RESUMEN
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.
Asunto(s)
Apolipoproteínas/genética , Furosemida/administración & dosificación , Insuficiencia Cardíaca/tratamiento farmacológico , Lipoproteínas HDL/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/administración & dosificación , Administración Intravenosa , Anciano , Anciano de 80 o más Años , Apolipoproteína L1 , Ensayos Clínicos como Asunto , Femenino , Transferencias de Fluidos Corporales/efectos de los fármacos , Genotipo , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Farmacogenética , Fenotipo , Factores de Tiempo , Resultado del Tratamiento , Equilibrio Hidroelectrolítico/efectos de los fármacosRESUMEN
Cisplatin is a widely used chemotherapeutic agent for the treatment of solid tumors. A serious complication of cisplatin treatment is permanent hearing loss. The aim of this study was to replicate previous genetic findings in an independent cohort of 155 pediatric patients. Associations were replicated for genetic variants in TPMT (rs12201199, P = 0.0013, odds ratio (OR) 6.1) and ABCC3 (rs1051640, P = 0.036, OR 1.8). A predictive model combining variants in TPMT, ABCC3, and COMT with clinical variables (patient age, vincristine treatment, germ-cell tumor, and cranial irradiation) significantly improved the prediction of hearing-loss development as compared with using clinical risk factors alone (area under the curve (AUC) 0.786 vs. 0.708, P = 0.00048). The novel combination of genetic and clinical factors predicted the risk of hearing loss with a sensitivity of 50.3% and a specificity of 92.7%. These findings provide evidence to support the importance of TPMT, COMT, and ABCC3 in the prediction of cisplatin-induced hearing loss in children.