GENETIC EPIDEMIOLOGY OF NONALCOHOLIC FATTY LIVER DISEASE

简介(由申请人提供)：罗希特·伦巴，医学博士，硕士(PI)，是加州大学圣地亚哥分校的肝病专家和医学助理教授。伦巴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。他感兴趣的是支持与NAFLD相关的遗传和环境风险因素，并确定与进展型NAFLD相关的新的机制途径，这被称为非酒精性脂肪性肝炎(NASH)。NAFLD是美国最常见的肝病。它与代谢综合征的特征有关，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可能导致肝硬变。非酒精性脂肪性肝病患者治疗和现场研究进展的一个关键障碍是代谢特征与非酒精性脂肪肝之间的联系以及与非酒精性脂肪肝进展相关的机制还不是很清楚。为了填补这一知识空白，Loomba博士在Daniel O‘Connor博士、Elizabeth Barrett-Connor博士和David Brenner博士的指导下，提议通过一种新的磁共振成像(MRI)技术，在一大批先前已有很好特征的现有双生子队列中，对肝脏脂肪进行定量测量：(特定目的1)检测NAFLD与包括高血压(HTN)、胰岛素抵抗(IR)和甘油三酯(TG)在内的代谢风险因素之间的遗传协方差，在调整了年龄和性别后，将使用多变量广义估计方程进行评估。以前的研究表明，肾上腺素能系统与HTN、IR和TG有很强的遗传学联系；体内外研究表明，去甲肾上腺素(肾上腺素能活性增加)激活肝星状细胞，诱导饮食诱导的纤维化和NAFLD小鼠模型的纤维化形成。因此，我们推测肾上腺素能基因与人NAFLD相关，并可能与NAFLD与HTN、IR和TG共同的基因效应有关。(特定目的2)检查肾上腺素能系统中的基因(已经进行了基因分型：初步数据表明，在这对双生子队列中，2-2肾上腺素能基因与NAFLD的标志物--血清γ-谷氨酰转肽酶(GGT)有关)是否与NAFLD相关。这项双胞胎研究包括同卵双胞胎和双卵双胞胎，使我们能够梳理出代谢特征和NAFLD之间的遗传与环境协变。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。这些创新将推动该领域的知识进步。为了获得遗传流行病学和双胞胎研究方面的专门知识，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，旨在提供密切指导的、以患者为中心的研究经验，并结合遗传和高级流行病学的全面结构教学课程。这一独特的双胞胎研究设计将阐明NAFLD和这些代谢综合征特征之间的共同基因效应，并有助于识别肾上腺素能基因中可能解释这种共同基因效应的新的遗传变异。这些发现可能被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，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.