Sex hormones and HCV-related liver disease progression

性激素和 HCV 相关肝病进展

• 批准号: 9979785
• 负责人: Donna Lorraine White
• 金额: --
• 依托单位: MICHAEL E DEBAKEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979785
• 关键词: Accounting; Aging; Alcohol consumption; Alcoholic Fatty Liver; Androgen Antagonists; Androgens; Animal Model; Bioavailable; Biological; Biological Markers; Blood specimen; Carrier Proteins; Chronic Hepatitis C; Cirrhosis; Clinical; Cohort Studies; Computerized Medical Record; Consensus; Cross-Sectional Studies; DNA; Data; Databases; Diagnosis; Disease Progression; Drug Prescriptions; Electronic Health Record; Estradiol; Etiology; Female; Fibrosis; Finasteride; Gender; General Population; Genes; Geographic Locations; Gonadal Steroid Hormones; Healthcare; Hepatitis C; Hepatitis C virus; Hormone use; Individual; Laboratories; Liver; Liver Failure; Liver diseases; Long-Term Effects; Malignant neoplasm of liver; Measures; Medical center; Medicine; Molecular Epidemiology; Outcome; Patients; Performance; Pharmaceutical Preparations; Pharmacoepidemiology; Physicians; Play; Population; Prevalence; Primary Health Care; Primary carcinoma of the liver cells; Probability; Prognosis; Race; Regimen; Research; Retrospective cohort study; Risk; Risk Factors; Role; Same-sex; Sample Size; Sampling; Sex Hormone-Binding Globulin; Stanolone; Surveys; Testing; Testosterone; Time; Variant; Veterans; Viremia; age group; anti-hepatitis C; chronic infection; clinical practice; clinical risk; cohort; cost; design; dimorphism; disorder risk; electronic data; epidemiology study; genetic variant; improved; infection rate; lifetime risk; liver transplantation; male; member; men; non-alcoholic fatty liver disease; novel; novel therapeutics; phenotypic data; prospective; recruit; research study; response; risk stratification; routine care; searchable database; sex risk; sexual dimorphism; therapeutic target; virology

Over 260,000 male veterans accessing VA healthcare between 2000 and 2014 had a laboratory confirmed diagnosis of hepatitis C virus (HCV) infection. Chronic HCV infection (HCV+) is the leading cause of liver disease progression to cirrhosis, liver transplant and liver cancer. HCV+ males have much higher rates of liver disease progression than HCV+ females. One factor that may contribute to this difference is large and gender- defining biological differences in the levels of circulating sex hormones like testosterone. However, the role normal variability in these major sex hormones plays in risk of liver disease progression among HCV+ individuals of the same gender is not known. The long-term effects of medications that substantially alter sex hormone levels like testosterone therapy on risk of disease progression in HCV+ males are also unknown. We previously recruited baseline cohort of 1072 male veterans with chronic HCV infection seen for routine care at single VA. All completed a lifetime risk factor survey and had a blood sample taken to obtain DNA and to store for biomarker testing in approved future research studies. We propose to measure circulating levels of major sex hormones at baseline using stored blood samples for this cohort of 1,072 HCV+ male veterans. We will also perform DNA tests to assess specific variations in several genes related to sex hormone function. We will prospectively follow all cohort members for liver disease progression with outcomes determined using electronic medical record review and VA database searches and expert physician consensus review. We will examine the association between baseline levels of sex hormones after accounting for sex hormone gene variants on risk of liver disease progression including to cirrhosis and liver cancer in our baseline HCV+ male cohort from 1-9 years later. We propose to measure use of commonly prescribed medications that alter levels of androgen sex hormones like testosterone in the >267,000 males with laboratory confirmed HCV and seen at the VA between 2000 and 2014. We will extract extensive information about each individual at baseline to account for their likelihood to ever receive these medications and calculate medication propensity scores. We will account for these propensity scores in our assessment of the association between use of these hormone altering medications and risk of HCV-related liver disease progression from 1-18 years later. In addition to uncovering new potential therapeutic targets for HCV-related liver disease progression, this study has rapid and important potential impact on clinical practice in terms of better criteria to risk stratify veterans and help prioritize them for early access to costly new anti-HCV medications and may alter practice for prescribing sex hormone altering medications in aging HCV-infected males.

2000年至2014年期间，超过26万名男性退伍军人获得VA医疗保健， 诊断丙型肝炎病毒（HCV）感染。慢性HCV感染（HCV+）是导致肝脏损害的主要原因。 疾病进展为肝硬化、肝移植和肝癌。HCV+男性的肝脏感染率要高得多， 比HCV+女性的疾病进展。可能导致这种差异的一个因素是巨大的和性别- 定义了循环性激素如睾丸激素水平的生物学差异。然而，作用 这些主要性激素的正常变异性在HCV+患者的肝病进展风险中起作用 同一性别的人不知道。药物的长期影响，大大改变性别 激素水平如睾酮治疗对HCV阳性男性疾病进展风险的影响也是未知的。 我们先前招募了1072名接受常规护理的慢性HCV感染男性退伍军人作为基线队列 在单一VA。所有人都完成了一项终生危险因素调查，并采集了血液样本以获得DNA， 储存用于批准的未来研究中的生物标志物检测。我们建议测量循环 基线时主要性激素水平，使用储存的血液样本，用于该队列的1，072人 HCV阳性男性退伍军人。我们还将进行DNA测试，以评估几个相关基因的特定变异， 性激素的功能。我们将前瞻性随访所有队列成员的肝病进展， 使用电子病历审查和VA数据库检索以及专家医生确定结局 共识审查。我们将检查性激素基线水平之间的关联， 解释性激素基因变异对肝脏疾病进展的风险，包括 肝硬化和肝癌在我们的基线HCV+男性队列从1-9年后。 我们建议测量改变雄激素水平的常用处方药的使用情况 性激素如睾酮在> 267，000名实验室确诊的HCV男性中， 在退伍军人事务部工作我们将在以下网站上提取有关每个人的广泛信息： 基线，以说明他们接受这些药物的可能性并计算药物倾向 成绩.我们将在评估关联时考虑这些倾向评分 使用这些激素改变药物与HCV相关肝病风险之间的关系 1-18年后的发展。 除了发现HCV相关肝病进展的新的潜在治疗靶点外， 这项研究对临床实践具有快速和重要的潜在影响， 帮助退伍军人优先考虑他们抢先体验昂贵的新的抗HCV药物，并可能改变实践 为老年HCV感染男性开出改变性激素的药物。

项目成果

Post-Traumatic Stress Disorder is Associated with further Increased Parkinson's Disease Risk in Veterans with Traumatic Brain Injury.

创伤后应激障碍与脑外伤退伍军人帕金森病风险进一步增加有关。

• DOI: 10.1002/ana.25726
• 发表时间: 2020
• 期刊: Annals of neurology
• 影响因子: 11.2
• 作者: White,DonnaL;Kunik,MarkE;Yu,Hong;Lin,HelenL;Richardson,PeterA;Moore,Suzanne;Sarwar,AliyaI;Marsh,Laura;Jorge,RicardoE
• 通讯作者: Jorge,RicardoE