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

描述(申请人提供)：酒精性肝硬变(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一小部分长期重度酗酒者会患上ALC。饮酒量与ALC的发展之间存在微弱的关系，因此一些人会发展成严重的肝病，中等水平的酒精使用，而另一些人非常高的饮酒量只会进展为轻微的肝脏损伤。除了女性比男性更易受感染外，几乎没有发现对ALC的发展有贡献的因素。到目前为止，只有一个基因多态(在PNPLA3中)显示出作为ALC危险因素的可复制的阳性结果，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。候选基因研究一直没有定论，但这些研究通常太小，不能产生明确的结果。风险识别可能提供对致病过程的洞察，并可能建议减少哈米病的策略。高通量的全基因组遗传变化搜索称为单核苷酸多聚体(SNPs)，为识别导致这种多基因疾病的基因提供了一个理想的机会，现在在技术上是可行的。我们聚集了一支来自美国、澳大利亚、法国、德国、瑞士和英国的经验丰富的多学科团队，他们在酒精性肝病临床和遗传学方面有着良好的记录。我们建议前瞻性地收集1250名无已知肝病的酗酒者(对照组)和1250名患有ALC的酗酒者(病例)的临床数据和DNA。对于这2500个样本，我们将从现有的数据库/生物库中添加2700多名酗酒者(约1100名ALC患者)的临床数据/DNA，这些数据/DNA由几个研究联合PIs拥有。病例和对照将根据年龄、性别、种族/族裔和原籍国进行匹配。DNA将在CIDR上用llLumina Human 660-Quad SNP进行基因分型，以生成病例和对照的SNP图谱。将对数据进行分析，以确定使一些酗酒者易患酒精性肝硬化症的基因变异，以回答这样一个问题：为什么只有一小部分酗酒者会患上肝硬变？

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?"