Genetic risk factors for bortezomib-induced peripheral neuropathy in an Asian population: A genome-wide association study in South Korea

Abstract

Bortezomib-induced peripheral neuropathy (BIPN) poses a challenge in multiple myeloma (MM) treatment. Genetic factors play a key role in BIPN susceptibility, but research has predominantly focused on Caucasian populations. This research explored novel genetic risk loci and pathways associated with BIPN development in Korean MM patients, while evaluating reproducibility of variants from Caucasians. Clinical data and buffy coat samples from 185 MM patients on bortezomib were collected. The cohort was split into discovery and validation cohorts through random stratification of clinical risk factors for BIPN. GWAS was performed on the discovery cohort (n = 74) with Infinium Global Screening Array-24 v3.0 BeadChip (654,027 SNPs). Relevant biological pathways were identified using pathway scoring algorithm (PASCAL). The top 20 SNPs were validated in the validation cohort (n = 111). Previously reported SNPs were validated in the entire cohort (n = 185). Pathway analysis of the GWAS results identified 31 relevant pathways, including immune systems and endosomal vacuolar pathways. Among top 20 SNPs from discovery cohort, 16 were replicated, which included intronic variants in ASIC2 and SMOC2, recently implicated in nociception, as well as intergenic variants or long non-coding RNAs. None of the 17 previously reported SNPs remained significant in our cohort (rs2274578, p = 0.085). This study represents the first investigation of novel genetic loci and biological pathways associated with BIPN occurrence. Our findings, in conjunction with existing Caucasian studies, expand the understanding of personalized risk prediction and disease mechanisms.