GENETIC EPIDEMIOLOGY OF NONALCOHOLIC FATTY LIVER DISEASE

描述（由申请人提供）：Rohit Loomba， MD, MHSc （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）的遗传流行病学方面发展独立的研究事业。他感兴趣的是与NAFLD相关的遗传和环境风险因素的基础，并确定与NAFLD进行性形式（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风险的增加，NASH可导致肝硬化。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之间关联的潜在机制，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dr。Daniel O'Connor， Elizabeth Barrett-Connor和David Brenner，建议通过一种新型的磁共振成像（MRI）技术，在一个大型的，先前已经被充分表征的，现有的人类双胞胎队列中定量测量肝脏脂肪：（具体目的1）研究NAFLD与代谢危险因素（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，通过调整年龄和性别后的多变量广义估计方程进行评估。既往研究表明肾上腺素能系统与HTN、IR、TG有较强的遗传相关性；体外和体内研究表明，在饮食性纤维化和NAFLD小鼠模型中，去甲肾上腺素（增加肾上腺素能活性）激活肝星状细胞并诱导纤维化发生。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（已经基因分型：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）的影响，这是该双胞胎队列中NAFLD的标志物）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，我们将利用尖端的MRI技术来量化肝脏脂肪部分，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方面的专业知识，提出了一项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，并结合遗传和高级流行病学的全面结构化教学课程。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同基因效应，并有助于识别可能解释这种共同基因效应的肾上腺素能基因的新遗传变异。这些发现可能用于评估肝脏疾病的进展和NAFLD治疗及相关代谢并发症的新靶点的发展。该研究计划的长期目标是减轻NAFLD的负担，并阻止NAFLD向NASH的发展。

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.