GENETIC EPIDEMIOLOGY OF NONALCOHOLIC FATTY LIVER DISEASE

非酒精性脂肪肝病的遗传流行病学

• 批准号: 8330790
• 负责人: ROHIT LOOMBA
• 金额: $ 18.04万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8330790
• 关键词: ADRB1 gene; Adrenergic Agents; Affect; Age; American; Biochemical; Biological; Biological Markers; California; Cirrhosis; Classification; Clinical; Data; Development; Development Plans; Diet; Disease Progression; Diseases in Twins; Environmental Risk Factor; Epidemiology; Equation; Fatty acid glycerol esters; Fibrosis; Future; Gamma-glutamyl transferase; Gastroenterology; Genes; Genetic; Genetic Risk; Genetic Variation; Genomics; Genotype; Goals; Hepatic; Hepatic Stellate Cell; Human; Hypertension; Hypertriglyceridemia; Imaging Techniques; In Vitro; Insulin Resistance; Intervention; Knowledge; Lead; Light; Link; Liver; Liver diseases; Magnetic Resonance Imaging; Measures; Medicine; Mentors; Mentorship; Metabolic; Metabolic syndrome; Modeling; Mono-S; Norepinephrine; Pathway interactions; Patients; Plasma; Publishing; Receptor Gene; Recording of previous events; Regulation; Research; Research Design; Resources; Risk; Risk Factors; Role; Serum; Structure; Supervision; System; Testing; Therapeutic Intervention; Triglycerides; Twin Multiple Birth; Twin Studies; United States; Universities; adrenergic; base; career; career development; clinical epidemiology; cohort; design; didactic education; epidemiology study; experience; fibrogenesis; follow-up; genetic association; genetic epidemiology; improved; in vivo; innovation; interest; mouse model; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; patient oriented; patient oriented research; professor; prognostic; programs; prospective; receptor; sex; trait; validation studies

DESCRIPTION (provided by applicant): Rohit Loomba, MD, MHSc (PI) is a hepatologist and Assistant Professor of Medicine at the University of California-San Diego. Dr. Loomba's long-term goal is to develop an independent research career in the genetic epidemiology of nonalcoholic fatty liver disease (NAFLD) by combining patient- centered research with clinical epidemiology. He is interested in underpinning genetic and environmental risk factors that are associated with NAFLD and identify novel mechanistic pathways that are linked with progressive form of NAFLD, which is termed as nonalcoholic steatohepatitis (NASH). NAFLD is the most common liver disease in the United States. It is associated with metabolic syndrome traits including hypertension (HTN), insulin resistance (IR), and hypertriglyceridemia. These metabolic traits predict increased risk of NASH, which can lead to cirrhosis. A critical barrier to progress in the field and to management of patients with NAFLD is that the mechanism underlying the association between metabolic traits and NAFLD, and those associated with progression of NAFLD, are not well understood. In order to fill this gap in knowledge, Dr. Loomba, under the mentorship of Drs. Daniel O'Connor, Elizabeth Barrett-Connor, and David Brenner, proposes to measure liver fat, quantitatively, by a novel magnetic resonance imaging (MRI) technique, in a large, previously well-characterized, existing, twin-pair cohort in humans: (specific aim 1) To examine genetic co-variance between NAFLD and metabolic risk factors including hypertension (HTN), insulin resistance (IR), and elevated triglycerides (TG), which would be assessed by using multivariate generalized estimating equations after adjustment for age and sex. Previous studies suggest that adrenergic system has a strong genetic association with HTN, IR & TG; and in-vitro and in-vivo studies suggest that norepinephrine (increased adrenergic activity) activates hepatic stellate cells & induces fibrogenesis in mice model of diet-induced fibrosis and NAFLD. Therefore, we hypothesize that adrenergic genes are associated with human NAFLD and may be responsible for the shared gene effects between NAFLD and HTN, IR, & TG. (specific aim 2) To examine if the genes in the adrenergic system (already genotyped: preliminary data suggests 2-2 adrenergic gene effect with serum gamma-glutamyl transpeptidase (GGT), a marker of NAFLD, in this twin cohort) are associated with NAFLD. This twin-pair study, which includes both mono-zygotic and di-zygotic twins, allows us to tease out the genetic versus environmental co-variance between the metabolic traits and NAFLD. Furthermore, we will be utilizing a cutting-edge MRI technique to quantify the liver fat fraction as a non-invasive biomarker of hepatic triglyceride content. These innovations would advance the knowledge in the field. In order to gain expertise in genetic epidemiology and twin studies, a rigorous career development plan is proposed that benefits from a multi-disciplinary approach designed to provide a closely mentored, patient-oriented research experience in association with a comprehensively structured didactic curriculum in genetic and advanced epidemiology. This unique twin study design would shed light on shared gene effects between NAFLD and these metabolic syndrome traits and help in identifying novel genetic variations in adrenergic genes that may explain this shared gene effect. These findings may be exploited in assessing liver disease progression and development of novel targets for treatment of NAFLD and associated metabolic complications. The long- term goal of the proposed research program is to reduce the burden of NAFLD and halt progression of NAFLD to NASH.

