透明质酸合酶 3 变体与蒽环类相关的心肌病：来自儿童肿瘤学组的报告。
Hyaluronan synthase 3 variant and anthracycline-related cardiomyopathy: a report from the children's oncology group.
机构信息
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.
出版信息
J Clin Oncol. 2014 Mar 1;32(7):647-53. doi: 10.1200/JCO.2013.50.3557. Epub 2014 Jan 27.
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.
目的
蒽环类药物与心肌病之间存在强烈的剂量依赖性关联，而心血管危险因素（糖尿病和高血压）的共同发生进一步加剧了这种关联。心肌病相关的高发病率要求我们了解其潜在发病机制，以便开发有针对性的干预措施。
方法
我们采用两阶段设计，使用 ITMAT/Broad CARe 心血管单核苷酸多态性（SNP）阵列来分析 2100 个与新发心血管疾病相关的基因中的常见 SNP，以此研究宿主对蒽环类药物相关心肌病的易感性。
结果
通过使用匹配的病例对照设计（93 例病例，194 例对照），我们在透明质酸合酶 3（HAS3）基因中发现了一个常见的 SNP，rs2232228，该 SNP 对蒽环类药物剂量依赖性心肌病风险具有修饰作用（P = 5.3×10(-7)）。在 rs2232228 GG 基因型个体中，心肌病罕见且与剂量无关。然而，在暴露于高剂量（>250mg/m(2)）蒽环类药物的个体中，与 GG 基因型相比，rs2232228 AA 基因型使心肌病风险增加了 8.9 倍（95%CI，2.1 至 37.5 倍；P =.003）。这种基因-环境相互作用在另一组 76 例蒽环类药物相关心肌病患者中得到了成功复制。在健康心脏中测量的相对 HAS3 mRNA 水平在 AA 基因型个体中往往低于 GA 基因型个体（P =.09）。
结论
透明质酸（HA）由 HAS3 产生，是细胞外基质的普遍成分，在组织重塑中发挥积极作用。此外，HA 已知可减少活性氧（ROS）诱导的心脏损伤。AA 基因型与高心肌病风险相关，可能是由于在高蒽环类药物暴露时，心脏的重塑不足和/或对 ROS 介导的损伤的保护不足所致。
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