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: 10491885
• 负责人: David Seth Goldberg
• 金额: $ 42.54万
• 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/10491885
• 关键词: Address; Admixture; African American; Age; Alcoholic Hepatitis; Alcoholic Liver Diseases; Animal Model; Biological; Black Populations; Cessation of life; Cirrhosis; Clinical; Clinical Trials; Cohort Studies; Data; Development; Enrollment; Enzymes; Equation; Esophageal Varix; Ethnic Origin; Ethnic group; Etiology; European; Event; Exposure to; Frequencies; Future; Genetic; Genetic Variation; Goals; HIV; Haplotypes; Hepatic; Hepatitis B; Hepatitis C Therapy; Hepatitis C virus; Hispanic; Hispanic Populations; Hydroxymethylglutaryl-CoA reductase; Knowledge; Lipids; Liver diseases; Measurement; Measures; Medical; Modeling; Native American Ancestry; Outcome; Patient Self-Report; Patients; Pharmacogenomics; Population; Population Analysis; Population Heterogeneity; Portal Hypertension; Primary carcinoma of the liver cells; Prospective Studies; Prospective cohort study; Race; Randomized Clinical Trials; Randomized Controlled Trials; Risk; Safety; Simvastatin; Socioeconomic Factors; Spain; Therapeutic; Thrombocytopenia; Time; Toxic effect; Underrepresented Populations; Variant; Veterans Health Administration; Viral hepatitis; base; clinical practice; clinically significant; cohort; comorbidity; demographics; ethnic diversity; genetic variant; liver stiffness; mortality; multi-ethnic; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; participant enrollment; patient subsets; prevent; racial and ethnic; racial diversity; 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.

项目总结