de Denus S, Rouleau J L, Mann D L, Huggins G S, Cappola T P, Shah S H, Keleti J, Zada Y F, Provost S, Bardhadi A, Phillips M S, Normand V, Mongrain I, Dubé M-P
Research Center, Montreal Heart Institute, Montreal, Quebec, Canada.
Université de Montréal Beaulieu-Saucier Pharmacogenomics Center, Montreal, Quebec, Canada.
Pharmacogenomics J. 2017 Mar;17(2):192-200. doi: 10.1038/tpj.2016.4. Epub 2016 Mar 1.
We conducted a meta-analysis of pharmacogenomic substudies of three randomized trials conducted in patients with decompensated heart failure (HF) that were led by National Heart Lung and Blood Institute (NHLBI)-funded HF Network to test the hypothesis that candidate genes modulate net fluid loss and weight change in patients with decompensated HF treated with a furosemide-based diuretic regimen. Although none of the genetic variants previously shown to modulate the effects of loop diuretics in healthy individuals were associated with net fluid loss after 72 h of treatment, a set of rare variants in the APOL1 gene, which codes for apolipoprotein L1 (P=0.0005 in the random effects model), was associated with this end point. Moreover, a common variant in the multidrug resistance protein-4 coding gene (ABCC4, rs17268282) was associated with weight loss with furosemide use (P=0.0001). Our results suggest that both common and rare genetic variants modulate the response to a furosemide-based diuretic regimen in patients with decompensated HF.
我们对由美国国立心肺血液研究所（NHLBI）资助的心力衰竭网络开展的三项针对失代偿性心力衰竭（HF）患者的随机试验的药物基因组学子研究进行了荟萃分析，以检验以下假设：候选基因可调节接受基于速尿的利尿剂治疗方案的失代偿性HF患者的净液体丢失和体重变化。尽管先前在健康个体中显示可调节袢利尿剂作用的基因变异均与治疗72小时后的净液体丢失无关，但载脂蛋白L1编码基因（APOL1）中的一组罕见变异（随机效应模型中P=0.0005）与该终点相关。此外，多药耐药蛋白4编码基因（ABCC4，rs17268282）中的一个常见变异与使用速尿导致的体重减轻相关（P=0.0001）。我们的结果表明，常见和罕见基因变异均可调节失代偿性HF患者对基于速尿的利尿剂治疗方案的反应。
