2026-04-29T04:09:57Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/175042025-05-13T11:16:05Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Leandro-García, Luis J
author
Inglada-Pérez, Lucía
author
Pita, Guillermo
author
Hjerpe, Elisabet
author
Leskelä, Susanna
author
Jara, Carlos
author
Mielgo, Xabier
author
Gonzalez-Neira, Anna
author
Robledo Batanero, Mercedes
author
Avall-Lundqvist, Elisabeth
author
Gréen, Henrik
author
Rodriguez Antona, Cristina
funder
Ministerio de Ciencia y Competitividad (España)
funder
Swedish Cancer Society (Cancerfonden)
funder
Swedish Research Council
2024-02-06T10:13:13Z
2024-02-06T10:13:13Z
2013-09
J Med Genet . 2013;50(9):599-605.
http://hdl.handle.net/20.500.12105/17504
23776197
10.1136/jmedgenet-2012-101466
1468-6244
Journal of medical genetics
BACKGROUND: Peripheral neuropathy is the dose limiting toxicity of paclitaxel, a chemotherapeutic drug widely used to treat solid tumours. This toxicity exhibits great inter-individual variability of unknown origin. The present study aimed to identify genetic variants associated with paclitaxel induced neuropathy via a whole genome approach. METHODS: A genome-wide association study (GWAS) was performed in 144 white European patients uniformly treated with paclitaxel/carboplatin and for whom detailed data on neuropathy was available. Per allele single nucleotide polymorphism (SNP) associations were assessed by Cox regression, modelling the cumulative dose of paclitaxel up to the development of grade 2 sensory neuropathy. RESULTS: The strongest evidence of association was observed for the ephrin type A receptor 4 (EPHA4) locus (rs17348202, p=1.0×10(-6)), and EPHA6 and EPHA5 were among the top 25 and 50 hits (rs301927, p=3.4×10(-5) and rs1159057, p=6.8×10(-5)), respectively. A meta-analysis of EPHA5-rs7349683, the top marker for paclitaxel induced neuropathy in a previous GWAS (r(2)=0.79 with rs1159057), gave a hazard ratio (HR) estimate of 1.68 (p=1.4×10(-9)). Meta-analysis of the second hit of this GWAS, XKR4-rs4737264, gave a HR of 1.71 (p=3.1×10(-8)). Imputed SNPs at LIMK2 locus were also strongly associated with this toxicity (HR=2.78, p=2.0×10(-7)). CONCLUSIONS: This study provides independent support of EPHA5-rs7349683 and XKR4-rs4737264 as the first markers of risk of paclitaxel induced neuropathy. In addition, it suggests that other EPHA genes also involved in axonal guidance and repair following neural injury, as well as LIMK2 locus, may play an important role in the development of this toxicity. The identified SNPs could form the basis for individualised paclitaxel chemotherapy.
eng
Genome-wide association study identifies ephrin type A receptors implicated in paclitaxel induced peripheral sensory neuropathy
research article
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