Zhang Luke, Kulkarni Prachi, Farshidfar Farshad, Tingley Whit, Hoey Tim, Wang Whedy, Priest James R, Figarska Sylwia M
Tenaya Therapeutics, South San Francisco, CA, USA.
University of California San Diego, San Diego, CA, USA.
BMC Cardiovasc Disord. 2025 May 7;25(1):353. doi: 10.1186/s12872-025-04753-1.
BACKGROUND: Human genetics is an important tool for identifying genes as potential drug targets, and the extensive genetic study of cardiovascular disease provides an opportunity to leverage genetics to match specific patient populations to specific drug targets to improve prioritization of patient selection for clinical studies. METHODS: We selected well described genetic variants in the region of PCSK9 (rs11591147 and rs562556), ADRB1 (rs7076938), ACE (rs4968782 and rs4363), GLP1R (rs10305492) and ABCC8 (rs757110) for use as proxies for the effects of drugs. Time-to-event analyses were utilized to evaluate their effects on atrial fibrillation (AF) and heart failure (HF) death and/or re-hospitalization using real-world longitudinal dataset. To mitigate the effect of confounding factors for cardiovascular (CV) outcomes, we employed propensity score matching. RESULTS: After matching, a genetic proxy for PCSK9 inhibition (rs11591147) improved survival from CV death/heart transplant in individuals following a diagnosis of ischemic heart disease (Hazard Ratio (HR) 0.78, P = 0.03). A genetic proxy for beta-blockade (rs7076938) improved freedom from rehospitalization or death in individuals with AF (HR 0.92, P = 0.001), and a genetic proxy of ACE inhibition (rs7076938) improved freedom from rehospitalization for HF or death (HR 0.8, P = 0.017) and AF (HR 0.85, P = 0.0014). A protective variant in GLP1R (rs10305492) showed decreased risk of developing HF or CV death after diagnosis of ischemic heart disease (HR = 0.82, P = 0.031) and a protective variant in ABCC8 (rs757110) showed decreased risk of CV mortality since ischemic disease diagnosis (HR = 0.88, P = 0.04) and decreased risk of AF in diabetic patients with ischemic heart disease (HR = 0.68, P = 0.001). Notably, despite smaller cohort sizes after matching, we often observed numerically smaller HRs and reduced P, indicating more pronounced effects and increased statistical association. However, not all genetic proxies replicated known treatment effects. CONCLUSIONS: Genetic proxies for well-known drugs corroborate findings from clinical trials in cardiovascular disease. Our results demonstrate a useful analytical approach that leverages genetic evidence from a large cohort with longitudinal outcomes data to effectively select patient populations where specific drug targets may be most effective.
背景：人类遗传学是识别作为潜在药物靶点的基因的重要工具，对心血管疾病的广泛遗传学研究提供了一个机会，可利用遗传学将特定患者群体与特定药物靶点相匹配，以改善临床研究中患者选择的优先级。 方法：我们选择了前蛋白转化酶枯草溶菌素9（PCSK9）区域（rs11591147和rs562556）、β1肾上腺素能受体（ADRB1，rs7076938）、血管紧张素转换酶（ACE，rs4968782和rs4363）、胰高血糖素样肽-1受体（GLP1R，rs10305492）和磺脲类受体1（ABCC8，rs757110）中描述详尽的基因变异作为药物效应的替代指标。利用生存分析，通过真实世界纵向数据集评估它们对房颤（AF）和心力衰竭（HF）死亡及/或再次住院的影响。为减轻心血管（CV）结局混杂因素的影响，我们采用了倾向评分匹配法。 结果：匹配后，PCSK9抑制的基因替代指标（rs11591147）改善了缺血性心脏病患者CV死亡/心脏移植后的生存率（风险比（HR）0.78，P = 0.03）。β受体阻滞剂的基因替代指标（rs7076938）改善了房颤患者再次住院或死亡的自由度（HR 0.92，P = 0.001），ACE抑制的基因替代指标（rs7076938）改善了HF再次住院或死亡的自由度（HR 0.8，P = 0.017）以及房颤的自由度（HR 0.85，P = 0.0014）。GLP1R中的一个保护性变异（rs10305492）显示，在诊断为缺血性心脏病后发生HF或CV死亡的风险降低（HR = 0.82，P = 0.031），ABCC8中的一个保护性变异（rs757110）显示，自缺血性疾病诊断以来CV死亡率降低（HR = 0.88，P = 0.04），且在患有缺血性心脏病的糖尿病患者中房颤风险降低（HR = 0.68，P = 0.001）。值得注意的是，尽管匹配后的队列规模较小，但我们经常在数值上观察到较小的HR和降低的P值，表明效应更显著且统计关联性增加。然而，并非所有基因替代指标都能重复已知的治疗效果。 结论：知名药物的基因替代指标证实了心血管疾病临床试验的结果。我们的结果展示了一种有用的分析方法，该方法利用来自具有纵向结局数据的大型队列的遗传证据，有效选择特定药物靶点可能最有效的患者群体。
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