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

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，也是发达国家肝脏疾病的最常见原因。目前尚不清楚为什么只有少数重度和长期酗酒者会患上ALC。饮酒量与ALC的发展之间存在微弱的关系，因此，一些人在适度饮酒的情况下发展为严重的肝脏疾病，而另一些人在非常高的饮酒量下只发展为轻度肝损伤。除了女性比男性更易患外，几乎没有确定导致ALC发展的因素。迄今为止，只有一种基因多态性（PNPLA3）作为ALC的危险因素显示出可重复的阳性结果，尽管来自双胞胎研究和ALC死亡率的种族间差异的证据支持ALC的遗传成分。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。风险识别可能提供对致病过程的见解，并可能提出减少危害的策略。高通量全基因组搜索被称为单核苷酸多态性（SNPs）的遗传变化提供了一个理想的机会来识别导致这种多基因疾病的基因，现在在技术上是可行的。我们汇集了来自美国、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例无肝脏疾病的重度饮酒者（对照组）和1250例ALC重度饮酒者（病例）的临床数据和DNA。在这2500个样本中，我们将添加来自现有数据库/生物库的2700多个重度饮酒者（约1100个患有ALC）的临床数据/ dna，这些数据库/生物库由几个研究合作伙伴拥有。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用lllumina Human660-Quad SNP进行基因分型，以生成病例和对照组的SNP图谱。为了回答“为什么只有少数酗酒者会患上肝硬化”这个问题，研究人员将对数据进行分析，以确定使一些重度饮酒者易患ALC的基因变异。

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?"