背景:药物基因组学知识作为癌症治疗的生物标志物已经改变了临床实践,然而,因为目前的指导方针主要来自以欧洲为中心的人群,这限制了它们在拉丁美洲的应用,特别是在西班牙裔或拉丁裔群体中。尽管取得了进步,全身化疗在药物毒性和疗效欠佳方面仍然存在挑战.这项研究探索了智利队列中与抗癌药物相关的药物遗传学标志物,填补了拉丁美洲研究的空白。值得注意的是,南美本土马普切-胡利切血统的影响。
方法:探索与抗癌药物相关的药物遗传学标志物,我们使用了1,095个无关个体的智利全基因组关联研究(GWAS)种族混合数据集.药物基因组标记选自PharmGKB,共有36个1级和2级证据单核苷酸多态性(SNP)和571个3级SNP。比较分析涉及评估来自1000基因组项目的不同人群的SNP频率。估计了单倍型,并检查了连锁不平衡。基于祖先的关联分析探讨了SNP与Mapuche-Huilliche和欧洲祖先之间的关系。p≤0.05的卡方分布和Bonferroni的多重调整检验确定了等位基因频率之间的统计学差异。
结果:我们的研究揭示了智利人群中SNP频率的显著差异。值得注意的是,二氢嘧啶脱氢酶(DPYD)变体(rs75017182和rs67376798),与严重的氟嘧啶毒性风险增加有关,表现出异常低的频率(次要等位基因频率(MAF)<0.005)。Nudix水解酶15(NUDT15)rs116855232,与血液系统巯基嘌呤毒性相关,相对常见(MAF=0.062),并进一步与马普切-胡利切血统有关。硫嘌呤甲基转移酶(TPMT),与巯基嘌呤的严重毒性有关,TMPT基因的SNPrs1142345和rs1800460在混合的美国人和智利人群中显示出更高的MAF(MAF范围为0.031-0.057)。最后,UDP-葡糖醛酸基转移酶1基因(UGT1A1)rs4148323中的变体,与伊立替康中性粒细胞减少症相关,在东亚(MAF=0.136)和智利(MAF=0.025)人口中表现出最高的MAF,将它们与其他调查人群区分开来。
结论:本研究首次对癌症治疗相关SNP进行了全面的药物遗传学表征,并强调了智利人群SNP频率的显著差异。我们的发现强调了包容性研究和个性化治疗策略的必要性,以确保精准医学在全球不同社区的公平和有效应用。
BACKGROUND: Pharmacogenomic knowledge as a biomarker for cancer care has transformed clinical practice, however, as current guidelines are primarily derived from Eurocentric populations, this limits their application in Latin America, particularly among Hispanic or Latino groups. Despite advancements, systemic chemotherapy still poses challenges in drug toxicity and suboptimal response. This study explores pharmacogenetic markers related to anticancer drugs in a Chilean cohort, filling a gap in Latin American research. Notably, the influence of native South American Mapuche-Huilliche ancestry.
METHODS: To explore pharmacogenetic markers related to anticancer drugs, we utilized an ethnically Admixed Chilean genome-wide association studies (GWAS) dataset of 1095 unrelated individuals. Pharmacogenomic markers were selected from PharmGKB, totaling 36 level 1 and 2 evidence single nucleotide polymorphisms (SNPs) and 571 level 3 SNPs. Comparative analyses involved assessing SNP frequencies across diverse populations from the 1000 Genomes Project. Haplotypes were estimated, and linkage disequilibrium was examined. Ancestry-based association analyses explored relationships between SNPs and Mapuche-Huilliche and European ancestries. Chi-square distribution with p ≤ 0.05 and Bonferroni\'s multiple adjustment tests determined statistical differences between allele frequencies.
RESULTS: Our study reveals significant disparities in SNP frequency within the Chilean population. Notably, dihydropyrimidine dehydrogenase (DPYD) variants (rs75017182 and rs67376798), linked to an increased risk of severe fluoropyrimidine toxicity, exhibit an exceptionally low frequency (minor allele frequency (MAF) < 0.005). Nudix hydrolase 15 (NUDT15) rs116855232, associated with hematological mercaptopurine toxicity, is relatively common (MAF = 0.062), and is further linked to Mapuche-Huilliche ancestry. Thiopurine methyltransferase enzyme (
TPMT), implicated in severe toxicity to mercaptopurines, SNPs rs1142345 and rs1800460 of TMPT gene demonstrate higher MAFs in Admixed Americans and the Chilean population (MAF range 0.031-0.057). Finally, the variant in the UDP-glucuronosyltransferase 1 gene (UGT1A1) rs4148323, correlated with irinotecan neutropenia, exhibits the highest MAF in East Asian (MAF = 0.136) and Chilean (MAF = 0.025) populations, distinguishing them from other investigated populations.
CONCLUSIONS: This study provides the first comprehensive pharmacogenetic characterization of cancer therapy-related SNPs and highlights significant disparities in SNP frequencies within the Chilean population. Our findings underscore the necessity for inclusive research and personalized therapeutic strategies to ensure the equitable and effective application of precision medicine across diverse global communities.