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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

基本信息

批准号：
9792371
负责人：
Heather Jane Cordell
金额：
$ 33.65万
依托单位：
SOUTHERN CALIFORNIA INST FOR RES/EDUC
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-25 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9792371
关键词：
Alcohol consumption Alcohol dependence Alcoholic Liver Cirrhosis Alcoholic Liver Diseases Alcoholic beverage heavy drinker Alcohols Alleles Behavioral Biological Markers Blood Case-Control Studies Cirrhosis Collaborations DNA Data Data Analyses Data Collection Databases Development Disease Environment Enzymes Europe Genes Genetic Genetic Polymorphism Genetic Risk Genetic Variation Genomics Genotype Grant Health Infrastructure Insulin Intervention Iron Knowledge Life Style Lipids Liver Liver Cirrhosis Meta-Analysis Metabolic syndrome Non-Insulin-Dependent Diabetes Mellitus North America Obesity Pathogenesis Pathway interactions Patient Care Pharmacologic Substance Pharmacotherapy Phenotype Population Predisposition Reporting Research Personnel Risk Risk Factors Source Testing Time Validation Veterans World Health Organization bead chip biobank case control clinical phenotype cohort cost genetic risk factor genome wide association study genome-wide improved inflammatory marker mortality non-alcoholic fatty liver disease non-genetic nonalcoholic steatohepatitis novel personalized medicine phenotypic data programs sample collection skills

项目摘要

Alcoholic liver cirrhosis (ALC) causes a significant mortality worldwide. World Health Organization 2014 Report on ‘alcohol and health’ reports 50% of liver cirrhosis mortality worldwide is due to alcohol, reaching as high as ~60% in north America and Europe. In principle, all alcoholic liver diseases are preventable with appropriate behavioral and lifestyle change, including pharmaceutical approaches. However, progress in developing specific pharmaceutical interventions has been hampered by poor understanding of both genetic and non-genetic factors contributing towards the pathogenesis of this disease. The OVERALL GOAL is to identify loci, genes and polymorphisms underlying genetic risk for the development of ALC in heavy drinkers. To do this the multinational GenomALC Consortium has successfully collected extensive phenotype data and blood/DNAs from >5000 heavy drinkers with and without cirrhosis which will be subjected to genotyping via genome-wide SNP association approach in 2016-2017 (UO1-AA018389). Through other significant collaborations, the consortium has access to additional ~2000 genotype- phenotype data making it the largest discovery cohort for ALC genetics. The consortium has also done the groundwork in identifying and accessing ‘mega-cohort’ Genomics Biobanks (e.g UK Biobank) as independent validation cohorts. The specific aims of the current application are, aim 1: To identify genetic risk factors for ALC through case-control GWAS in GenomALC discovery cohort (n=~7411); aim 2: To confirm allelic associations in independent validation cohorts available from established ‘mega-cohort’ genomic databases; aim 3: To perform meta-analysis with results from other GWAS on alcoholic cirrhosis; aim 4: To examine overlap in genetic risk between alcoholic cirrhosis and potentially related diseases and biomarkers of cirrhosis. The GenomALC team (geneticists, genetic statisticians, clinicians) has the right expertise, skills and established infrastructure to perform these analyses. This large case-control GWAS has the power to identify novel SNPs, create new knowledge and infer pathways/mechanisms leading to alcoholic cirrhosis, thus identifying potential targets for new or repurposed drug treatments.

酒精性肝硬变(ALC)在世界范围内造成了巨大的死亡率。世界卫生组织2014 《酒精与健康》报告称，全球50%的肝硬变死亡是由酒精引起的，达到在北美和欧洲高达60%。原则上，所有酒精性肝病都可以通过适当的行为和生活方式改变，包括药物治疗方法。然而，在这方面的进展由于对两者的理解不足，开发特定的药物干预措施受到阻碍遗传和非遗传因素导致了这种疾病的发病。整体而言目的是确定阿尔茨海默病发生的遗传风险的基因座、基因和多态。酗酒者。为此，跨国GenomALC联盟成功地收集了广泛的 5000名患有和不患有肝硬变的酗酒者的表型数据和血液/DNA 2016-2017年通过全基因组SNP关联方法进行基因分型(UO1-AA018389)。通过其他重要的合作，该联盟可以获得额外的~2000个基因型- 表型数据使其成为ALC遗传学最大的发现队列。该财团也已经完成了识别和访问‘巨型’基因组生物库(如英国生物库)的基础工作独立的验证队列。目前应用的具体目标是，目标1：通过以下方式确定ALC的遗传风险因素病例对照：在GenomALC发现队列中(n=~7411)；目的2：证实可从已建立的“百万队列”基因组数据库中获得独立验证队列；目标3：至对酒精性肝硬变进行荟萃分析；目标4：检查酒精性肝硬变与潜在相关疾病和肝硬变生物标志物之间的遗传风险。 GenomALC团队(遗传学家、遗传统计学家、临床医生)拥有适当的专业知识、技能和建立了执行这些分析的基础设施。这一大型病例对照GWA有能力发现新的SNP，创造新的知识，推断导致酒精性肝硬变的途径/机制，从而确定新的或重新调整用途的药物治疗的潜在目标。