Full Project II: Novel Risk Factors and Disease Associations of Liver Cancer in Guam

项目摘要/摘要 美国领土关岛的肝癌负担高得惊人，发病率和死亡率都超过了 是美国总体利率的两倍，在过去30年里，美国的利率几乎增加了两倍。 超额风险在关岛的土著查莫鲁斯人中最为突出，占 人口。肝细胞癌是肝癌的主要形式，完全在以下背景下发展 以纤维化程度升高为特征的进行性慢性肝病(CLD)。因此，有一个紧急的 需要了解CHAMORUS进行性CLD的病因，并确定新的治疗策略和靶点 预防和早期干预。我们提议的研究将解决口腔微生物失调和睡眠/昼夜节律问题 节律紊乱通过糖脂代谢紊乱促进肝纤维化 其他曝光的修正效果。我们建议对300例肝纤维化病例和300例配对病例进行病例对照研究。 关岛查莫鲁斯人之间的控制。肝纤维化，一个公认的肝癌的先兆，以及肝脏 脂肪变性作为次要结果，将通过瞬时弹力成像(Fibrocan)进行测量。 第二个完整项目的具体目标是： 1)评估口腔微生物失调与肝纤维化和脂肪变性的关系。口腔生态失调将被定义为 口腔微生物群的有害模式和/或牙周病的存在。我们会表演细菌 16S rRNA测序测定口腔细菌多样性和组成。我们会做牙周检查 疾病通过临床检查和自我报告。口腔微生物失调与肝纤维化之间的关系，或 不按脂肪变性分级分层，将被评估；其他暴露的潜在修改效果 (例如，咀嚼槟榔、病毒性肝炎、酒精)以及葡萄糖和脂肪代谢异常的调节作用 将会被评估。我们假设，患有中度到重度肝纤维化与以下因素有关： 口腔微生物多样性，丰富的致病菌和枯竭的共生菌，以及胰岛素的异常- 细菌基因信号；1b)牙周病的存在和严重程度；以及1c)口腔生态失调 不受糖/脂代谢障碍的影响。 2)评估睡眠(数量和质量)与循环昼夜节律基因表达水平的关系 时钟基因与肝纤维化和脂肪变性。我们将使用经验证的数据确定睡眠持续时间和质量 问卷调查和分析细胞周期(PER1、PER2、PER3)和隐花色素(Cry2)基因的表达 血液作为昼夜节律的生物标志物。我们假设肝纤维化与睡眠不足有关 持续时间和睡眠呼吸暂停；2b)时钟基因表达减少；以及2c)睡眠/昼夜节律 通过和独立于糖/脂代谢紊乱。

PROJECT SUMMARY/ABSTRACT The US territory of Guam has a staggeringly high burden of liver cancer with incidence and mortality more than twice that of overall rates in the United States (US) where rates have nearly tripled over the past three decades. Excess risk is most prominent among CHamorus who are the native people of Guam, comprising 42% of the population. Hepatocellular carcinoma (HCC), the primary form of liver cancer, develops entirely within the context of progressive chronic liver disease (CLD) characterized by advancing levels of fibrosis. Thus, there is an urgent need to understand the etiology of progressive CLD in CHamorus and to identify novel strategies and targets for prevention and early intervention. Our proposed research will address whether oral dysbiosis and sleep/circadian rhythm disturbance contribute to liver fibrosis through glucose and lipid dysmetabolism and the potential modifying effect of other exposures. We propose a case-control study of 300 liver fibrosis cases and 300 matched controls among CHamorus in Guam. Liver fibrosis, a well-established precursor of liver cancer, as well as liver steatosis as a secondary outcome, will be measured by transient elastrography (Fibroscan). The Specific Aims of Full Project II are to: 1) Evaluate the association of oral dysbiosis with liver fibrosis and steatosis. Oral dysbiosis will be defined as deleterious patterns of the oral microbiome and/or the presence of periodontal disease. We will perform bacterial 16S rRNA sequencing to measure oral bacterial diversity and composition. We will determine periodontal disease by clinical examination and self-report. The association between oral dysbiosis and liver fibrosis, with or without stratification by steatosis grades, will be evaluated; the potential modifying effects of other exposures (e.g., betel nut chewing, viral hepatitis, alcohol) and the mediating effects of glucose and lipid dysmetabolism will be assessed. We hypothesize that having moderate to severe liver fibrosis is associated with: 1a) reduced oral microbial diversity, enriched pathogenic and depleted commensal bacteria, and aberrations in insulin- signaling bacterial genes; 1b) the presence and severity of periodontal disease; and 1c) oral dysbiosis through and independently of glucose/lipid dysmetabolism. 2) Evaluate the associations of sleep (quantity and quality) and circulating Mrna expression levels of circadian clock genes with liver fibrosis and steatosis. We will determine sleep duration and quality using validated questionnaires and analyze the expression of the period (Per1, Per2, Per3) and cryptochrome (Cry2) genes in blood as a biomarker of circadian rhythm. We hypothesize that liver fibrosis is associated with: 2a) short sleep duration and sleep apnea; 2b) reduced expression of the clock genes; and 2c) sleep/circadian rhythm disturbances through and independently of glucose/lipid dysmetabolism.