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: 8189622
• 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/8189622
• 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; Educational Curriculum; 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; 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. PUBLIC HEALTH RELEVANCE: NAFLD affects one out of every three Americans. The proposed twin study will improve our understanding of disease progression in NAFLD. This study would lead to discovery of specific adrenergic genotypes that are associated with NAFLD, which may be exploited to develop new prognostic models for predicting disease progression and develop newer targets of therapy.

描述（由申请人提供）：Rohit Loomba，医学博士，理学硕士（PI），是加州大学圣地亚哥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，在非酒精性脂肪性肝病 (NAFLD) 遗传流行病学领域发展独立的研究事业。他对支持与 NAFLD 相关的遗传和环境风险因素感兴趣，并确定与 NAFLD 进展型（称为非酒精性脂肪性肝炎 (NASH)）相关的新机制途径。 NAFLD 是美国最常见的肝脏疾病。它与代谢综合征特征相关，包括高血压（HTN）、胰岛素抵抗（IR）和高甘油三酯血症。这些代谢特征预示着 NASH 风险增加，从而导致肝硬化。该领域进展和 NAFLD 患者管理的一个关键障碍是，代谢特征与 NAFLD 之间的关联机制以及与 NAFLD 进展相关的机制尚不清楚。 为了填补这一知识空白，Loomba 博士在 Drs. 的指导下进行了研究。 Daniel O'Connor、Elizabeth Barrett-Connor 和 David Brenner 提议通过一种新型磁共振成像 (MRI) 技术，在一个大型的、先前已充分表征的、现有的人类双胞胎队列中定量测量肝脏脂肪：（具体目标 1）检查 NAFLD 与代谢危险因素（包括高血压 (HTN)、胰岛素抵抗）之间的遗传协方差 （IR）和甘油三酯升高（TG），在调整年龄和性别后，使用多元广义估计方程进行评估。先前的研究表明，肾上腺素能系统与 HTN、IR 和 TG 具有很强的遗传相关性；体外和体内研究表明，去甲肾上腺素（增加肾上腺素能活性）可激活肝星状细胞，并在饮食诱导的纤维化和 NAFLD 小鼠模型中诱导纤维形成。因此，我们假设肾上腺素能基因与人类 NAFLD 相关，并且可能是 NAFLD 与 HTN、IR 和 TG 之间共有基因效应的原因。 （具体目标 2）检查肾上腺素能系统中的基因（已进行基因分型：初步数据表明 2-2 肾上腺素能基因对血清 γ-谷氨酰转肽酶 (GGT)（该双胞胎队列中 NAFLD 的标志物）的影响）是否与 NAFLD 相关。 这项双胞胎研究包括单卵双胞胎和双卵双胞胎，使我们能够梳理出代谢特征与 NAFLD 之间的遗传与环境协方差。此外，我们将利用尖端的 MRI 技术来量化肝脏脂肪分数，作为肝脏甘油三酯含量的非侵入性生物标志物。这些创新将推进该领域的知识。 为了获得遗传流行病学和双胞胎研究方面的专业知识，我们提出了严格的职业发展计划，该计划受益于多学科方法，旨在提供密切指导、以患者为导向的研究经验，并结合全面结构化的遗传和高级流行病学教学课程。 这种独特的双胞胎研究设计将揭示 NAFLD 和这些代谢综合征特征之间的共享基因效应，并有助于识别肾上腺素能基因中的新遗传变异，从而解释这种共享基因效应。这些发现可用于评估肝病进展和开发治疗 NAFLD 及相关代谢并发症的新靶点。拟议研究计划的长期目标是减轻 NAFLD 的负担并阻止 NAFLD 进展为 NASH。 公共卫生相关性：三分之一的美国人患有 NAFLD。拟议的双胞胎研究将提高我们对 NAFLD 疾病进展的了解。这项研究将发现与 NAFLD 相关的特定肾上腺素能基因型，可用于开发新的预后模型来预测疾病进展并开发新的治疗靶点。