METHODS: Pharmacogenomic data regarding variant-drug pairs of genes CYP2D6, DPYD, NUDT15, EPAS1, and XRCC1 with clinical annotations labelled as evidence levels 1A-2B were obtained from the Pharmacogenomics Knowledgebase database. Their frequencies in Sri Lankans were obtained from an anonymized database that was derived from 541 Sri Lankans who underwent exome sequencing at the Human Genetics Unit, Faculty of Medicine, University of Colombo. Variations in DPYD, NUDT15, and EPAS1 genes are related to increased toxicity to fluoropyrimidines, mercaptopurines, and sorafenib respectively. Variations in CYP2D6 and XRCC1 genes are related to changes in efficacy of tamoxifen and platinum compounds, respectively. Minor allele frequencies of these variants were calculated and compared with other populations.
RESULTS: MAFs of rs1065852 c.100 C > T (CYP2D6), rs3918290 c.1905 + 1G > A (DPYD), rs56038477 c.1236G > A (DPYD), rs7557402 c.1035-7 C > G (EPAS1), rs116855232 c.415 C > T (NUDT15*3), and rs25487 c.1196 A > G (XRCC1) were: 12.9% [95%CI:10.9-14.9], 1.5% [95%CI:0.8-2.2], 1.2% [95%CI:0.5-1.8], 37.7% [95%CI:34.8-40.6], 8.3% [95%CI:6.7-10.0], and 64.0% [95%CI:61.1-66.8], respectively. Frequencies of rs1065852 c.100 C > T (CYP2D6), rs7557402 c.1035-7 C > G (EPAS1), and rs25487 (XRCC1) were significantly lower in Sri Lankans, while frequencies of rs116855232 c.415 C > T (NUDT15*3) and rs56038477 c.1236G > A (DPYD) were significantly higher in Sri Lankans when compared to some Western and Asian populations.
CONCLUSIONS: Sri Lankans are likely to show lower toxicity risk with sorafenib (rs7557402 c.84,131 C > G) and, higher toxicity risk with fluoropyrimidines (rs56038477 c.1236G > A) and mercaptopurine (rs116855232 c.415 C > T), and reduced effectiveness with tamoxifen (rs1065852 c.100 C > T) and platinum compounds (rs25487). These findings highlight the potential contribution of these genetic variations to the individual variability in anti-cancer dosage requirements among Sri Lankans.
方法:关于基因CYP2D6,DPYD,具有标记为证据水平1A-2B的临床注释的NUDT15、EPAS1和XRCC1从药物基因组学知识库数据库获得。他们在斯里兰卡的频率是从一个匿名数据库中获得的,该数据库来自541名在人类遗传学部门接受外显子组测序的斯里兰卡人,医学院,科伦坡大学。DPYD的变化,NUDT15和EPAS1基因与氟嘧啶的毒性增加有关,巯基嘌呤,和索拉非尼分别。CYP2D6和XRCC1基因的变异与他莫昔芬和铂化合物的功效变化有关,分别。计算这些变体的次要等位基因频率并与其他群体进行比较。
结果:rs1065852c.100C>T(CYP2D6)的MAFs,rs3918290c.1905+1G>A(DPYD),rs56038477c.1236G>A(DPYD),rs7557402c.1035-7C>G(EPAS1),rs116855232c.415C>T(NUDT15*3),rs25487c.1196A>G(XRCC1)为:12.9%[95CI:10.9-14.9],1.5%[95CI:0.8-2.2],1.2%[95CI:0.5-1.8],37.7%[95CI:34.8-40.6],8.3%[95CI:6.7-10.0],和64.0%[95CI:61.1-66.8],分别。rs1065852c.100C>T(CYP2D6)的频率,rs7557402c.1035-7C>G(EPAS1),rs25487(XRCC1)在斯里兰卡明显较低,与某些西方和亚洲人群相比,斯里兰卡人的rs116855232c.415C>T(NUDT15*3)和rs56038477c.1236G>A(DPYD)的频率明显更高。
结论:与索拉非尼(rs7557402c.84,131C>G)和,氟嘧啶(rs56038477c.1236G>A)和巯基嘌呤(rs116855232c.415C>T)的毒性风险更高,三苯氧胺(rs1065852c.100C>T)和铂化合物(rs25487)的有效性降低。这些发现强调了这些遗传变异对斯里兰卡人抗癌剂量需求的个体差异的潜在贡献。