Identification and Characterization of Loci Associated with Non-alcoholic Fatty Liver Disease

与非酒精性脂肪肝相关基因座的鉴定和表征

• 批准号: 10230705
• 负责人: Nicholette D. Allred
• 金额: $ 70.38万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10230705
• 关键词: Affect; African; Alleles; Biological; CRISPR screen; CRISPR/Cas technology; Cell Line; Cells; Data; Diagnosis; Disease; Ethnic Origin; Ethnic group; Etiology; European; Fatty Liver; Fatty acid glycerol esters; Functional disorder; Gene Frequency; Genes; Genetic; Genomics; Glycogen; Goals; Hepatocyte; Heritability; High Prevalence; Hispanic; Histologic; Histology; Human; Image; Individual; Investments; Knock-out; Link; Liver; Liver diseases; Measures; Medical; Meta-Analysis; Minority Groups; National Heart, Lung, and Blood Institute; Obesity associated liver disease; Pathology; Population; Population Heterogeneity; Predisposition; Prevalence; Prevention; Public Health; Publishing; Resources; Risk; Role; Signal Transduction; Testing; Therapeutic Intervention; Time; Trans-Omics for Precision Medicine; United States National Institutes of Health; Validation; Variant; Weight; Work; X-Ray Computed Tomography; attenuation; base; causal variant; chronic liver disease; clinical practice; cohort; cost; disease diagnosis; ethnic diversity; follow-up; genetic architecture; genome sequencing; genome wide association study; genome wide screen; genome-wide; genomic locus; improved; insight; minimal risk; multi-ethnic; non-alcoholic fatty liver disease; novel; obesity genetics; population based; prevent; rare variant; targeted treatment; whole genome

PROJECT SUMMARY Non-alcoholic fatty liver disease (NAFLD), caused by excess accumulation of fat in the liver (steatosis), has a global prevalence of 25.2% and is the most common cause of chronic liver disease worldwide. There are few effective ways to prevent or treat NAFLD making it one of the biggest unmet public health needs of our time. A better understanding of the pathophysiology is needed to improve diagnosis and treatment. NAFLD is a highly heritable disease (20-70%) with prevalence rates that vary across ethnic groups, i.e. individuals of Hispanic ancestry have a higher prevalence than European and African ancestry individuals. One of the first published GWAS was our work from the Genetics of Obesity-associated Liver Disease (GOLD) Consortium identifying five loci associated with computed tomography-measured liver attenuation in European-ancestry populations. Trans ethnic analyses confirmed some associations and also identified ancestry specific alleles suggesting novel disease promoting loci may exist in minority populations. Since known variation explains only 4.8% of the variance in liver attenuation, additional genetic loci that impact predisposition to NAFLD remain to be discovered. The objective of this application is to identify additional rare variants with effects on NAFLD through whole genome sequencing (WGS) in ethnically diverse populations included in NHLBI’s Trans-Omics for Precision Medicine (TOPMed) Consortium (n=23,156). We will replicate effects in GOLD cohorts (n=8,865) lacking WGS by imputing GWAS data to the TOPMed reference panel. Implicated genes from these single rare variant and rare variant burden testing analyses will be functionally tested for effects on hepatic steatosis to confirm causality. Our central hypothesis is that rare variants contribute to variation and risk. These WGS identified variants can help prioritize loci that can be targeted for NAFLD therapy. Our long-term goal is to improve the diagnosis, management, treatment and ultimately prevention of NAFLD by understanding the genomic contributions to pathophysiology. Results from our work will help us to understand the genetic architecture of NAFLD and link these associations to genes that can be targeted for therapeutic intervention.

项目总结 非酒精性脂肪性肝病(NAFLD)是由肝脏脂肪过度堆积(脂肪变性)引起的，全球患病率为25.2%，是全球慢性肝病的最常见原因。几乎没有有效的方法来预防或治疗非酒精性脂肪肝，这使其成为我们这个时代最大的未得到满足的公共卫生需求之一。需要对病理生理学有更好的了解，以提高诊断和治疗水平。NAFLD是一种高度可遗传的疾病(20%-70%)，其患病率因族裔群体而异，即西班牙裔血统的人比欧洲人和非洲人血统的人患病率更高。最早发表的GWAS之一是我们在肥胖相关肝病遗传学(GOLD)联合会的工作，确定了与欧洲血统人群中计算机断层扫描测量的肝脏衰减相关的五个基因座。跨种族分析证实了一些关联，也发现了祖先特有的等位基因，这表明新的致病基因可能存在于少数群体中。由于已知的变异只解释了4.8%的肝脏衰减变异，其他影响NAFLD易感性的遗传位点仍有待发现。这项应用的目标是通过全基因组测序(WGS)在NHLBI的全基因组精密医学(TOPMed)联盟(n=23,156)中包括的不同种族的人群中识别对NAFLD有影响的其他罕见变异。我们将通过将Gwas数据输入TOPMed参考小组，在缺乏WGS的黄金队列(n=8,865)中复制影响。这些单一的罕见变异和罕见变异负荷测试分析中涉及的基因将进行功能测试，以确定对肝脏脂肪变性的影响，以确认因果关系。我们的中心假设是，罕见的变异会导致变异和风险。这些WGS确定的变异可以帮助确定NAFLD治疗的靶点。我们的长期目标是通过了解基因组对病理生理学的贡献来改善NAFLD的诊断、管理、治疗和最终预防。我们的工作结果将帮助我们了解NAFLD的遗传结构，并将这些关联与可以作为治疗干预目标的基因联系起来。