PDF(Pubmed)
Abstract：
Clopidogrel is widely used worldwide as an antiplatelet therapy in patients with acute coronary disease. Genetic factors influence interindividual variability in response. Some studies have explored the polygenic contributions in the drug response, generating pharmacogenomic risk scores (PgxPRS). Importantly, these factors are less explored in underrepresented populations, such as Latin-American countries. Identifying patients at risk of high-on-treatment platelet reactivity (HTPR) is highly valuable in translational medicine. In this study we used a custom next-generation sequencing (NGS) panel composed of 91 single nucleotide polymorphisms (SNPs) and 28 genes related to clopidogrel metabolism, to analyze 70 patients with platelet reactivity values, assessed through closure time (CT). Our results demonstrated the association of SNPs with HTPR and non-HTPR, revealing the strongest associations with rs2286823 (OR: 5,0; 95% CI: 1,02-24,48; p: 0,03), rs2032582 (OR: 4,41; 95% CI: 1,20-16,12; p: 0,019), and rs1045642 (OR: 3,38; 95% CI: 0,96-11,9; p: 0,05). Bivariate regression analysis demonstrated the significant association of several SNPs with the CT value, a \"surrogate\" biomarker of clopidogrel response. Exploratory results from the LASSO regression model showed a high discriminatory capacity between HTPR and non-HTPR patients (AUC: 0,955), and the generated PgxPRS demonstrated a significant negative association between the risk score, CT value, and the condition of HTPR and non-HTPR. To our knowledge, our study addresses for the first time the analysis of the polygenic contribution in platelet reactivity using NGS and establishes PgxPRS derived from the LASSO model. Our results demonstrate the polygenic implication of clopidogrel response and offer insights applicable to the translational medicine of antiplatelet therapy in an understudied population.
摘要：
氯吡格雷在世界范围内被广泛用作急性冠心病患者的抗血小板治疗。遗传因素影响反应中的个体差异。一些研究探索了药物反应中的多基因贡献，生成药物基因组风险评分（PgxPRS）。重要的是,这些因素在代表性不足的人群中很少被探索，比如拉丁美洲国家。识别处于高治疗血小板反应性（HTPR）风险的患者在转化医学中非常有价值。在这项研究中，我们使用了由91个单核苷酸多态性（SNP）和28个与氯吡格雷代谢相关的基因组成的自定义下一代测序（NGS）小组，分析70例患者的血小板反应性值，通过闭合时间（CT）评估。我们的结果表明SNP与HTPR和非HTPR的关联，揭示了与rs2286823的最强关联(OR：5,0;95%CI：1,02-24,48;p：0,03)，rs2032582（OR：4,41；95%CI：1,20-16,12；p：0,019），和rs1045642（OR：3,38；95%CI：0,96-11,9；p：0,05）。双变量回归分析表明几个SNP与CT值显著相关，氯吡格雷反应的“替代”生物标志物。LASSO回归模型的探索性结果显示HTPR和非HTPR患者之间具有很高的辨别能力（AUC：0.955），生成的PgxPRS显示出风险评分之间的显着负相关，CT值,以及HTPR和非HTPR的状况。据我们所知,我们的研究首次利用NGS分析血小板反应性中的多基因贡献,并建立了源自LASSO模型的PgxPRS.我们的结果证明了氯吡格雷反应的多基因意义，并提供了适用于未研究人群的抗血小板治疗转化医学的见解。
