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

项目摘要 尽管丙型肝炎病毒(丙型肝炎病毒)的治疗取得了进展，但与肝病相关的死亡人数 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- 诱发性肝病；2)肝细胞癌的死亡率。前进的时间进程 失代偿性肝硬变的代偿情况因多种因素而异，如种族/民族、 肝脏疾病，以及医学上的并存。西班牙裔人的年龄调整后的肝硬变死亡率最高。 在美国最大的肝硬变队列研究中代表性不足。要理清差距是否符合 人口代表性不足是由于生物、文化和/或社会经济因素需要 在种族和民族多元化人群中进行的前瞻性研究。考虑到遗传变异可能与 与肝硬变相关的并发症和这些变异的频率可能在不同的人群中不同， 分析不能简单地集中在自我报告的种族/民族上，而必须结合遗传祖先 由于美国人口的可变遗传混合而产生的信息。另一个已经成为 显示出肝脏失代偿风险增加，且存活率较差的是感染艾滋病毒的患者。 然而，这些数据在很大程度上仅限于艾滋病毒和病毒性肝炎患者。除了……之外 确定代偿性肝硬变的发展轨迹，有必要确定延缓进展的治疗方法。 有几条证据表明他汀类药物可以延缓肝硬变的进展和/或降低风险。 失代偿的问题。HMGCR中存在与临床反应相关的遗传变异/单倍型 他汀类药物在某些种族/民族中更为普遍。这些基因变异可能如何影响 肝硬变患者对他汀类药物的反应尚不清楚，来自其他人群的数据可能也不清楚 由于美国人口的多样性而申请。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脏失代偿，并评估是否存在不同的反应 他汀类药物治疗在一定程度上取决于潜在的基因变异。我们的首要目标是开发一种 代偿性肝硬变患者评价肝脏运动轨迹的纵向前瞻性队列研究 僵硬和肝脏失代偿的时间。我们将招募具有临床意义门户的子集 辛伐他汀随机对照试验中的高血压。通过瞄准种族和民族多样化的队列 对于肝硬变患者，通过有针对性地登记艾滋病毒患者，我们寻求解决这些目标：1) 确定肝脏硬度的变化和肝脏失代偿或死亡的时间是否有所不同 不同的肝硬变患者的遗传血统和HIV状况；2)决定辛伐他汀是否 降低代偿性肝硬变患者肝脏失代偿或死亡的风险 显著门静脉高压症(CSPH)；以及3)评估a)遗传性疾病之间是否存在交互作用 血统或b)艾滋病毒状况和对辛伐他汀的反应。

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.