Southern Liver Health Cohort

南方肝脏健康队列

• 批准号: 10336820
• 负责人: Cathrine Hoyo
• 金额: $ 113.84万
• 依托单位: NORTH CAROLINA STATE UNIVERSITY RALEIGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10336820
• 关键词: Address; Adult; Adverse effects; Affect; African American; Age; Air; Alcohol consumption; Animals; Arsenic; Biological Specimen Banks; Body Burden; Cadmium; Cancer Etiology; Carcinogens; Case-Control Studies; Cessation of life; Chemicals; Chronic; Cirrhosis; Communities; DNA Methylation; Data; Data Collection; Dose; Enrollment; Environment; Environmental Exposure; Environmental Pollutants; Environmental Pollution; Epigenetic Process; Ethnic Origin; Excretory function; Exposure to; Fatty Liver; Federally Qualified Health Center; Female; Fibrosis; Food Packaging; General Population; Geography; Health; Health system; Hepatology; Hispanic Americans; House Dust; Human; Incidence; Industrialization; International Agency for Research on Cancer; Knowledge; Link; Liquid substance; Liver; Liver Cirrhosis; Liver Fibrosis; Liver diseases; Longitudinal cohort study; Malignant Neoplasms; Malignant neoplasm of liver; Mass Spectrum Analysis; Measures; Mediating; Metals; Molecular; Mycotoxins; National Health and Nutrition Examination Survey; Nested Case-Control Study; North Carolina; Not Hispanic or Latino; Obesity; Outcome; Participant; Phase; Poison; Poly-fluoroalkyl substances; Population Heterogeneity; Prevalence; Primary Health Care; Primary Malignant Neoplasm of Liver; Primary carcinoma of the liver cells; Protocols documentation; Reporting; Research; Resources; Risk; Risk Factors; Role; Rural; Rural Minority; Sampling; Source; Testing; Textiles; Time; United States; Universities; Variant; Viral hepatitis; Water; aged; alcohol exposure; bioaccumulation; cancer diagnosis; cancer risk; case control; cohort; community clinic; data modeling; data repository; design; disease registry; environmental chemical; ethnic diversity; ethnic minority population; exposed human population; follow-up; human data; insight; male; mouse model; non-alcoholic; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; pollutant; programs; recruit; response; rural dwellers; sex; toxic metal

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.

项目概要/摘要 原发性肝癌，其中绝大多数是肝细胞癌（HCC），是少数几种癌症之一 在美国发病率不断增加。自 1980 年以来，HCC 的发病率增加了两倍，这一点尤其令人担忧 HCC 的中位生存期不到两年。发病率增长最快的是南部地区 农村国家和少数民族之间。虽然 HCC 的患病率与病毒性肝炎的高发病率相平行 近几十年来，非酒精性脂肪性肝病 (NAFLD) 的患病率不断上升， 近年来，其进展为伴有纤维化和肝硬化的非酒精性脂肪性肝炎（NASH），加剧了肝癌的发生。 然而，仅这些因素并不能解释 HCC 进展的巨大地区和种族差异。一 未被充分研究但潜在有效的 HCC 危险因素，其患病率不断增加，影响不成比例 少数民族，正在接触环境污染物。这些污染物降解缓慢，因此 持久存在于环境中，为人类暴露提供了稳定的外源源。有毒金属，例如 镉和砷被列为可能的致癌物，来自小鼠模型的新数据表明 该暴露与肝脂肪变性、肝硬化和肝癌有关。全氟烷基和多氟烷基 人类接触 PFAS 物质（PFAS）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，从而可能促进不良反应 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的需要 数据来评估这些污染物是否以及如何影响 HCC 风险。为了解决这些知识差距，并且 为了回应 RFA-CA-20-049，我们提出了南方肝脏健康研究，这是一项针对两项研究的纵向队列研究 子队列由 16,000 名年龄在 40 岁及以上的男性和女性组成，分布于东南部两个州、北 卡罗莱纳州和佐治亚州。我们将测试单独的镉或与其他物质的混合物的总体假设 有毒金属和 PFAS 会增加从 NAFLD 进展为肝纤维化和 HCC 的风险。该队列将 从社区诊所招募，包括联邦合格的健康中心和大学健康系统 杜克大学、北卡罗来纳大学教堂山分校和埃默里大学的初级保健中心和肝病学项目。我将组成的小组 10,000 名原本健康的成年人将被跟踪 1-5 年，预计约有 800 例纤维化病例， 包括肝硬化，将会发展，第二亚队列将包括 6,000 例晚期纤维化病例，预计约 750 例 HCC 病例将会发展。我们将在队列中进行病例对照研究，评估之间的关联 环境暴露和 HCC 发病率，并识别对污染物有反应的表观遗传标记 预测 HCC 的进展。影响：这将是纵向确定链接的第一个大规模努力 在居住和种族多样化的环境污染物、肝病和癌症之间 人口。此外，我们将创建一个数据和样本存储库，为研究社区提供 拥有研究 HCC 和其他癌症的宝贵资源。