Genetic risk factors for alcoholic cirrhosis - genome-wide case-control study

酒精性肝硬化的遗传危险因素——全基因组病例对照研究

• 批准号: 8525258
• 负责人: Christopher Paul Day
• 金额: $ 51.84万
• 依托单位: SOUTHERN CALIFORNIA INST FOR RES/EDUC
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8525258
• 关键词: Accounting; Affect; Age; Age related macular degeneration; Alcohol abuse; Alcohol consumption; Alcoholic Liver Cirrhosis; Alcoholic Liver Diseases; Alcoholic beverage heavy drinker; Alcoholism; Alcohols; Aldehydes; Algorithms; Alleles; Animal Model; Applications Grants; Architecture; Australia; Biliary; Biological; Candidate Disease Gene; Case-Control Studies; Child; Cirrhosis; Clinical; Clinical Data; Code; Collection; Complex; Consumption; Country; DNA; DNA Library; Data; Data Analyses; Data Collection; Databases; Death Rate; Development; Diagnosis; Disease; Dizygotic Twins; Drug Targeting; Ensure; Ethnic Origin; Exclusion Criteria; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Floxacillin; France; Functional disorder; Gender; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Genomics; Genotype; Germany; HLA-B Antigens; Hand; Heavy Drinking; Hepatic; Hepatitis C; Heritability; Indiana; Individual; Inflammation; Inflammatory; International; LDL Cholesterol Lipoproteins; Lead; Life; Link; Linkage Disequilibrium; Liver Cirrhosis; Liver diseases; Location; Metabolism; Microarray Analysis; Minority; Modality; Morbidity - disease rate; Nucleotides; Organ; Outcome; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Plasma; Predisposition; Preparation; Prevalence; Principal Investigator; Process; Protocols documentation; RNA; Race; Recommendation; Reporting; Research; Research Personnel; Risk; Risk Factors; Sampling; Schizophrenia; Series; Severity of illness; Shipping; Ships; Site; Specimen; Staging; Susceptibility Gene; Switzerland; Techniques; Testing; Therapeutic; Time; Twin Studies; Variant; Veterans; Woman; base; biobank; case control; chronic liver disease; cohort; cost effective; design; disorder control; disorder risk; exome; experience; genetic risk factor; genome sequencing; genome-wide; human disease; improved; innovation; insight; light microscopy; liver biopsy; liver injury; meetings; member; men; mortality; multidisciplinary; non-alcoholic fatty liver; novel; novel diagnostics; prevent; primary sclerosing cholangitis; problem drinker; programs; prospective; repository; sample collection; success; therapeutic target; tool; trait; working group

DESCRIPTION (provided by applicant): Alcoholic liver cirrhosis (ALC) remains a major cause of morbidity and mortality and is the most common cause of liver disease In the developed world. It is unknown why only a minority of heavy and prolonged alcohol mis-users develop ALC. There is a weak relationship between the amount of alcohol consumed and development of ALC such that some develop severe liver disease with moderate levels of alcohol use although others with very high levels of consumption only progress to mild liver Injury. Apart from a greater vulnerability in women than men, few contributory factors have been identified for the development of ALC. To date, only one genetic polymorphism (in PNPLA3) has shown replicable positive result as a risk factor for ALC, although evidence from twin studies and Inter-ethnic variability in ALC mortality rates, supports a genetic component in ALC. Candidate gene studies have been inconclusive but these have generally been too small to yield definitive re-sults. Risk identification is likely to provide Insights into the pathogenic process and may suggest strategies for hami reduction. High-throughput genome-wide search for genetic changes called single nucleotide polymor-phlsms (SNPs) provides an ideal opportunity to Identify genes responsible for this polygenic disorder and is now technically feasible. We have gathered an experienced multidisciplinary team from the USA, Australia, France, Germany, Switzerland and UK with a proven track record in clinical alcoholic liver disease and in genetics. We propose to prospectively collect clinical data and DNA from 1250 heavy drinkers without known liver disease (Controls) and 1250 heavy drinkers with ALC (Cases). To these 2500 specimens we will add clinical data/DNAfrom more than 2700 heavy drinkers (~1100 with ALC) from existing databases/biorepositories in the possession of several study co-PIs. Cases and controls will be matched for age, gender, race/ethnicity and country of origin. DNA will be genotyped with the lllumina Human660-Quad SNP an-ay at CIDR to generate SNP profiles in the Cases and Controls. Data will be analysed to identify genetic variants that predispose some heavy drinkers to ALC in order to answer the question 'Why do only a minority of alcoholics develop liver cirrhosis?"

描述（由申请人提供）：酒精性肝硬化（ALC）仍然是发病率和死亡率的主要原因，是发达国家最常见的肝病原因。目前还不清楚为什么只有少数重度和长期酒精滥用者会发展为ALC。酒精消耗量与ALC的发展之间存在微弱的关系，例如一些人在中度饮酒的情况下发展为严重的肝病，而其他人在非常高的饮酒水平下只会发展为轻度肝损伤。除了妇女比男子更易受伤害之外，已查明的造成非洲劳工市场发展的因素很少。迄今为止，只有一种遗传多态性（PNPLA 3）显示出可复制的阳性结果作为ALC的风险因素，尽管来自双胞胎研究和ALC死亡率种族间差异的证据支持ALC中的遗传成分。候选基因的研究一直没有定论，但这些研究通常太小，无法产生明确的结果。风险识别可能提供对致病过程的深入了解，并可能提出减少哈米的策略。单核苷酸多态性（SNPs）的高通量全基因组搜索为确定这种多基因疾病的基因提供了理想的机会，并且现在在技术上是可行的。我们聚集了来自美国，澳大利亚，法国，德国，瑞士和英国的经验丰富的多学科团队，在临床酒精性肝病和遗传学方面有着良好的记录。我们建议前瞻性地收集1250名没有已知肝病的重度饮酒者（对照组）和1250名患有ALC的重度饮酒者（病例组）的临床数据和DNA。在这2500份标本中，我们将从现有数据库/生物储存库中添加2700多名重度饮酒者（约1100名患有ALC）的临床数据/DNA，这些数据库/生物储存库由几个研究共同PI拥有。病例和对照将在年龄、性别、人种/种族和原籍国方面匹配。将在CIDR处使用Illumina Human 660-Quad SNP分析对DNA进行基因分型，以生成病例和对照中的SNP图谱。数据将被分析，以确定遗传变异，使一些酗酒者易患酒精性肝硬化，以回答这个问题“为什么只有少数酗酒者发展肝硬化？”"