Polygenic risk of paclitaxel-induced peripheral neuropathy: a genome-wide association study
Kosar Hooshmand, David Goldstein, Hannah C. Timmins, Tiffany Li, Michelle Harrison, Michael Friedländer, Craig Lewis, Justin G. Lees, Gila Moalem‐Taylor, Boris Guennewig, Susanna B. Park, John B. Kwok
Abstract
Abstract Background Genetic risk factors for chemotherapy-induced peripheral neuropathy (CIPN), a major dose-limiting side-effect of paclitaxel, are not well understood. Methods We performed a genome-wide association study (GWAS) in 183 paclitaxel-treated patients to identify genetic loci associated with CIPN assessed via comprehensive neuropathy phenotyping tools (patient-reported, clinical and neurological grading scales). Bioinformatic analyses including pathway enrichment and polygenic risk score analysis were used to identify mechanistic pathways of interest. Results In total, 77% of the cohort were classified with CIPN (n = 139), with moderate/severe neuropathy in 36%. GWAS was undertaken separately for the three measures of CIPN. GWAS of patient-reported CIPN identified 4 chromosomal regions that exceeded genome-wide significance (rs9846958, chromosome 3; rs117158921, chromosome 18; rs4560447, chromosome 4; rs200091415, chromosome 10). rs4560447 is located within a protein-coding gene, LIMCH1 , associated with actin and neural development and expressed in the dorsal root ganglia (DRG). There were additional risk loci that exceeded the statistical threshold for suggestive genome-wide association ( P < 1 × 10 –5 ) for all measures. A polygenic risk score calculated from the top 46 ranked SNPs was highly correlated with patient-reported CIPN (r 2 = 0.53; P = 1.54 × 10 –35 ). Overlap analysis was performed to identify 3338 genes which were in common between the patient-reported CIPN, neurological grading scale and clinical grading scale GWAS. The common gene set was subsequently analysed for enrichment of gene ontology (GO) and Reactome pathways, identifying a number of pathways, including the axon development pathway (GO:0061564; P = 1.78 × 10 –6 ) and neuronal system (R-HSA-112316; adjusted P = 3.33 × 10 –7 ). Conclusions Our findings highlight the potential role of axon development and regeneration pathways in paclitaxel-induced CIPN.