Hyaluronan synthase 3 variant and anthracycline-related cardiomyopathy: a report from the children's oncology group.
OBJECTIVE
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.


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).


CONCLUSIONS
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.
Xuexia Wang, University of Wisconsin-Milwaukee, Milwaukee, WI; Wei Liu and Yutaka Yasui, University of Alberta; Sunil Desai, Stollery Children's Hospital, Edmonton, AB, Canada; Can-Lan Sun, Saro H. Armenian, Lindsey Hageman, Yan Ding, Wendy Landier, and Smita Bhatia, City of Hope, Duarte; Lu Chen, University of Southern California, Los Angeles, CA; Hakon Hakonarson and Jill P. Ginsberg, Children's Hospital of Philadelphia, Philadelphia, PA; Javier G. Blanco, Alfo Quiñones, and Daniel Ferguson, The State University of New York at Buffalo, Buffalo; Charles A. Sklar, Memorial Sloan-Kettering Cancer Center, New York City; Irene Cherrick, Upstate Medical University, Syracuse, NY; Naomi Winick, University of Texas Southwestern Medical Center, Dallas; Zoann E. Dreyer, Baylor College of Medicine, Houston, TX; Frank Keller, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, GA; Joseph P. Neglia, University of Minnesota Medical School, Minneapolis, MN; Sharon M. Castellino, Wake Forest University Health Sciences, Winston-Salem, NC; and Melissa M. Hudson, Leslie L. Robison, and Mary V. Relling, St. Jude Children's Research Hospital, Memphis, TN.
Xuexia
X
Wang
Wei
W
Liu
Can-Lan
CL
Sun
Saro H
SH
Armenian
Hakon
H
Hakonarson
Lindsey
L
Hageman
Yan
Y
Ding
Wendy
W
Landier
Javier G
JG
Blanco
Lu
L
Chen
Adolfo
A
Quiñones
Daniel
D
Ferguson
Naomi
N
Winick
Jill P
JP
Ginsberg
Frank
F
Keller
Joseph P
JP
Neglia
Sunil
S
Desai
Charles A
CA
Sklar
Sharon M
SM
Castellino
Irene
I
Cherrick
ZoAnn E
ZE
Dreyer
Melissa M
MM
Hudson
Leslie L
LL
Robison
Yutaka
Y
Yasui
Mary V
MV
Relling
Smita
S
Bhatia
D000293:Adolescent; D018943:Anthracyclines / Q000008:administration & dosage / Q000009:adverse effects*; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects*; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D000076002:Hyaluronan Synthases; D008297:Male; D020641:Polymorphism, Single Nucleotide; D017382:Reactive Oxygen Species / Q000378:metabolism
D018943:Anthracyclines; D000903:Antibiotics, Antineoplastic; D017382:Reactive Oxygen Species; D014453:Glucuronosyltransferase; C105458:HAS3 protein, human; D000076002:Hyaluronan Synthases