Southern Liver Health Cohort

项目概要/摘要 原发性肝癌，其中绝大多数是肝细胞癌（HCC），是少数几种与肝癌相关的癌症之一。 在美国发病率越来越高。自1980年以来，HCC的发病率增加了两倍， HCC的中位生存期不到两年。发病率增长最快的是南部地区， 农村和少数民族。肝细胞癌的患病率明显高于病毒性肝炎 在过去的几十年里，非酒精性脂肪肝（NAFLD）的患病率最近有所增加， 近年来，其进展为非酒精性脂肪性肝炎（NASH）伴纤维化和肝硬化，助长了HCC。 然而，这些因素本身并不能解释HCC进展中的重大区域和种族差异。一 研究不足，但潜在的潜在的HCC危险因素，随着患病率的增加， 少数民族面临环境污染。这些污染物降解缓慢， 持久存在于环境中，为人类接触提供了稳定的外源性来源。有毒金属（oid），如 镉和砷被归类为可能的致癌物，来自小鼠模型的新数据表明， 这种接触与肝脂肪变性、肝硬化和肝癌有关。全氟烷基和多氟烷基 人类中的PFAS暴露与肥胖和NASH相关。此外，新出现的证据 表明这些环境暴露可以诱导表观遗传改变， 对肝脏的影响，但我们缺乏纵向人体数据。这些数据强调了纵向人类 数据来评估这些污染物是否以及如何影响HCC风险。为了弥补这些知识差距， 作为对RFA-CA-20-049的回应，我们提出了南方肝脏健康研究，这是一项纵向队列研究， 包括16,000名40岁及40岁以上的男性和女性的子队列，分布在东南部的两个州，北 卡罗莱纳和格鲁吉亚。我们将测试总体假设，镉单独或与其他物质的混合物， 有毒金属和PFAS增加了从NAFLD发展为肝纤维化和HCC的风险。则将队列 从社区诊所招募，包括联邦合格的卫生中心和大学卫生系统。 在杜克、剑桥查佩尔山和埃默里的初级保健中心和肝病学项目。子队列I将包括 将对10，000名其他方面健康的成年人进行1-5年的随访，预计约800例纤维化病例， 包括肝硬化，将发展，亚队列II将包括6,000例晚期纤维化病例，预计约750例 HCC病例将会增加。我们将在队列中嵌套病例对照研究，评估 环境暴露和HCC发病率，并确定对污染物敏感的表观遗传标记， 预测进展为HCC。影响：这将是纵向确定联系的首次大规模努力 环境污染物、肝病和癌症之间的关系， 人口此外，我们将创建一个数据和标本库，为研究界提供 拥有研究HCC和其他癌症的宝贵资源。

PROJECT SUMMARY/ABSTRACT Primary liver cancer, the vast majority of which is hepatocellular carcinoma (HCC) is one of the few cancers with increasing incidence in the US. Incidence of HCC has tripled since 1980, which is particularly worrisome given that HCC confers a median survival of less than two years. The steepest increases in incidence are in Southern rural states and among ethnic minorities. While the prevalence of HCC had paralleled high rates of viral hepatitis in the last several decades, recent increases in the prevalence of nonalcoholic fatty liver disease (NAFLD) and its progression to nonalcoholic steatohepatitis (NASH) with fibrosis and cirrhosis, has fueled HCC in recent years. Yet, these factors alone do not explain the substantial regional and ethnic variation in HCC progression. One understudied but potentially potent HCC risk factor with increasing prevalence that disproportionately affects ethnic minorities, is exposure to environmental contaminants. These contaminants degrade slowly and therefore persist in the environment, providing a stable exogenous source for human exposure. Toxic metal(oid)s such as cadmium and arsenic are classified as probable carcinogens, and emerging data from murine models suggest that exposure is associated with hepatic steatosis, cirrhosis and liver cancer. Per- and poly-fluoroalkyl substances (PFAS) exposure in humans is associated with obesity and NASH. Further, emerging evidence indicates that these environmental exposures can induce epigenetic alterations that may promote adverse effects on the liver, but we lack longitudinal human data. These data underscore the need for longitudinal human data to assess whether and how these contaminants impact HCC risk. To address these knowledge gaps, and in response to RFA-CA-20-049, we propose the Southern Liver Health Study, a longitudinal cohort study of two sub-cohorts comprising 16,000 males and females aged 40 years and older in two Southeastern states, North Carolina and Georgia. We will test the overarching hypothesis that cadmium alone or in a mixture with other toxic metals and PFAS increases the risk of progression from NAFLD to liver fibrosis and HCC. The cohort will be recruited from community clinics including Federally Qualified Health Centers and University Health Systems’ Primary Care Centers and Hepatology programs at Duke, UNC Chapel Hill and Emory. Sub-cohort I will comprise 10,000 otherwise healthy adults who will be followed for 1–5 years, anticipating that ~800 fibrosis cases, including cirrhosis, will develop, and sub-cohort II will comprise 6,000 advanced fibrosis cases, anticipating ~750 HCC cases will develop. We will nest case-control studies within the cohorts, evaluate associations between environmental exposures and HCC incidence, and identify epigenetic marks responsive to contaminants that predict progression to HCC. Impact: This will be the first large-scale effort to longitudinally determine the link between environmental contaminants, liver disease and cancer in a residentially and ethnically diverse population. Additionally, we will create a data and specimen repository that will provide the research community with an invaluable resource to study HCC and other cancers.