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

项目总结/摘要 美国领土关岛的肝癌发病率和死亡率高得惊人， 是美国（US）总体发病率的两倍，而美国的发病率在过去三十年中几乎增加了两倍。 过度风险在关岛原住民查莫罗人中最为突出，占关岛人口的42%。 人口肝细胞癌（HCC），肝癌的主要形式，完全在上下文中发展 以纤维化水平进展为特征的进行性慢性肝病（CLD）。因此，迫切需要 需要了解CHAMORUS中进行性CLD的病因，并确定新的策略和靶点， 预防和早期干预。我们提出的研究将解决口腔生态失调和睡眠/昼夜节律是否 节律紊乱通过糖脂代谢紊乱和潜在的肝纤维化 修改其他曝光的影响。我们建议对300例肝纤维化病例和300例匹配的 控制着关岛的查莫罗斯肝纤维化是肝癌的一个公认的前兆， 脂肪变性作为次要结局，将通过瞬时弹性成像（Fibroscan）进行测量。 完整项目II的具体目标是： 1)评价口腔微生态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 口腔微生物组的有害模式和/或牙周病的存在。我们将进行细菌 16 S rRNA测序测量口腔细菌多样性和组成。我们将确定牙周 疾病的临床检查和自我报告。口腔微生态失调与肝纤维化之间的关系， 未按脂肪变性等级分层，将进行评价;其他暴露的潜在改变作用 (e.g.,槟榔嚼食、病毒性肝炎、酒精）与糖脂代谢异常的介导作用 将被评估。我们假设中度至重度肝纤维化与以下因素相关：1a）减少 口腔微生物多样性、致病菌富集和肠道细菌耗竭以及胰岛素的畸变， 信号细菌基因; 1b）牙周病的存在和严重程度;和1c）口腔生态失调， 并且与葡萄糖/脂质代谢异常无关。 2)评估睡眠（数量和质量）与昼夜节律的循环mRNA表达水平的关系 时钟基因与肝纤维化和脂肪变性有关。我们将使用经过验证的 问卷调查，并分析期间（Per 1，Per 2，Per 3）和隐花色素（Cry 2）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以下因素有关：2a）睡眠不足 持续时间和睡眠呼吸暂停; 2b）生物钟基因表达减少;和2c）睡眠/昼夜节律 通过和独立于葡萄糖/脂质代谢异常的紊乱。

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.