A Genome-Wide Association Study Identifies a Novel Locus for Bortezomib-Induced Peripheral Neuropathy in European Multiple Myeloma Patients
Abstract
Purpose: Painful peripheral neuropathy is a frequent toxicity associated with bortezomib therapy.
This study aimed to identify loci that affect susceptibility to this toxicity.
Experimental Design: A genome-wide association study (GWAS) of 370,605 SNPs was
performed to identify risk variants for developing severe bortezomib-induced peripheral neuropathy
(BiPN) in 469 multiple myeloma (MM) patients who received bortezomib-dexamethasone therapy
prior to autologous stem-cell in randomized clinical trials of the Intergroupe Francophone du
Myelome (IFM) and findings were replicated in 114 MM patients of the HOVON-65/GMMG-HD4
clinical trial.
Results: A single SNP in the PKNOX1 gene was associated with BiPN in the exploratory cohort
(rs2839629; OR, 1.89, 95% CI: [1.45-2.44]; P = 7.6 x 10-6) and in the replication cohort (OR, 2.04;
95% CI = [1.11-3.33]; P= 8.3 x 10-3). In addition, rs2839629 is in strong linkage disequilibrium (r2
= 0.87) with rs915854, located in the intergenic region between PKNOX1 and CBS . Expression
quantitative trait loci mapping showed that both rs2839629 and rs915854 genotypes impact
PKNOX1 expression in nerve tissue while rs2839629 affects CBS expression in skin and blood.
Conclusions: The use of GWAS in MM pharmacogenomics has identified a novel candidate genetic
locus mapping to PKNOX1 and in the immediate vicinity of CBS at 21q22.3 associated with the
severe bortezomib-induced toxicity. The proximity of these two genes involved in neurologic pain
whose tissue-specific expression is modified by the two variants provides new targets for neuroprotective
strategies.
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