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.

中文翻译：

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评估智利人群中癌症化疗相关药物遗传学等位基因的发生和影响

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，由于当前的指南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，全身化疗仍然在药物毒性和次优反应方面带来挑战。这项研究在智利队列中探索了与抗癌药物相关的药物遗传学标记，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-威利切血统的影响。方法：为了探索与抗癌药物相关的药物遗传学标记，我们利用了 1095 名无关个体的种族混合智利全基因组关联研究 (GWAS) 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。比较分析涉及评估千人基因组计划中不同人群的 SNP 频率。估计单倍型，并检查连锁不平衡。基于祖先的关联分析探讨了 SNP 与马普切-惠利切和欧洲祖先之间的关系。 p ≤ 0.05 的卡方分布和 Bonferroni 的多重调整测试确定了等位基因频率之间的统计差异。结果：我们的研究揭示了智利人群中 SNP 频率的显着差异。值得注意的是，二氢嘧啶脱氢酶 (DPYD) 变体（rs75017182 和 rs67376798）与严重氟嘧啶毒性风险增加相关，表现出极低的频率（次要等位基因频率 (MAF) < 0.005）。 Nudix 水解酶 15 (NUDT15) rs116855232 与血液学巯嘌呤毒性相关，相对常见 (MAF = 0.062)，并且进一步与马普切-Huilliche 血统相关。硫嘌呤甲基转移酶 (TPMT) 与巯嘌呤具有严重毒性有关，TMPT 基因的 SNP rs1142345 和 rs1800460 在美国人和智利混血人群中表现出较高的 MAF（MAF 范围 0.031–0.057）。最后，UDP-葡萄糖醛酸基转移酶 1 基因 (UGT1A1) rs4148323 中的变异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) 人群中表现出最高的 MAF，将其与其他研究人群区分开来。结论：本研究首次提供了癌症治疗相关 SNP 的全面药物遗传学特征，并强调了智利人群中 SNP 频率的显着差异。我们的研究结果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。