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

Young Gi Min; Sung-Yeoun Lee; Ehyun Lim; Mi-Young Park; Dong-Ho Kim; Ja Min Byun; Youngil Koh; Junshik Hong; Dong-Yeop Shin; Sung-Soo Yoon; Jung-Joon Sung; Seog Bae Oh; Inho Kim

doi:10.1016/j.jpain.2024.104552

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

J Pain. 2024 Apr 29:104552. doi: 10.1016/j.jpain.2024.104552. Online ahead of print.

Authors

Affiliations

¹ Department of Translational Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
² LAS Inc., Gimpo, Republic of Korea.
³ Department of Internal Medicine, Seoul National University Hospital, Biomedical Research Institute, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea.
⁴ Department of Neurobiology and Physiology, School of Dentistry, and Dental Research Institute, Seoul National University, Seoul, Republic of Korea.

PMID: 38692398
DOI: 10.1016/j.jpain.2024.104552

Abstract

Bortezomib-induced neuropathic pain (BINP) poses a challenge in multiple myeloma (MM) treatment. Genetic factors play a key role in BINP susceptibility, but research has predominantly focused on Caucasian populations. This research explored novel genetic risk loci and pathways associated with BINP 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 BINP. 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 BINP occurrence. Our findings, in conjunction with existing Caucasian studies, expand the understanding of personalized risk prediction and disease mechanisms. PERSPECTIVE: This article is the first to explore novel genetic loci and pathways linked to bortezomib-induced neuropathic pain (BINP) in Korean multiple myeloma patients, offering novel insights beyond the existing research focused on Caucasian populations, into personalized risk assessment and therapeutic strategies of BINP.

Keywords: Bortezomib; GWAS; neuropathic pain; pharmacogenomics; risk prediction.