Evaluating the impact of genetic ancestry and HIV on cirrhosis progression and response to statin therapy among a diverse multi-ethnic cohort of patients with cirrhosis

评估遗传血统和 HIV 对不同多种族肝硬化患者的肝硬化进展和他汀类药物治疗反应的影响

• 批准号: 10700141
• 负责人: David Seth Goldberg
• 金额: $ 48.03万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700141
• 关键词: 3-hydroxy-3-methylglutaryl-coenzyme A; Acceleration; Address; Admixture; African American; Age; Alcoholic Liver Diseases; Animal Model; Biological; Black Populations; Cessation of life; Cirrhosis; Clinical; Clinical Trials; Cohort Studies; Compensation; Data; Development; Disparity; Enrollment; Enzymes; Equation; Esophageal Varix; Ethnic Origin; Ethnic Population; Etiology; European; Event; Exposure to; Frequencies; Future; Genetic; Genetic Variation; Goals; HIV; Haplotypes; Hepatic; Hepatitis C Therapy; Hepatitis C virus; Hispanic; Hispanic Populations; Knowledge; Lipids; Liver diseases; Measurement; Measures; Medical; Modeling; Native American Ancestry; Outcome; Oxidoreductase; Patient Self-Report; Patients; Pharmacogenomics; Population; Population Heterogeneity; Portal Hypertension; Primary carcinoma of the liver cells; Prospective Studies; Prospective, cohort study; Race; Randomized, Controlled Trials; Rattus; Risk; Safety; Simvastatin; Socioeconomic Factors; Spain; Taiwan; Therapeutic; Thrombocytopenia; Time; Toxic effect; Underrepresented Populations; Variant; Veterans Health Administration; Viral hepatitis; clinical practice; clinically significant; cohort; comorbidity; demographics; elastography; ethnic diversity; genetic variant; liver stiffness; mortality; multi-ethnic; nonalcoholic steatohepatitis; participant enrollment; patient subsets; prevent; racial diversity; racial population; randomized, clinical trials; recruit; response; secondary analysis

Project Summary Despite advances in the treatment of hepatitis C virus (HCV), the number of liver disease-related deaths has increased annually since 2009 due to: 1) liver disease from non-alcoholic steatohepatitis (NASH) and alcohol- induced liver disease; and 2) mortality from hepatocellular carcinoma (HCC). The time course to progress from compensated to decompensated cirrhosis varies based on many factors, such as race/ethnicity, etiology of liver disease, and medical co-morbidities. Hispanics have the highest age-adjusted cirrhosis mortality rates yet are underrepresented in the largest US cirrhosis cohort studies. To disentangle whether disparities for underrepresented populations are due to biological, cultural, and/or socioeconomic factors requires a prospective study in a racially and ethnically diverse population. Given that genetic variants may be associated with cirrhosis-related complications and the frequency of these variants likely differ across populations, analyses cannot simply focus on self-reported race/ethnicity, but rather must incorporate genetic ancestry information due to the variable genetic admixture of the US population. Another population that has been shown to have increased risk of hepatic decompensation, and worse survival are HIV-infected patients. However, these data have been largely restricted to patients with HIV and viral hepatitis. In addition to identifying the trajectory of compensated cirrhosis, there is a need to identify therapeutics to slow progression. There are several lines of evidence to suggest that statins slow cirrhosis progression and/or decrease the risk of decompensation. There are genetic variants/haplotypes in HMGCR associated with clinical responses to statins that are more prevalent in certain racial/ethnic groups. How these genetic variants might impact the response to statin therapy among patients with cirrhosis is unknown, and data from other populations may not apply due to the diversity of the US population. This underscores the need to establish the safety and efficacy of statins to prevent hepatic decompensation in a US population, and to assess if there are variable responses to statin therapy that depend in part on underlying genetic variation. Our overarching goal is to develop a longitudinal prospective cohort study of patients with compensated cirrhosis to assess trajectories of hepatic stiffness and time to hepatic decompensation. We will enroll a subset with clinically significant portal hypertension in a randomized controlled trial of simvastatin. By targeting a racially and ethnically diverse cohort of patients with cirrhosis, with targeted enrollment of patients with HIV, we seek to address these aims to: 1) determine whether changes in hepatic stiffness and time to hepatic decompensation or death differ based on genetic ancestry and HIV status in a diverse cohort of patients with cirrhosis; 2) determine whether simvastatin decreases the risk of hepatic decompensation or death in patients with compensated cirrhosis and clinically significant portal hypertension (CSPH); and 3) assess whether there are interactions between a) genetic ancestry or b) HIV status and response to simvastatin.

项目摘要 尽管丙型肝炎病毒（HCV）的治疗方面取得了进步，但与肝病相关的死亡人数具有 自2009年以来，每年增加每年由于：1）非酒精性脂肪性肝炎（NASH）和酒精 - 诱发肝病； 2）肝细胞癌（HCC）的死亡率。从中进步的时间课程 对代偿性肝硬化的补偿是根据许多因素，例如种族/种族，病因，病因 肝病和医疗合并症。西班牙裔人的年龄调整后的肝硬化死亡率最高 在美国最大的肝硬化队列研究中的人为不足。删除是否存在差异 代表人群不足是由于生物学，文化和/或社会经济因素需要的 在种族和种族多样性的人群中进行的前瞻性研究。鉴于遗传变异可能与 随着肝硬化相关的并发症和这些变体的频率在各个人群中可能有所不同， 分析不能简单地关注自我报告的种族/种族，而必须纳入遗传血统 由于美国人口的遗传混合而导致的信息。另一个人口 证明肝功能补偿的风险增加，生存率较差的是HIV感染的患者。 但是，这些数据在很大程度上仅限于HIV和病毒肝炎患者。此外 鉴定有补偿肝硬化的轨迹，有必要识别治疗剂以减慢进展。 有几条证据表明他汀类药物降低了肝硬化的进展和/或降低风险 代偿作用。 HMGCR中有与临床反应有关的遗传变异/单倍型 他汀类药物在某些种族/族裔群体中更为普遍。这些遗传变异如何影响 肝硬化患者对他汀类药物治疗的反应尚不清楚，其他人群的数据可能不会 由于美国人口的多样性而申请。这强调了建立安全性和功效的需求 他汀类药物以防止美国人口中的肝功能补偿，并评估是否有可变的反应 致他汀类药物疗法，部分取决于潜在的遗传变异。我们的总体目标是开发 对肝硬化的纵向前瞻性队列研究，以评估肝的轨迹 肝功能不足的时间和时间。我们将注册具有临床意义的门户的子集 在辛伐他汀的随机对照试验中高血压。通过针对种族和种族多样的队列 在肝硬化患者中，有针对性的艾滋病毒患者的入学人数，我们试图解决这些目的：1） 确定肝刚度的变化和肝功能不全或死亡的时间是否有所不同 各种肝硬化患者的遗传血统和HIV状况； 2）确定辛伐他汀是否 降低肝硬化和临床的患者的肝功能不全或死亡的风险 显着的门静脉高压（​​CSPH）； 3）评估a）遗传之间是否存在相互作用 祖先或b）艾滋病毒状况和对辛伐他汀的反应。