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）：肝病是美国实质性发病率和死亡率的原因，而胆汁淤积（胆汁流量损害）是肝病的常见且破坏性的表现。这项修订后的实验集中在增加我们对胆汁淤积性肝病基础发展的遗传病因学发展的理解。这项目标是NIH在2004年制备的“肝病研究行动计划”中表达的那些目标。该提案中的遗传研究包括研究一种罕见的孟德尔氏病，以及更常见的假定复杂病因的胆汁淤积性疾病。在特定的目标1中，将确定位于15号染色体的LCS1候选区域的淋巴水肿 - 胆汁疾病综合征（LCS）的遗传病变。该目标的结果将增加对胆汁淤积病因的理解，并提供对肝脏与淋巴系统之间生物学相互作用的见解。在特定的目标2-4中，了解罕见胆固性疾病的遗传基础的最新进展将被杠杆化，以提高我们对更常见的疾病妊娠胆汁淤积（ICP）的知识。 ICP危及婴儿，增加了过早分娩，胎儿痛苦和宫内死亡的风险。在特定的目标2中，将建立一项研究队列的400名诊断患有肝内胆汁淤积的妇女（ICP）和匹配的对照组；该队列的一半将从旧金山湾地区收集，另一半是从智利疾病特别普遍的。在特定的目标3中，以前与原发性胆固醇疾病的遗传病因相关的基因将在这些患者和对照组的DNA中进行测序，以鉴定可能增加ICP易感性的稀有遗传变异。在特定的目标4中，这些基因中的单核苷酸多态性（SNP）的基因分型将在样品的拉丁裔部分进行，并进行混合校正，以检验这些基因中SNP和ICP敏感性之间的sNP之间的关联假设。特定目的的研究结果2-4将增加我们对这种临床上重要原因和发病率的遗传病因的理解。由于本提案中描述的研究计划的结果，我们对胆汁淤积的病因的了解将得到显着提高。