Determinants of late cardiovascular morbidity among survivors of hematopoietic ce

描述（由申请人提供）：周博士的长期目标是成为一名独立的，以患者为导向的研究者，专注于了解影响癌症幸存者的代谢和心血管（CV）并发症。结果研究和遗传流行病学方面严格的教学和指导计划将为申请人提供全面检查癌症治疗后影响CV疾病的治疗，环境和宿主因素的基础。具体而言，他建议研究造血细胞移植（HCT）后不良CV晚期效应的决定因素。HCT的改进导致长期存活者的数量增加，并且需要更好地描述该人群中除复发和慢性移植物抗宿主病（GVHD）外的发病率和死亡率原因。存活者出现不良晚期效应（如高血压、血脂异常和糖尿病）的风险增加，所有这些均导致CV发病率和死亡率增加。据称的风险因素包括：1）移植前蒽环类抗生素和放射治疗暴露，其与晚期心肌病、瓣膜和血管损伤相关;以及2）慢性GVHD和全身照射（TBI），其被假设为引起内皮损伤和动脉粥样硬化。以往的研究受到选择和回忆偏差、样本量小以及主要评价临床因素而不考虑遗传决定因素的限制。来自集中登记的数据包含较大的样本，但通常缺乏详细的HCT前治疗、环境暴露和遗传信息。为了解决这些局限性，Chow博士建议研究自1969年以来在Fred哈钦森癌症研究中心（FHCRC）接受治疗的近5000例e2年HCT幸存者。该队列具有以下优势：FHCRC的特殊临床研究数据库（失访率<1%）、出院和死亡记录的可用性以及记录与CV疾病相关的医疗、环境和家族史的患者问卷。该队列改善了CV结局的表型特征，并补充了丰富的环境和家族史，将有助于对该人群中易患CV疾病的风险因素进行更深入的分析（通过嵌套病例-队列设计），包括对遗传变异进行有意义的研究。FHCRC收集的现有全基因组变异数据将用于识别新的基因座并复制先前发表的关联。总体而言，这些结果将允许对可能处于晚期CV疾病风险增加的个体进行更好的分类，并为临床医生和患者提供调整治疗和/或通过早期干预开发更具针对性的HCT后监测的机会。这项研究也与接受类似治疗暴露的癌症幸存者群体直接相关。完成这些目标将为候选人提供必要的技能，经验和初步数据，以启动独立的研究计划。

DESCRIPTION (provided by applicant): Dr. Chow's long-term goal is to become an independent, patient-oriented investigator focused on understanding the metabolic and cardiovascular (CV) complications affecting cancer survivors. A rigorous didactic and mentoring program in outcomes research and genetic epidemiology will provide the applicant the foundation to comprehensively examine treatment, environmental, and host factors that influence CV disease following cancer treatment. Specifically, he proposes to investigate determinants of adverse CV late effects following hematopoietic cell transplantation (HCT). Refinements in HCT have led to an increasing number of long-term survivors and a need to better characterize causes of morbidity and mortality in this population besides relapse and chronic graft versus host disease (GVHD). Survivors appear to be at increased risk of adverse late effects such as hypertension, dyslipidemia, and diabetes, all of which contribute to increased CV morbidity and mortality. Purported risk factors include: 1) pre-transplant anthracycline and radiotherapy exposure, which are associated with late cardiomyopathy, valvular and vascular injury; and 2) chronic GVHD and total body irradiation (TBI), which are hypothesized to cause endothelial injury and atherosclerosis. Previous studies have been limited by selection and recall biases, small sample size, and evaluation of primarily clinical factors without consideration of genetic determinants. Data from centralized registries contain larger samples, but often lack detailed pre-HCT treatment, environmental exposure, and genetic information. To address these limitations, Dr. Chow proposes to study a cohort of nearly 5000 e2 yr HCT survivors treated at the Fred Hutchinson Cancer Research Center (FHCRC) since 1969. This cohort has advantages of an exceptional clinical research database at FHCRC with <1% loss to follow-up, and availability of hospital discharge and death records, and patient questionnaires documenting medical, environmental, and family histories relevant to CV disease. This cohort, with improved phenotypic characterization of CV outcomes supplemented by enriched environmental and family histories, will facilitate more in-depth analyses (via a nested case-cohort design) of risk factors that predispose towards CV disease in this population, including meaningful investigation of genetic variation. Existing genome-wide variation data collected at FHCRC will be used to identify novel loci and to replicate prior published associations. Overall, these results will allow better classification of individuals who may be at increased risk of late CV disease and give clinicians and patients an opportunity to modify therapy and/or develop more targeted post-HCT surveillance with earlier intervention. This research also has direct relevance to the larger population of cancer survivors who receive similar treatment exposures. Completion of these aims will provide the candidate with the necessary skills, experience, and preliminary data to launch an independent research program.