A Genome-Wide Association Study Identifies a Novel Locus for Bortezomib-Induced Peripheral Neuropathy in European Patients with Multiple Myeloma.
A Genome-Wide Association Study Identifies a Novel Locus for Bortezomib-Induced Peripheral Neuropathy in European Patients with Multiple Myeloma.
复制标题
DOI：
10.1158/1078-0432.ccr-15-3163
复制
发表时间：
2016-09-01
期刊：
影响因子：
--
通讯作者：
Minvielle S
中科院分区：
文献类型：
--
作者：
Magrangeas F;Kuiper R;Avet-Loiseau H;Gouraud W;Guérin-Charbonnel C;Ferrer L;Aussem A;Elghazel H;Suhard J;Sakissian H;Attal M;C Munshi N;Sonneveld P;Dumontet C;Moreau P;van Duin M;Campion L;Minvielle S
疼痛性周围神经病变是与硼替佐米治疗相关的常见毒性。本研究旨在确定影响这种毒性敏感性的位点。对 370,605 个 SNP 进行的全基因组关联研究 (GWAS) 旨在确定 469 名多发性骨髓瘤 (MM) 患者发生严重硼替佐米诱导的周围神经病变 (BiPN) 的风险变异，这些患者在 Intergroupe Francophone du Myelome (IFM) 的随机临床试验中在自体干细胞治疗之前接受硼替佐米-地塞米松治疗，结果在 114 名多发性骨髓瘤 (MM) 患者中得到重复HOVON-65/GMMG-HD4 临床试验。 PKNOX1 基因中的单个 SNP 与探索队列 (rs2839629; OR, 1.89, 95% CI: [1.45-2.44]; P = 7.6 × 10−6) 和复制队列 (OR, 2.04; 95% CI = [1.11-3.33]; P= 8.3 × 10−3).此外，rs2839629与位于PKNOX1和CBS之间基因间区域的rs915854存在强连锁不平衡(r2 = 0.87)。表达数量性状位点作图显示，rs2839629和rs915854基因型均影响神经组织中的PKNOX1表达，而rs2839629影响皮肤和血液中的CBS表达。 GWAS 在 MM 药物基因组学中的应用已经确定了一个新的候选遗传位点，该位点映射到 PKNOX1 并位于 21q22.3 的 CBS 附近，与硼替佐米引起的严重毒性相关。这两个基因与神经疼痛有关，其组织特异性表达被这两种变体所改变，这为神经保护策略提供了新的靶点。
Painful peripheral neuropathy is a frequent toxicity associated with bortezomib therapy. This study aimed to identify loci that affect susceptibility to this toxicity. 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. 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 × 10−6) and in the replication cohort (OR, 2.04; 95% CI = [1.11-3.33]; P= 8.3 × 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. 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 neuro-protective strategies.