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: 8718935
• 负责人: Christopher Paul Day
• 金额: $ 51.86万
• 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/8718935
• 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; risk variant; 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）仍然是发病和死亡的主要原因，并且是发达国家肝病的最常见原因。目前尚不清楚为什么只有少数长期酗酒的人会患上 ALC。饮酒量与 ALC 的发展之间关系较弱，因此一些人在适度饮酒的情况下会出现严重的肝病，而另一些人饮酒量非常高时只会发展为轻度肝损伤。除了女性比男性更容易受到伤害之外，几乎没有发现 ALC 发生的影响因素。迄今为止，只有一种基因多态性（PNPLA3）显示出可重复的阳性结果作为 ALC 的危险因素，尽管来自双胞胎研究和 ALC 死亡率的种族间变异的证据支持 ALC 的遗传因素。候选基因研究尚无定论，但这些研究通常规模太小，无法得出明确的结果。风险识别可能会提供对致病过程的见解，并可能提出减少哈米的策略。对被称为单核苷酸多态性 (SNP) 的遗传变化进行高通量全基因组搜索，为识别导致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拥有良好的记录。我们建议前瞻性地收集 1250 名无已知肝病的重度饮酒者（对照）和 1250 名患有 ALC 的重度饮酒者（病例）的临床数据和 DNA。对于这 2500 个样本，我们将从多个研究联合 PI 拥有的现有数据库/生物存储库中添加来自 2700 多名重度饮酒者（约 1100 名 ALC）的临床数据/DNA。病例和对照将根据年龄、性别、种族/民族和原籍国进行匹配。 DNA 将在 CIDR 中使用 lllumina Human660-Quad SNP 进行基因分型，以生成病例和对照中的 SNP 图谱。我们将对数据进行分析，以确定导致某些酗酒者易患 ALC 的基因变异，从而回答“为什么只有少数酗酒者会患上肝硬化？”的问题。