The Genetic Basis of Hereditary Liver Disease

遗传性肝病的遗传基础

基本信息

批准号：
7885653
负责人：
LAURA N BULL
金额：
$ 36.14万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-30 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7885653
关键词：
15q26 ATP phosphohydrolase Admixture Affect African Alleles Alopecia Alpha-mannosidase Amish Area Arthrogryposis Arts Avian Sarcoma Benign recurrent intrahepatic cholestasis Bile Acids Bile fluid Binding Biochemical Biological Biological Assay Biological Process Candidate Disease Gene Caucasians Caucasoid Race Cessation of life Childhood Chile Cholestasis Chromosomes, Human, Pair 15 Cirrhosis Clinical Code Cohort Studies Complex Core Facility County Cytokinesis DNA Data Development Diagnosis Disease EPHX1 gene Enrollment Etiology Evaluation FPS-FES Oncogene FURIN gene Family Family Felidae Fetal Distress Follow-Up Studies Functional disorder Gamma-glutamyl transferase Genes Genetic Genetic Predisposition to Disease Genomics Genotype Goals Haplotypes Health Hepatocyte High Pressure Liquid Chromatography Homologous Gene Human Ichthyoses Impairment Incidence Individual Inherited Investigation Kidney Knowledge Latina Lesion Leukocytes Liver Liver diseases Lymphatic System Lymphedema Maintenance Maps Membrane Transport Proteins Methods Microsomal Epoxide Hydrolase Morbidity - disease rate Mutate Mutation Native Americans North American Indians Oxidoreductase PRC1 Protein Participant Patients Performance Perinatal mortality demographics Pharmacogenetics Play Polymerase Chain Reaction Predisposition Premature Birth Process Progressive intrahepatic cholestasis Promoter Regions Protein Export Pathway Proteins Pulsed-Field Gel Electrophoresis RNA Splicing Reporting Research Research Personnel Risk Role Sampling San Francisco Scandinavian Sclerosing Cholangitis Screening procedure Serum Short Tandem Repeat Single Nucleotide Polymorphism Smooth Muscle Myocytes Societies Sodium Specimen Steroid delta-isomerase Steroids Study of serum Susceptibility Gene Synaptic Vesicles Syndrome Testing Tight Junctions United States National Institutes of Health Untranslated Regions Vacuolar Protein Sorting Vacuole Variant Viral Viral Oncogene Woman base bile acid transporter bile acid-CoA amino acid N-acyltransferase bile salts claudin-1 protein cohort cost genetic variant improved insight intrahepatic cholestasis of pregnancy liver transplantation member mortality multidrug resistance protein 3 paired basic amino acid cleaving enzyme programs research study sarcoma

项目摘要

DESCRIPTION (provided by applicant): Liver disease is a cause of substantial morbidity and mortality in the U.S., and cholestasis (impairment of bile flow) is a common and devastating manifestation of liver disease. The experiments in this revised application are focused on increasing our understanding of the genetic etiology underlying development of cholestatic liver disease; such a goal is amongst those articulated in the "Action Plan for Liver Disease Research," a report prepared by the NIH in 2004. The genetic studies in this proposal include investigation of a rare, Mendelian disease, as well as a more common cholestatic disorder of presumed complex etiology. In Specific Aim 1, the genetic lesion(s) responsible for lymphedema-cholestasis syndrome (LCS), located in the LCS1 candidate region on chromosome 15, will be determined. Results of this Aim will increase understanding of the etiology of cholestasis, and provide insight into the biological interplay between the liver and the lymphatic system. In Specific Aims 2-4, recent progress in understanding the genetic underpinnings of rare cholestatic disorders will be leveraged to increase our knowledge regarding a more common disorder intrahepatic cholestasis of pregnancy (ICP). ICP endangers babies, increasing the risk of premature delivery, fetal distress, and intrauterine death. In Specific Aim 2, a study cohort of 400 women diagnosed with intrahepatic cholestasis of pregnancy (ICP), and matched controls, will be established; half of this cohort will be collected from the San Francisco Bay Area, and the other half, from Chile, where the disorder is particularly common. In Specific Aim 3, genes previously implicated in the genetic etiology of primary cholestatic disorders will be sequenced in DNA from these patients and controls to identify rare genetic variants that likely increase susceptibility to ICP. In Specific Aim 4, genotyping of single nucleotide polymorphisms (SNPs) in these genes will be performed in the Latina portion of the sample, with correction for admixture, to test the hypothesis of association between SNPs in these genes and susceptibility to ICP. The results of the studies in Specific Aims 2-4 will increase our understanding of the genetic etiology of this clinically important cause of perinatal mortality and morbidity. As a result of the program of research described in this proposal, our knowledge of the etiology of cholestasis will be significantly advanced.

描述（由申请人提供）：在美国，肝病是导致大量发病和死亡的一个原因，而胆汁淤积（胆汁流动受损）是肝病的一种常见且具有破坏性的表现。修订后的申请中的实验重点是增加我们对胆汁淤积性肝病发展的遗传病因学的理解；这样的目标是美国国立卫生研究院 (NIH) 2004 年编写的一份报告“肝病研究行动计划”中阐述的目标之一。该计划中的遗传学研究包括对一种罕见的孟德尔疾病以及一种更常见的胆汁淤积性疾病的调查推测的复杂病因。在具体目标 1 中，将确定导致淋巴水肿胆汁淤积综合征 (LCS) 的遗传病变（位于 15 号染色体上的 LCS1 候选区域）。该目标的结果将增进对胆汁淤积病因学的了解，并深入了解肝脏和淋巴系统之间的生物相互作用。在具体目标 2-4 中，我们将利用最近在了解罕见胆汁淤积性疾病的遗传基础方面取得的进展来增加我们对更常见的妊娠期肝内胆汁淤积症 (ICP) 的了解。 ICP 危及婴儿，增加早产、胎儿窘迫和宫内死亡的风险。在具体目标 2 中，将建立一个由 400 名被诊断患有妊娠期肝内胆汁淤积 (ICP) 的妇女和匹配对照组成的研究队列；该队列的一半将来自旧金山湾区，另一半则来自智利，这种疾病在该地区尤为常见。在具体目标 3 中，将对这些患者和对照组的 DNA 中先前涉及原发性胆汁淤积性疾病遗传病因的基因进行测序，以识别可能增加 ICP 易感性的罕见遗传变异。在具体目标 4 中，将在样本的拉丁裔部分中对这些基因中的单核苷酸多态性 (SNP) 进行基因分型，并进行混合校正，以测试这些基因中的 SNP 与 ICP 易感性之间关联的假设。具体目标 2-4 中的研究结果将增进我们对围产期死亡率和发病率这一临床重要原因的遗传病因学的理解。由于本提案中描述的研究计划，我们对胆汁淤积病因学的了解将得到显着提高。