Common Genetic Pathways Underlying CVD and COPD

 描述(由申请人提供)：这是为Sharon Lutz博士重新提交的导师研究科学家发展奖(家长K01)的申请，Sharon Lutz博士是科罗拉多大学安舒茨医学院科罗拉多公共卫生学院(CSPH)生物统计学助理教授。卢茨博士在慢性阻塞性肺疾病(COPD)和心脏血管疾病(CVD)的基因重叠方面确立了自己作为年轻研究员的地位。这一K01奖项将为Lutz博士提供必要的支持，以便通过正式培训获得COPD和CVD重叠的病理生理学和流行病学的坚实基础知识，以便成为研究COPD和CVD共同遗传易感性的独立研究员。为了实现这一目标，卢茨博士组建了一个由流行病学导师约翰·霍坎森博士和生物统计学导师塔莎·芬格林博士组成的指导团队。Hokanson博士是CSPH的流行病学教授，也是国家心肺血液研究所(NHLBI)资助的COPD基因研究的流行病学中心主任。芬格林博士是CSPH生物统计学副教授和国家犹太人健康中心基因、环境和健康中心主任。除了Lutz博士的主要导师外，还将有两名顾问参与该项目：专门研究慢性阻塞性肺疾病统计遗传学的哈佛大学公共卫生学院生物统计学教授Christoph Lange博士和港湾加州大学洛杉矶分校医学中心心脏病学教授、美国心脏协会(AHA)关于EBT和多层CT扫描仪的科学声明主席Matthew Budoff博士。心血管疾病是慢性阻塞性肺疾病患者最常见的两种死亡原因之一。然而，COPD患者独特的高心血管风险的炎症和遗传基础仍不清楚。Lutz博士的研究将检验COPD基因研究(AIM 1)中以FEV1和FEV1/FVC衡量的COPD的遗传重叠，以及以冠状动脉钙(CAC)和胸主动脉钙(TAC)衡量的心血管疾病的基因重叠。Lutz博士将开发统计方法来量化二元表型、两个以上表型和罕见变异之间的遗传重叠。(目的1)由于吸烟可能影响COPD和CVD之间的遗传重叠，Lutz博士将通过吸烟在肺功能(FEV1和FEV1/FVC)和血管钙化(CAC和TAC)这两个指标上检验基因的相互作用。(目标2)由于基因与环境相互作用的标准方法往往缺乏效力，Lutz博士提出了一种利用已知遗传信息并保持分层原则的基因与环境相互作用的贝叶斯方法。(目标2)为了确定通过吸烟从基因到疾病的路径，卢茨博士将开发一种统计方法，以确定罕见的变异是否与 吸烟引起的肺功能(FEV1和FEV1/FVC)和血管钙化(CAC和TAC)。(目标3)

 DESCRIPTION (provided by applicant): This is a resubmission of the application for a Mentored Research Scientist Development Award (Parent K01) for Dr. Sharon Lutz, an Assistant Professor of Biostatistics at the Colorado School of Public Health (CSPH) at the University of Colorado, Anschutz Medical Campus. Dr. Lutz is establishing herself as a young investigator in the genetic overlap of Chronic Obstructive Pulmonary Disease (COPD) and Cardio Vascular Disease (CVD). This K01 award will provide Dr. Lutz with the support necessary to acquire a solid foundational knowledge of the pathophysiology and epidemiology of the overlap between COPD and CVD through formal training in order to become an independent investigator studying common genetic susceptibility for COPD and CVD. To achieve this goal, Dr. Lutz has assembled a mentoring team comprised of an Epidemiology mentor, Dr. John Hokanson, and a Biostatistics mentor, Dr. Tasha Fingerlin. Dr. Hokanson is a Professor of Epidemiology at CSPH and Director of the Epidemiology Center for the National Heart, Lung, and Blood Institute (NHLBI) funded COPDGene study. Dr. Fingerlin is an Associate Professor of Biostatistics at CSPH and director of the Center for Gene, Environment, and Health at National Jewish Health. In addition to Dr. Lutz's primary mentors, two consultants will serve on this project: Dr. Christoph Lange, a Professor of Biostatistics at Harvard School of Public Health who specializes in the statistical genetics of COPD and Dr. Matthew Budoff, a Professor of Cardiology at Harbor-UCLA Medical Center who is the chairman of the American Heart Association (AHA) Scientific Statement on EBT and Multi-slice CT Scanner. CVD is one of two most common causes of death in patients with COPD. However, the inflammatory and genetic basis for the uniquely high CVD risk in subjects with COPD remains unknown. Dr. Lutz's research will examine the genetic overlap of COPD as measured by FEV1 and FEV1/FVC and CVD as measured by coronary artery calcium (CAC) and thoracic aortic calcium (TAC) in the COPDGene study (AIM 1). Dr. Lutz will develop statistical methodology to quantify genetic overlap amongst binary phenotypes, more than 2 phenotypes, and rare variants. (AIM 1) Since smoking may influence the genetic overlap between COPD and CVD, Dr. Lutz will examine gene by smoking interactions in both measures of pulmonary function (FEV1 and FEV1/FVC) and vascular calcification (CAC and TAC). (AIM 2) Because standard methods for gene by environment interactions tend to be underpowered, Dr. Lutz proposes a Bayesian method for gene by environment interactions that leverages known genetic information and maintains the hierarchical principle. (AIM 2) To determine the path from gene to disease through smoking, Dr. Lutz will develop a statistical method to determine if rare variants are associated indirectly with pulmonary function (FEV1 and FEV1/FVC) and vascular calcification (CAC and TAC) through smoking. (AIM 3)