描述（由申请人提供）：MHSC（PI）医学博士Rohit Loomba（PI）是加利福尼亚大学迭戈分校的肝病学家和医学助理教授。 Loomba博士的长期目标是通过将以患者为中心的研究与临床流行病学相结合，在非酒精性脂肪肝病（NAFLD）的遗传流行病学方面发展独立的研究生涯。他对与NAFLD相关的遗传和环境风险因素的基础感兴趣，并确定了与NAFLD进行性形式有关的新型机械途径，该途径被称为非酒精性脂肪性肝炎（NASH）。 NAFLD是美国最常见的肝病。它与包括高血压（HTN），胰岛素抵抗（IR）和高甘油三酸酯血症在内的代谢综合征性状有关。这些代谢特征预测了纳什的风险增加，这可能导致肝硬化。该领域进步和管理NAFLD患者的关键障碍是，尚不清楚代谢性状与NAFLD之间的关联的基础机制，以及与NAFLD进展相关的机制。 为了填补这一知识的差距，Loomba博士在Drs的指导下。丹尼尔·奥康纳（Daniel O'Connor），伊丽莎白·巴雷特·科诺（Elizabeth Barrett-Connor）和戴维·布伦纳（David Brenner）提议通过一种新颖的磁共振成像（MRI）技术来测量肝脏脂肪，以一种大型，以前良好的，现有的，现有的，现有的，双对在人类中的双对组​​）的态度来检查人类：（特定的目标1）： （IR）和升高的甘油三酸酯（TG），将在调整年龄和性别后使用多元广义估计方程来评估。先前的研究表明，肾上腺素能系统与HTN，IR＆TG具有很强的遗传关联。体内和体内研究表明，去甲肾上腺素（肾上腺素能活性的增加）激活肝星状细胞，并在饮食诱导的纤维化和NAFLD的小鼠模型中诱导纤维化。因此，我们假设肾上腺素能基因与人类NAFLD有关，并且可能是NAFLD和HTN，IR和TG之间的共同基因效应的原因。 （具体目的2）检查肾上腺素能系统中的基因是否（已经是基因分型：初步数据表明2-2肾上腺素能基因效应与NAFLD的标记）是NAFLD的标记，在此双胞胎队列中）与NAFLD相关联。 这项双对研究包括单二旋性和Di-zygotic双胞胎，使我们能够取消代谢性状和NAFLD之间的遗传与环境的共同变量。此外，我们将利用尖端的MRI技术将肝脏脂肪分数量化为肝甘油三酸酯含量的非侵入性生物标志物。这些创新将提高该领域的知识。 为了获得遗传流行病学和双研究研究的专业知识，提出了一项严格的职业发展计划，该计划旨在从多学科方法中受益，旨在提供与遗传和高级流行病学中一项结构化结构化的教学课程相关的密切指导，以患者为导向的研究经验。 这种独特的双胞胎研究设计将阐明NAFLD与这些代谢综合征性状之间的共同基因效应，并有助于识别肾上腺素能基因中新型的遗传变异，这可能解释了这种共同的基因效应。这些发现可以在评估肝病的进展和开发NAFLD和相关代谢并发症的新靶标的发展中得到利用。拟议的研究计划的长期目标是减轻NAFLD和NAFLD对NASH的停顿的负担。