Identifying clinical and genetic correlates of hepatic fibrosis from fatty liver disease in the community

确定社区脂肪肝病肝纤维化的临床和遗传相关性

• 批准号: 10064628
• 负责人: Michelle T Long
• 金额: $ 18.84万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-12 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064628
• 关键词: Affect; Alcohol consumption; American; Ancillary Study; Area; Award; Benign; Biochemical Genetics; Biometry; Blood; Boston; Cardiovascular Diseases; Cessation of life; Clinical; Clinical Investigator; Clinical Research; Cohort Studies; Collaborations; Communities; Data; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Education; Epidemiologist; Epidemiology; European; Evaluation; Event; Faculty; Fatty Liver; Fibrosis; Foundations; Framingham Heart Study; Funding; Future; Gastroenterology; Generations; Genetic; Genetic Determinism; Genetic Models; Genetic Risk; Genetic study; Genomics; Genotype; Goals; Gold; Hepatic; High Prevalence; Individual; Infiltration; Intervention; Liver; Liver Fibrosis; Liver diseases; Master of Science; Measures; Medical Genetics; Medical center; Mentors; Mentorship; Meta-Analysis; Metabolic Diseases; Methods; Minority; Modeling; Netherlands; Outcome; Participant; Pathologic; Patients; Performance; Physical activity; Population; Positioning Attribute; Prevalence; Program Development; Progressive Disease; Public Health; Public Health Schools; Publications; Recording of previous events; Reporting; Research; Research Personnel; Research Training; Risk; Risk Factors; Sample Size; Sampling; Scanning; Scientist; Screening procedure; Serum; Single Nucleotide Polymorphism; Testing; Time; Training; Translational Research; United States; Universities; Validation; Work; X-Ray Computed Tomography; base; biomarker development; cardiovascular disorder risk; career; career development; clinical diagnostics; clinically significant; cohort; cost; diagnosis standard; drug development; elastography; genetic variant; genome sciences; genome wide association study; genomic data; high risk; histological studies; imaging modality; implementation science; improved; indexing; insight; liver biopsy; medical schools; member; mortality; new therapeutic target; non-alcoholic fatty liver disease; novel; predictive modeling; prevent; professor; prospective; risk prediction; risk stratification; supportive environment; therapeutic target; tool; trait; vibration

Project Summary Michelle T. Long, MD, is a faculty member of the Boston Medical Center, Division of Gastroenterology and an Assistant Professor at the Boston University (BU) School of Medicine. Her research has focused on non-alcoholic fatty liver disease (NAFLD) as measured by computed tomography scan in the Framingham Heart Study (FHS). In her prior work, she has evaluated the association between NAFLD and physical activity and NAFLD and sub- clinical measures of cardiovascular disease (CVD) in the FHS cohort. Her work in these areas has resulted in 4 first author publications including the development and validation of a simple clinical diagnostic score for hepatic steatosis called the Framingham Steatosis Index. Her recent study utilizing blood-based non-invasive hepatic fibrosis markers in the FHS determined that the available fibrosis markers give widely disparate predictions of the risk for significant hepatic fibrosis when applied to this community-based cohort. NAFLD associated hepatic fibrosis is an important public health problem. More than 15 million Americans are estimated to suffer from hepatic fibrosis from NAFLD which worsens metabolic disease and increases the risk of liver- related and CVD- related death. Studies to date examining NAFLD in community-based cohorts in the United States have relied on imaging modalities that are insensitive to hepatic fibrosis. Dr. Long's proposal will focus on testing three hypotheses; 1) FHS participants with hepatic fibrosis, as measured by vibration-controlled transient elastography (VCTE), have a more adverse CVD risk factor profile compared to those with no fibrosis, 2) Genetic determinants for the risk of hepatic fibrosis are identifiable by genome wide association studies and 3) A diagnostic model based on clinical and genetic traits distinguishes NAFLD patients with and without fibrosis as defined by VCTE and the model performs well when applied to an external validation cohort. The study of the clinical and genetic traits associated with hepatic fibrosis in the community will lead to insights into disease mechanisms, biomarker development, and novel therapeutic targets, which has the potential to improve public health. This study will be performed as an ancillary study of approximately 3,500 FHS Third Generation and OMNI 2 cohort participants who are undergoing evaluation for hepatic fibrosis using VCTE. Dr. Long’s ultimate career goal is to use epidemiological insights for two purposes: a) identify potential novel drug targets; and b) develop tools to identify high risk NAFLD patients to prevent disease progression. To complete this proposal and progress towards these goals, Dr. Long has developed a five year mentored career development program that incorporates both didactic and formal research training guided by two well established investigators with expertise in clinical and translational research in CVD and NAFLD. She will receive formal didactic training in epidemiology, advanced biostatistics, predictive modeling, and implementation science through the BU School of Public Health. With this additional education and guidance, as well as the supportive environment provided by BU, Dr. Long will be well positioned to complete this proposal and develop into an independent clinical investigator.

项目摘要 米歇尔·T Long，医学博士，是波士顿医学中心胃肠病学分部的一名教员， 波士顿大学（BU）医学院助理教授。她的研究主要集中在非酒精性 脂肪肝疾病（NAFLD），如在心脏研究（FHS）中通过计算机断层扫描测量。 在她之前的工作中，她评估了NAFLD和体力活动以及NAFLD和亚健康之间的关联。 FHS队列中心血管疾病（CVD）的临床指标。她在这些领域的工作取得了4 第一作者出版物，包括开发和验证肝脏的简单临床诊断评分 脂肪变性指数（Frachial Steatosis Index）。她最近的研究利用血液为基础的非侵入性肝 FHS中的纤维化标志物确定了可用的纤维化标志物给出了广泛不同的预测， 显著肝纤维化的风险，当应用于这个以社区为基础的队列。NAFLD相关肝 纤维化是一个重要的公共卫生问题。据估计，超过1500万美国人患有 非酒精性脂肪肝引起的肝纤维化，会导致代谢性疾病，增加肝脏相关疾病和心血管疾病的风险， 相关死亡迄今为止，在美国以社区为基础的队列中研究NAFLD的研究依赖于 对肝纤维化不敏感的成像模式。朗博士的建议将集中在测试三个 假设：1）FHS参与者肝纤维化，通过振动控制瞬时弹性成像测量 （VCTE），与无纤维化的患者相比，具有更不利的CVD风险因素特征，2）遗传决定因素 通过全基因组关联研究可识别肝纤维化风险; 3）诊断模型 基于临床和遗传特征区分NAFLD患者与非纤维化，如VCTE所定义的 并且该模型在应用于外部验证群组时表现良好。临床和遗传学的研究 社区中与肝纤维化相关的特征将导致对疾病机制，生物标志物 开发和新的治疗靶点，这有可能改善公众健康。本研究将 作为一项辅助研究，对约3，500名FHS第三代和OMNI 2队列受试者进行了研究 正在接受VCTE肝纤维化评估的患者。龙博士的最终职业目标是利用 流行病学的见解有两个目的：a）确定潜在的新药靶点;和B）开发工具，以确定 高风险NAFLD患者，以防止疾病进展。为了完成这一提案并取得进展， 龙博士制定了一个为期五年的职业发展计划，其中包括教学， 和正式的研究培训，由两名具有临床和 CVD和NAFLD的转化研究。她将接受正式的流行病学教学培训， 生物统计学，预测建模，并通过公共卫生的BU学校实施科学。与此 在BU提供的额外教育和指导以及支持性环境下，Long博士将很好 能够完成这份提案，并发展成为一名独立的临床研究者。