Determinants of late cardiovascular morbidity among survivors of hematopoietic ce

描述(申请人提供)：周博士的长期目标是成为一名独立的、以患者为中心的研究人员，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者提供全面检查治疗、环境和宿主因素的基础，这些因素影响癌症治疗后的心血管疾病。具体地说，他建议调查造血细胞移植(HCT)后心血管不良反应的决定因素。HCT的改进导致了越来越多的长期幸存者，除了复发和慢性移植物抗宿主病(GVHD)外，还需要更好地描述这一人群的发病率和死亡率的原因。幸存者似乎面临着更高的不良后遗症风险，如高血压、血脂异常和糖尿病，所有这些都会增加心血管疾病的发病率和死亡率。所谓的危险因素包括：1)移植前的蒽环类药物和放射治疗暴露，这与晚期心肌病、瓣膜和血管损伤有关；以及2)慢性移植物抗宿主病和全身照射(TBI)，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、样本量小以及对主要临床因素的评估而没有考虑遗传决定因素的限制。来自集中登记的数据包含更大的样本，但往往缺乏详细的血细胞移植前治疗、环境暴露和遗传信息。为了解决这些局限性，周博士建议对自1969年以来在弗雷德·哈钦森癌症研究中心(FHCRC)接受治疗的近5000名e2岁HCT幸存者进行研究。这一队列具有以下优势：FHCRC有一个特殊的临床研究数据库，有1%的随访损失，可以获得出院和死亡记录，以及记录与心血管疾病相关的医疗、环境和家族病史的患者问卷。这一队列具有更好的心血管结局的表型特征，并辅之以丰富的环境和家族史，将有助于对该人群中易患心血管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)，包括对遗传变异的有意义的调查。在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，这些结果将使可能面临晚期心血管疾病风险增加的个人得到更好的分类，并使临床医生和患者有机会修改治疗和/或通过更早的干预来制定更有针对性的HCT后监测。这项研究还与接受类似治疗暴露的更大数量的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、经验和初步数据，以启动独立研究计划。

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.