Integrated molecular epidemiologic analysis of the one-carbon metabolism pathway and risk of HCC

一碳代谢途径与肝癌风险的综合分子流行病学分析

• 批准号: 10394717
• 负责人: Samuel O. Antwi
• 金额: $ 15.07万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10394717
• 关键词: Alcohol abuse; Anabolism; Animals; Biochemical; Bioinformatics; Candidate Disease Gene; Carbon; Choline; Chronic Hepatitis B; Clinical; Competence; Cytosine; DNA; DNA Methylation; DNA Modification Methylases; Data; Development; Diagnosis; Discipline; Early Diagnosis; Educational workshop; Enzymes; Epidemiology; Epigenetic Process; Folic Acid; Fostering; Gene Expression Regulation; Genes; Genetic; Genetic Risk; Genetic Variation; Goals; Hepatic; Hepatitis C; Human; Human Genetics; Impairment; Incidence; Individual Differences; Infection; Inherited; Liver; Liver Cell Adenoma; Malignant Neoplasms; Mentors; Metabolic; Metabolism; Methionine; Methylation; Modification; Molecular; Molecular Epidemiology; Nutrient; Pathway interactions; Patients; Persons; Play; Predisposition; Prevention; Prevention strategy; Primary Malignant Neoplasm of Liver; Primary carcinoma of the liver cells; Recording of previous events; Research; Risk; Risk Assessment; Role; S-Adenosylhomocysteine; S-Adenosylmethionine; Signal Transduction; Structure; Testing; Variant; Viral hepatitis; base; career development; design; disorder control; epigenetic variation; genetic epidemiology; genetic variant; improved; indexing; inhibitor; insight; loss of function mutation; member; metabolomics; methyl group; mortality; mouse model; non-alcoholic fatty liver disease; novel; programs; risk stratification; risk variant; skills

ABSTRACT: The one-carbon metabolism pathway is strongly implicated in the development of hepatocellular carcinoma (HCC) in patients with non-alcoholic fatty liver disease (NAFLD). The incidence of HCC has increased in the US, and about a third of all HCC cases diagnosed in the US do not have a history of viral hepatitis or alcohol abuse, but these cases of HCC often have clinical or biochemical features of NAFLD. Indeed, NAFLD-related HCC cases are expected to increase further in the US. Functionally, the one-carbon metabolism pathway regulates DNA methylation through metabolism of one-carbon nutrients, such as choline, methionine and folate, to form S-adenosylmethionine (SAM). SAM is the universal methyl donor used for DNA methylation; the formation of 5-methylcytosine (5mC). Following the transfer of methyl groups from SAM for methylation, SAM is converted to S-adenosylhomocysteine (SAH), which is a potent inhibitor of the activities of DNA methyltransferases (DNMTs) and thus suppresses DNA methylation. Hence, while SAM promotes methylation, SAH inhibits methylation, and the SAM/SAH ratio reflects a “hepatic methylation index” because both SAM and SAH are formed primarily in the liver. Additionally, recent data show that 5mC is not a static DNA mark, it is converted to 5-hydroxymethylcytosine (5hmC) by TET enzymes. 5hmC is now recognized as a unique epigenetic modification to DNA that is distinct from 5mC. However, both 5mC and 5hmC are involved in gene regulation and both have been implicated in the progression of established HCC, but it is unclear which of these DNA marks is most relevant to HCC development. The central hypothesis of this proposal is that individual differences in hepatic methylation index or epigenetic modifications to DNA influence susceptibility to HCC in isolation or in concert with genetic variants in one-carbon, DNMT or TET genes. The Specific Aims are: (1) to identify common and rare genetic risk variants in the one-carbon metabolism pathway associated with HCC risk. (2) To assess the association between hepatic methylation index (SAM/SAH ratio) and HCC risk, and identify one-carbon gene modifiers of the association. (3) To assess the association between epigenetic modifications to DNA (5mC and 5hmC) and HCC risk, and evaluate interaction by one-carbon, DNMT, and TET genes. Findings from this research are expected to yield novel insights into the one-carbon metabolism pathway as a previously under-recognized, potentially modifiable contributor to HCC and improve strategies for the prevention, risk stratification, and early detection of HCC. The activities outlined in this application are designed to extend the applicant’s expertise in genetic and molecular epidemiology, and acquire new skills in epigenetics, metabolomics, and bioinformatics. Members of the mentoring team have complementary expertise that spans these disciplines. Overall, the cross-disciplinary, integrative molecular epidemiologic approach of this proposal and the career development activities that include formal coursework and “hands-on” workshops will enable the applicant to acquire the needed competencies to foster his transition to independence.

摘要：一碳代谢途径与肝细胞的发育密切相关。 非酒精性脂肪性肝病（NAFLD）患者的癌症（HCC）。肝癌的发病率已 在美国有所增加，并且在美国诊断的所有 HCC 病例中约三分之一没有病毒病史 肝炎或酗酒，但这些 HCC 病例通常具有 NAFLD 的临床或生化特征。 事实上，在美国，与 NAFLD 相关的 HCC 病例预计将进一步增加。从功能上讲，一碳 代谢途径通过一碳营养素（如胆碱）的代谢来调节DNA甲基化， 甲硫氨酸和叶酸，形成S-腺苷甲硫氨酸（SAM）。 SAM 是用于 DNA 的通用甲基供体 甲基化； 5-甲基胞嘧啶（5mC）的形成。甲基从 SAM 转移后 甲基化后，SAM 转化为 S-腺苷同型半胱氨酸 (SAH)，这是一种有效的活性抑制剂 DNA 甲基转移酶 (DNMT)，从而抑制 DNA 甲基化。因此，虽然 SAM 提倡 甲基化，SAH抑制甲基化，SAM/SAH比值反映了“肝甲基化指数”，因为 SAM 和 SAH 主要在肝脏中形成。此外，最近的数据表明 5mC 不是静态的 DNA标记，被TET酶转化为5-羟甲基胞嘧啶(5hmC)。 5hmC现已被公认为 与 5mC 不同的独特 DNA 表观遗传修饰。然而，5mC 和 5hmC 均参与 基因调控，两者都与已形成的 HCC 的进展有关，但尚不清楚是哪一个 这些 DNA 标记中的一些与 HCC 的发展最相关。该提案的中心假设是 肝甲基化指数或 DNA 表观遗传修饰的个体差异影响易感性 HCC 与一碳、DNMT 或 TET 基因的遗传变异单独或相关。具体目标是： (1) 识别与相关的一碳代谢途径中常见和罕见的遗传风险变异 肝癌风险。 (2) 评估肝甲基化指数（SAM/SAH比值）与HCC风险之间的关联， 并确定该关联的一碳基因修饰因子。 (3) 评估表观遗传之间的关联 DNA 修饰（5mC 和 5hmC）与 HCC 风险，并通过一碳、DNMT 和 TET 基因。这项研究的结果有望对一碳代谢产生新的见解 途径作为以前未被充分认识的、潜在可改变的 HCC 贡献者，并改进策略 HCC 的预防、风险分层和早期发现。本申请中概述的活动是 旨在扩展申请人在遗传和分子流行病学方面的专业知识，并获得以下方面的新技能 表观遗传学、代谢组学和生物信息学。指导团队成员具有互补的专业知识 跨越这些学科。总体而言，跨学科、综合的分子流行病学方法 该提案以及包括正式课程和“实践”研讨会在内的职业发展活动 将使申请人能够获得促进其向独立过渡所需的能力。