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）的治疗取得了进展，但与肝病相关的死亡人数仍在增加。 自2009年以来每年增加，原因是：1）非酒精性脂肪性肝炎（NASH）和酒精引起的肝病- 诱导的肝病;和2）肝细胞癌（HCC）的死亡率。从开始到结束的时间过程 代偿性到失代偿性肝硬化基于许多因素而变化，例如种族/民族、肝硬化的病因学、 肝脏疾病和医学合并症。西班牙裔有最高的年龄调整肝硬化死亡率 在美国最大的肝硬化队列研究中代表性不足。为了弄清是否存在差异， 由于生物、文化和/或社会经济因素，代表性不足的人口需要一个 在不同种族和民族人群中进行的前瞻性研究。鉴于基因变异可能与 与肝硬化相关的并发症以及这些变异的频率可能因人群而异， 分析不能简单地关注自我报告的种族/民族，而必须纳入遗传祖先 由于美国人口的可变遗传混合物，另一个种群 HIV感染者肝失代偿的风险增加，生存率更差。 然而，这些数据主要限于艾滋病毒和病毒性肝炎患者。除了 为了确定代偿性肝硬化的轨迹，需要确定减缓进展的治疗方法。 有几条证据表明，他汀类药物减缓肝硬化进展和/或降低风险 失代偿HMGCR中存在与对以下药物的临床应答相关的遗传变异/单倍型： 他汀类药物在某些种族/民族群体中更普遍。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也不清楚。 由于美国人口的多样性。这强调了建立安全性和有效性的必要性 他汀类药物在美国人群中预防肝代偿失调，并评估是否存在不同的反应 到部分依赖于潜在遗传变异的他汀类药物治疗。我们的首要目标是开发一个 对代偿性肝硬化患者进行纵向前瞻性队列研究，以评估肝硬化的轨迹 僵硬度和肝失代偿时间。我们将招募一个具有临床意义的门户网站子集 辛伐他汀治疗高血压的随机对照试验通过针对不同种族和民族的群体 肝硬化患者，有针对性地招募艾滋病毒感染者，我们寻求解决这些目标：1） 确定肝硬度的变化和至肝失代偿或死亡的时间是否不同， 不同肝硬化患者队列的遗传血统和HIV状态; 2）确定辛伐他汀是否 降低代偿性肝硬化患者肝失代偿或死亡的风险， 显著的门静脉高压症（CSPH）;和3）评估是否存在a）遗传 血统或B）HIV状态和对辛伐他汀的反应。