiple myeloma
Organism Homo sapiens
Experiment type Genome variation profiling by SNP array
SNP genotyping by SNP array
Summary Performing GWAS on multiple myeloma in relation to the development of the toxicity neuropathy. This set was used as validation set.
We performed a genome-wide association study using Affymetrix HD-SNP arrays 6.0 to identify risk variants for developing bortezomib-induced peripheral neuropathy (BiPN) in 469 multiple myeloma (MM) patients who received bortezomib-dexamethasone therapy prior to autologous stem-cell transplantation and conducted validation in an independent cohort of 116 MM patients. We identified one previously unreported BiPN risk locus at 21q22.3 (rs2839629, PKNOX1; OR = 0.53, 95% CI: [0.40-0.69]). PKNOX1 is known to regulate MCP-1, a potent mediator of chemotherapy-induced peripheral neuropathy. rs2839629 is in strong linkage disequilibrium ( r2 = 0.87) with rs915854, localized 6.5kb centromeric to CBS encoding endogenous H2S-producing enzyme. CBS-H2S signalling pathway is implicated in the pathogenesis of a variety of neurodegenerative and inflammatory disorders, and specifically in neuropathy models. Our data provide conclusive evidence for genetic susceptibility to BiPN in MM and new potential targets in neuro-protective strategies of treatment.
Overall design Each patient of both IFM and HOVON cohorts was genotyped using the Affymetrix SNP6.0 Human DNA chip (Affymetrix, Santa Clara, CA) according to manufacturer’s instructions (Affymetrix, Santa Clara, CA). The HOVON65 samples were genotyped using CRLMM v2 resulting in a call rate higher than 95%. Unannotated SNPs according to the hg19 na32 SNP6 Affymetrix annotations (n= 130) along with SNPs from MT and sexual chromosomes (n= 37,326) were not considered in the study. To perform GWAS in the IFM cohort, we used stringent criteria to select a total of 370,605 SNPs from the 872,166 SNPs available onto the array. A SNP was analysed if an AA or BB genotype was present in more than 5% of patients, if its genotype was determined in at least 95% of the patients and if the Hardy-Weinberg rule was not rejected. Statistical analyses were performed using SNPTEST v2.5.11. Firstly, we compared 370,605 genotypes from 155 IFM patients with neuropathy (grade >= 2) after bortezomib exposure to 314 control patients treated with bortezomib who did not develop neuropathy (grade 0-1). Secondly, we performed a validation in the HOVON 65/GMMG-HD4cohort for the highest associated SNPs as identified in the discovery cohort. We compared 41 bortezomib-treated patients with neuropathy (grade >= 2) with 75 bortezomib-treated controls who did not develop neuropathy. We applied a one-sided logistic regression with 10,000 label swapping permutations to correct for multiple testing in order to confirm BiPN association in this independent cohort.
This set was used as a validation set. An independent dataset was used for discovery [GSE65777].
Contributor(s) Kuiper R, van Duin M
Citation(s) 27060151
Submission date Mar 13, 2015
Last update date Nov 27, 2018
Contact name Mark van Duin
Organization name Erasmus MC
Street address Wytemaweg 80
City Rotterdam
ZIP/Postal code 3015CN
Country Netherlands
Platforms (1)
GPL6801 [GenomeWideSNP_6] Affymetrix Genome-Wide Human SNP 6.0 Array
Samples (116)
GSM1633929 Myeloma sample [EMC_2815137_v1]
GSM1633930 Myeloma sample [EMC_2129996_v1]
GSM1633931 Myeloma sample [EMC_4475026_v1]
BioProject PRJNA278296

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE66903_RAW.tar 3.1 Gb (http)(custom) TAR (of CEL)
Processed data included within Sample table

| NLM | NIH | GEO Help | Disclaimer | Accessibility |
NCBI Home NCBI Search NCBI SiteMap