RESUMO
AIM: To identify novel variants associated with anthracycline-induced cardiotoxicity and to assess these in a genotype-guided risk prediction model. PATIENTS & METHODS: Two cohorts treated for childhood cancer (n = 344 and 218, respectively) were genotyped for 4578 SNPs in drug ADME and toxicity genes. RESULTS: Significant associations were identified in SLC22A17 (rs4982753; p = 0.0078) and SLC22A7 (rs4149178; p = 0.0034), with replication in the second cohort (p = 0.0071 and 0.047, respectively). Additional evidence was found for SULT2B1 and several genes related to oxidative stress. Adding the SLC22 variants to the prediction model improved its discriminative ability (AUC 0.78 vs 0.75 [p = 0.029]). CONCLUSION: Two novel variants in SLC22A17 and SLC22A7 were significantly associated with anthracycline-induced cardiotoxicity and improved a genotype-guided risk prediction model, which could improve patient risk stratification.
Assuntos
Antraciclinas/efeitos adversos , Cardiotoxicidade/genética , Cardiopatias/induzido quimicamente , Cardiopatias/genética , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Estresse Oxidativo/genética , RiscoRESUMO
PURPOSE: Anthracycline-induced cardiotoxicity (ACT) is a serious adverse drug reaction limiting anthracycline use and causing substantial morbidity and mortality. Our aim was to identify genetic variants associated with ACT in patients treated for childhood cancer. PATIENTS AND METHODS: We carried out a study of 2,977 single-nucleotide polymorphisms (SNPs) in 220 key drug biotransformation genes in a discovery cohort of 156 anthracycline-treated children from British Columbia, with replication in a second cohort of 188 children from across Canada and further replication of the top SNP in a third cohort of 96 patients from Amsterdam, the Netherlands. RESULTS: We identified a highly significant association of a synonymous coding variant rs7853758 (L461L) within the SLC28A3 gene with ACT (odds ratio, 0.35; P = 1.8 × 10(-5) for all cohorts combined). Additional associations (P < .01) with risk and protective variants in other genes including SLC28A1 and several adenosine triphosphate-binding cassette transporters (ABCB1, ABCB4, and ABCC1) were present. We further explored combining multiple variants into a single-prediction model together with clinical risk factors and classification of patients into three risk groups. In the high-risk group, 75% of patients were accurately predicted to develop ACT, with 36% developing this within the first year alone, whereas in the low-risk group, 96% of patients were accurately predicted not to develop ACT. CONCLUSION: We have identified multiple genetic variants in SLC28A3 and other genes associated with ACT. Combined with clinical risk factors, genetic risk profiling might be used to identify high-risk patients who can then be provided with safer treatment options.
Assuntos
Antraciclinas/efeitos adversos , Antibióticos Antineoplásicos/efeitos adversos , Cardiopatias/etiologia , Neoplasias/tratamento farmacológico , Polimorfismo de Nucleotídeo Único , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Adolescente , Fatores Etários , Antraciclinas/metabolismo , Antibióticos Antineoplásicos/metabolismo , Biotransformação , Canadá , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Cardiopatias/induzido quimicamente , Cardiopatias/genética , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Países Baixos , Razão de Chances , Farmacogenética , Fenótipo , Medição de Risco , Fatores de RiscoRESUMO
OBJECTIVES: To determine if the Nuchal index (NIx) is increased in euploid fetuses with structural congenital heart defects (CHD). METHODS: Euploid fetuses with CHD between 18 and 24 weeks gestation were identified. The next fetus meeting the same criteria with a normal fetal echocardiogram were selected as a control. The NIx [(mean nuchal thickness /mean biparietal diameter) x 100] and cardiac axis (CA; degrees) were calculated for each fetus. Standard descriptive tests and two-tailed t test were used. RESULTS: The NIx in the abnormal (n = 20) and control (n = 20) groups were 9.10 (2.35) and 7.54 (p = 0.04) and CA was 55.8 degrees and 48.6 degrees (p = 0.02), respectively. CONCLUSIONS: The NIx and CA were significantly different in fetuses with CHD. A prospective study to confirm these findings and determine clinical utility is warranted.
Assuntos
Coração Fetal/diagnóstico por imagem , Cardiopatias Congênitas/diagnóstico por imagem , Medição da Translucência Nucal , Feminino , Coração Fetal/anormalidades , Cardiopatias Congênitas/embriologia , Humanos , Recém-Nascido , Gravidez , Primeiro Trimestre da GravidezRESUMO
An arterial stiffness index based on the transmission line model is defined. The parameters of the transmission line model are initially estimated using measured pressure, flow and aortic root diameter. Pressure is measured at the carotid using applanation tonometry. Flow is measured using Doppler at the ascending aorta. Aortic root diameter is measured using 2-D echocardiography. The initial estimates are then refined using grey-box identification. The resulting estimate of the distributive compliance of the transmission line model is proposed to be an arterial stiffness index. Similar to the Windkessel compliance, this index describes the global stiffness. However, it is based on a more realistic 1-D model that can simulate wave propagation and wave reflection.
