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: 10301356
• 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 2022-08-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301356
• 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; 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; fatty liver disease; 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·朗，医学博士，波士顿医学中心胃肠病科教员， 波士顿大学医学院助理教授。她的研究主要集中在非酗酒者身上 弗雷明翰心脏研究(FHS)中通过计算机断层扫描测量的脂肪肝(NAFLD)。 在她之前的工作中，她评估了NAFLD和体力活动之间的联系，以及NAFLD和亚 FHS队列中心血管疾病(CVD)的临床测量。她在这些领域的工作已经产生了4个 首批作者发表文章，包括开发和验证一种简单的肝脏临床诊断评分 脂肪变性被称为弗雷明翰脂肪变性指数。她最近的研究利用基于血液的非侵入性肝脏 FHS中的纤维化标志物确定了可用的纤维化标志物给出了截然不同的 当应用于这个基于社区的队列时，发生显著的肝纤维化的风险。非酒精性脂肪肝相关肝 纤维化是一个重要的公共卫生问题。据估计，超过1500万美国人患有这种疾病 NAFLD引起的肝纤维化会加剧代谢性疾病，增加与肝脏相关的风险和心血管疾病- 相关死亡。迄今为止，在美国社区队列中检查非酒精性脂肪肝的研究依赖于 关于对肝纤维化不敏感的成像方法。龙博士的提案将重点测试三个 假说：1)通过振动控制的瞬时弹性成像技术测量患有肝纤维化的FHS参与者 (VCTE)，与无纤维化者相比，具有更不利的CVD危险因素；2)遗传决定因素 因为肝纤维化的风险可以通过全基因组关联研究和3)诊断模型来确定 根据临床和遗传特征区分VCTE定义的伴有和不伴有纤维化的NAFLD患者 该模型在应用于外部验证队列时表现良好。临床和遗传学研究进展 社区中与肝纤维化相关的特征将导致对疾病机制的洞察，生物标记物 发展和新的治疗目标，这有可能改善公共健康。这项研究将是 作为对大约3,500名FHS第三代和OMNI 2队列参与者的辅助研究 他们正在接受VCTE的肝纤维化评估。龙博士的最终职业目标是利用 用于两个目的的流行病学洞察：a)确定潜在的新药物靶点；b)开发工具，以确定 预防疾病进展的高危非酒精性脂肪肝患者。完成这项提议并朝着这些目标取得进展 Goals，Long博士制定了一个五年的有指导的职业发展计划，其中包括两种说教 和正式的研究培训，由两名具有临床和医疗专业知识的知名研究人员指导 心血管疾病和非酒精性脂肪肝的翻译研究。她将接受正规的流行病学教学培训，高级 生物统计学、预测模型和实施科学通过波士顿大学公共卫生学院。有了这个 再加上北大的教育和指导，再加上北大提供的支持环境，龙博士一定会好起来的 定位于完成这项建议并发展成为一家独立的临床研究机构。

项目成果

Standardized measurement of abdominal muscle by computed tomography: association with cardiometabolic risk in the Framingham Heart Study.

• DOI: 10.1007/s00330-022-08934-w
• 发表时间: 2022-10
• 期刊: EUROPEAN RADIOLOGY
• 影响因子: 5.9
• 作者: Kammerlander, Andreas;Lyass, Asya;Mahoney, Taylor F.;Taron, Jana;Eslami, Parastou;Lu, Michael T.;Long, Michelle T.;Vasan, Ramachandran S.;Massaro, Joseph M.;Hoffmann, Udo
• 通讯作者: Hoffmann, Udo

NAFLD Associates with Sarcopenia Defined by Muscle Mass and Slow Walking Speed: A Cross-Sectional Analysis from the Framingham Heart Study.

NAFLD与肌肉质量和步行速度缓慢定义的肌肉减少症：弗雷明汉心脏研究的横断面分析。

• DOI: 10.3390/jcm12247523
• 发表时间: 2023-12-06
• 期刊: Journal of clinical medicine
• 影响因子: 3.9

Cognitive Function, Sarcopenia, and Inflammation Are Strongly Associated with Frailty: A Framingham Cohort Study.

• DOI: 10.1016/j.amjmed.2021.07.012
• 发表时间: 2021-12
• 期刊: AMERICAN JOURNAL OF MEDICINE
• 影响因子: 5.9
• 作者: Mehta, Manaav;Louissaint, Jeremy;Parikh, Neal S;Long, Michelle T;Tapper, Elliot B
• 通讯作者: Tapper, Elliot B

Nonheavy Alcohol Use Associates With Liver Fibrosis and Nonalcoholic Steatohepatitis in the Framingham Heart Study.

弗雷明汉心脏研究中，非重度饮酒与肝纤维化和非酒精性脂肪性肝炎有关。

• DOI: 10.1016/j.cgh.2022.10.039
• 发表时间: 2023
• 期刊: Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association
• 作者: Rice,BrookeA;Naimi,TimothyS;Long,MichelleT
• 通讯作者: Long,MichelleT

Sugar-Sweetened Beverage, Diet Soda, and Nonalcoholic Fatty Liver Disease Over 6 Years: The Framingham Heart Study.

• DOI: 10.1016/j.cgh.2021.11.001
• 发表时间: 2022-11
• 期刊: Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association