Determinants of late cardiovascular morbidity among survivors of hematopoietic ce

描述（由申请人提供）：Dr. Chow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。在结果研究和遗传流行病学方面的严格教学和指导计划将为申请人提供全面检查治疗，环境和宿主因素影响癌症治疗后心血管疾病的基础。具体来说，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的改进导致了长期幸存者数量的增加，除了复发和慢性移植物抗宿主病（GVHD）外，需要更好地确定这一人群中发病率和死亡率的原因。幸存者出现高血压、血脂异常和糖尿病等不良晚期反应的风险增加，所有这些都导致心血管发病率和死亡率增加。可能的危险因素包括：1)移植前蒽环类药物和放疗暴露，与晚期心肌病、瓣膜和血管损伤有关；2)慢性GVHD和全身照射（TBI），这两种物质被认为会导致内皮损伤和动脉粥样硬化。以前的研究受到选择和回忆偏差、小样本量和主要临床因素评估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，但往往缺乏详细的hct前治疗、环境暴露和遗传信息。为了解决这些局限性，Dr. Chow建议研究自1969年以来在Fred Hutchinson癌症研究中心（FHCRC）接受治疗的近5000名2年HCT幸存者的队列。该队列的优势在于FHCRC拥有一个特殊的临床研究数据库，随访损失小于1%，并且可以获得出院和死亡记录，以及记录与CV疾病相关的医疗、环境和家族史的患者问卷。该队列通过丰富的环境和家族史，改善了CV结果的表型特征，将有助于更深入地分析（通过嵌套病例队列设计）该人群中易患CV疾病的危险因素，包括有意义的遗传变异调查。在FHCRC收集的现有全基因组变异数据将用于鉴定新的位点并复制先前发表的关联。总的来说，这些结果将有助于更好地对晚期CV疾病风险增加的个体进行分类，并使临床医生和患者有机会修改治疗方法和/或通过早期干预制定更有针对性的hct后监测。这项研究也与接受类似治疗暴露的更多癌症幸存者直接相关。完成这些目标将为候选人提供必要的技能、经验和启动独立研究计划的初步数据。

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.