ABSTRACT
BACKGROUND: The use of anthracyclines as effective antineoplastic drugs is limited by the occurrence of cardiotoxicity. Multiple genetic variants predictive of anthracycline-induced cardiotoxicity (ACT) in children were recently identified. The current study was aimed to assess replication of these findings in an independent cohort of children. PROCEDURE: . Twenty-three variants were tested for association with ACT in an independent cohort of 218 patients. Predictive models including genetic and clinical risk factors were constructed in the original cohort and assessed in the current replication cohort. RESULTS: . We confirmed the association of rs17863783 in UGT1A6 and ACT in the replication cohort (P = 0.0062, odds ratio (OR) 7.98). Additional evidence for association of rs7853758 (P = 0.058, OR 0.46) and rs885004 (P = 0.058, OR 0.42) in SLC28A3 was found (combined P = 1.6 × 10(-5) and P = 3.0 × 10(-5), respectively). A previously constructed prediction model did not significantly improve risk prediction in the replication cohort over clinical factors alone. However, an improved prediction model constructed using replicated genetic variants as well as clinical factors discriminated significantly better between cases and controls than clinical factors alone in both original (AUC 0.77 vs. 0.68, P = 0.0031) and replication cohort (AUC 0.77 vs. 0.69, P = 0.060). CONCLUSIONS: . We validated genetic variants in two genes predictive of ACT in an independent cohort. A prediction model combining replicated genetic variants as well as clinical risk factors might be able to identify high- and low-risk patients who could benefit from alternative treatment options.
Subject(s)
Anthracyclines/adverse effects , Antineoplastic Agents/adverse effects , Cardiotoxins/adverse effects , Cardiovascular Diseases/genetics , Glucuronosyltransferase/genetics , Membrane Transport Proteins/genetics , Models, Biological , Polymorphism, Single Nucleotide , Adolescent , Anthracyclines/administration & dosage , Antineoplastic Agents/administration & dosage , Cardiotoxins/administration & dosage , Cardiovascular Diseases/chemically induced , Child , Child, Preschool , Cohort Studies , Female , Genetic Markers , Humans , Infant , Male , Neoplasms/drug therapy , Neoplasms/genetics , Predictive Value of TestsABSTRACT
Anatomic repair of transposition of the great arteries (TGA) has been developed because of concerns about right ventricular function after atrial repair by the Mustard or the Senning technique. This study assessed left ventricular systolic and diastolic function in three patients after two-stage anatomic repair. Two patients had a ventricular septal defect (one with coarctation), and the third patient had right ventricular dysfunction precluding atrial repair. All had pulmonary artery banding. The mean ages at the time of repair and catheterization were 2.75 and 4.9 years, respectively. The control group included 10 patients with insignificant or no cardiac disease. At cardiac catheterization the group with TGA had a higher mean end-diastolic volume index (110.9 +/- 4.74 ml/m2) compared to normal subjects (79.1 +/- 14.55; p less than 0.001), mean end-systolic volume index (37.3 +/- 3.69 vs 22.7 +/- 4.42; p less than 0.001), mass index (101.0 +/- 16.9 vs 68.2 +/- 12.34; p = 0.038), and stroke volume index (73.6 +/- 3.52 vs 56.5 +/- 12.1; p = 0.0027). The ejection fractions, end-diastolic and peak systolic pressures, and stresses were not different. There was no difference in the relationship between the mean rate-corrected velocity of circumferential fiber shortening and end-systolic stress for the group with TGA, but myocardial stiffness was markedly elevated (29.5 +/- 1.84 vs 10.8 +/- 2.20; p less than 0.001). Thus, this study found abnormalities of left ventricular size after two-stage anatomic repair of TGA in this group of patients with TGA.(ABSTRACT TRUNCATED AT 250 WORDS)
