GENETIC EPIDEMIOLOGY OF NONALCOHOLIC FATTY LIVER DISEASE

描述（由申请人提供）：Rohit Loomba，MD，MHSc（PI）是加利福尼亚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，在非酒精性脂肪肝（NAFLD）的遗传流行病学方面发展独立的研究事业。他感兴趣的是支持与NAFLD相关的遗传和环境风险因素，并确定与NAFLD进行性形式相关的新机制途径，称为非酒精性脂肪性肝炎（NASH）。 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）和高脂血症。这些代谢特征预测NASH的风险增加，这可能导致肝硬化。在该领域取得进展和管理NAFLD患者的一个关键障碍是，代谢特征与NAFLD之间的关联以及与NAFLD进展相关的机制尚未得到很好的理解。 为了填补这一知识空白，Loomba博士在丹尼尔奥康纳、伊丽莎白巴雷特-康纳和大卫布伦纳博士的指导下，提出通过一种新的磁共振成像（MRI）技术，在一个大型的、先前已充分表征的、现有的人类双对队列中定量测量肝脏脂肪：（具体目的1）检查NAFLD与代谢风险因素（包括高血压（HTN）、胰岛素抵抗（IR）和甘油三酯（TG）升高）之间的遗传协方差，在对年龄和性别进行调整后，使用多变量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具有很强的遗传关联;体外和体内研究表明，去甲肾上腺素（增加的肾上腺素能活性）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发生。因此，我们假设肾上腺素能基因与人类NAFLD相关，并且可能负责NAFLD与HTN、IR和TG之间的共享基因效应。（具体目的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，在该双胞胎队列中，2-2肾上腺素能基因对血清γ-谷氨酰转肽酶（GGT）（NAFLD的标志物）的影响）是否与NAFLD相关。 这项双胞胎研究，包括单卵和双卵双胞胎，使我们能够梳理出代谢性状和NAFLD之间的遗传与环境协方差。此外，我们将利用最先进的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。这些创新将促进该领域的知识。 为了获得遗传流行病学和双胞胎研究的专业知识，提出了一个严格的职业发展计划，受益于多学科的方法，旨在提供一个密切指导，以病人为导向的研究经验，与全面结构的教学课程在遗传和先进的流行病学。 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，并有助于确定肾上腺素能基因中可能解释这种共享基因效应的新遗传变异。这些发现可用于评估肝病进展和开发治疗NAFLD和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向NASH的进展。

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.