학술논문
Hyaluronan synthase 3 variant and anthracycline-related cardiomyopathy: a report from the children's oncology group.
Document Type
Academic Journal
Author
Wang, Xuexia; Liu, Wei; Sun, Can-Lan; Armenian, Saro H; Hakonarson, Hakon; Hageman, Lindsey; Ding, Yan; Landier, Wendy; Blanco, Javier G; Chen, Lu; Quiñones, Adolfo; Ferguson, Daniel; Winick, Naomi; Ginsberg, Jill P; Keller, Frank; Neglia, Joseph P; Desai, Sunil; Sklar, Charles A; Castellino, Sharon M; Cherrick, Irene; et al
Source
Subject
Language
English
ISSN
0732-183X
Abstract
Purpose: The strong dose-dependent association between anthracyclines and cardiomyopathy is further exacerbated by the co-occurrence of cardiovascular risk factors (diabetes and hypertension). The high morbidity associated with cardiomyopathy necessitates an understanding of the underlying pathogenesis so that targeted interventions can be developed.Patients and Methods: By using a two-stage design, we investigated host susceptibility to anthracycline-related cardiomyopathy by using the ITMAT/Broad CARe cardiovascular single nucleotide polymorphism (SNP) array to profile common SNPs in 2,100 genes considered relevant to de novo cardiovascular disease.Results: By using a matched case-control design (93 cases, 194 controls), we identified a common SNP, rs2232228, in the hyaluronan synthase 3 (HAS3) gene that exerts a modifying effect on anthracycline dose-dependent cardiomyopathy risk (P = 5.3 × 10(-7)). Among individuals with rs2232228 GG genotype, cardiomyopathy was infrequent and not dose related. However, in individuals exposed to high-dose (> 250 mg/m(2)) anthracyclines, the rs2232228 AA genotype conferred an 8.9-fold (95% CI, 2.1- to 37.5-fold; P = .003) increased cardiomyopathy risk compared with the GG genotype. This gene-environment interaction was successfully replicated in an independent set of 76 patients with anthracycline-related cardiomyopathy. Relative HAS3 mRNA levels measured in healthy hearts tended to be lower among individuals with AA compared with GA genotypes (P = .09).Conclusion: Hyaluronan (HA) produced by HAS3 is a ubiquitous component of the extracellular matrix and plays an active role in tissue remodeling. In addition, HA is known to reduce reactive oxygen species (ROS) -induced cardiac injury. The high cardiomyopathy risk associated with AA genotype could be due to inadequate remodeling and/or inadequate protection of the heart from ROS-mediated injury on high anthracycline exposure.