Integrative Polygenic Genetic Studies of Non-alcoholic Fatty Liver Disease
非酒精性脂肪肝的综合多基因遗传学研究
基本信息
- 批准号:10598159
- 负责人:
- 金额:$ 68.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AdultAffectAfricanAlanineAlanine TransaminaseAspartateAspartate TransaminaseBiological MarkersCRISPR/Cas technologyCell LineCirrhosisCollectionDataDevelopmentDiagnosisDiseaseEconomic BurdenEthnic OriginEtiologyEuropeanFatty LiverFatty acid glycerol estersFrequenciesFunctional disorderGene DosageGenesGeneticGenetic studyGenomicsGoalsGrantHepatocyteHeritabilityHeterogeneityHigh PrevalenceHispanic PopulationsHispanic ancestryHistologyHumanImageIndividualInternational Classification of Disease CodesKnock-outLinkLipidsLiverLiver CirrhosisLiver FibrosisLiver diseasesMagnetic Resonance ImagingMeasuresMedicalMeta-AnalysisMetabolicMichiganObesityPrevalencePreventionPrimary carcinoma of the liver cellsPublic HealthPublishingRiskRoleSamplingSerumTestingTherapeuticTherapeutic InterventionTimeVariantWorkX-Ray Computed Tomographyattenuationbiobankcausal variantchronic liver diseasecohortdisease diagnosisdisorder subtypedosagefollow-upgene functiongenetic architecturegenetic variantgenome wide association studygenome-widegenomic locusimprovedliver imagingmulti-ethnicnon-alcoholic fatty liver diseasenon-invasive imagingnoveloverexpressionpolygenic risk scorepreventrisk predictiontargeted treatmenttrait
项目摘要
Integrative Polygenic Genetic Studies of Non-alcoholic Fatty Liver Disease
Summary
Nonalcoholic fatty liver disease (NAFLD) is caused by hepatic steatosis (lipid accumulation),
affects up to 29 million adults in the U.S. and has become the leading cause of liver disease.
NAFLD can lead to liver cirrhosis and hepatocellular carcinoma. There are few effective ways to
prevent or treat NAFLD. A better understanding of NAFLD etiology is needed to improve its
diagnosis and treatment. NAFLD is heritable (genetically influenced) and identified common
variants that explain ~20% of heritability of this trait, suggesting that more causal variants that
affect this trait remain to be discovered. While histology has historically been used to define
NAFLD steatosis, NAFLD is now routinely diagnosed using non invasive imaging or elevated
ALT/AST without the presence of other liver diseases. We recently published the world’s largest
cross ancestry GWAS analysis of serum ALT/AST/ALP GWAS where we identified >300
genome wide significant variants that associate with these traits; 23 of them also associated
with increased hepatic steatosis assessed in 7600 individuals using liver imaging. We showed
that a polygenic risk score (PRS) from the ALT but not AST or ALP genome wide significant
variants was able to predict steatosis, cirrhosis, and HCC. Here, we have assembled the largest
collection of multiethnic samples with hepatic steatosis measured with liver imaging or NAFLD
diagnosed by international classification of disease code with genome wide data also available.
We hypothesize that (1) common and low frequency variants contribute to NAFLD variation and
risk (2) identified variants in aggregate will improve risk prediction for liver steatosis, cirrhosis
and HCC compared to single variants and (3) GWAS NAFLD prioritized genes, when targeted,
will function autonomously in hepatocytes to cause steatosis. The objective of this application is
to carry out a GWAS meta analysis of NAFLD across imaging or ICD diagnosed NAFLD. A PRS
will be created from verified NAFLD associated variants effect and assessed for its ability to
predict, steatosis, cirrhosis, HCC. We will annotate verified NAFLD associated variants to
identify target genes for follow up functional studies for effects on steatosis alone and in
combination. Results from this work will help define the genetic and metabolic mechanisms that
cause NAFLD and inform development of new biomarkers as well as potential therapeutics for
this condition.
非酒精性脂肪性肝病的多基因遗传学研究
总结
非酒精性脂肪性肝病(NAFLD)是由肝脏脂肪变性(脂质积聚)引起的,
在美国影响多达2900万成年人,并已成为肝病的主要原因。
NAFLD可导致肝硬化和肝细胞癌。有几个有效的方法,
预防或治疗NAFLD。需要更好地了解NAFLD的病因,以提高其
诊断和治疗。NAFLD是可遗传的(遗传影响),并被确定为常见
解释该性状遗传力的约20%的变异,这表明更多的因果变异,
影响这一特性还有待发现。虽然组织学在历史上被用来定义
NAFLD脂肪变性,NAFLD现在常规使用非侵入性成像或升高的
ALT/AST,不存在其他肝病。我们最近发表了世界上最大的
血清ALT/AST/ALP GWAS的跨祖先GWAS分析,其中我们确定>300
与这些性状相关的全基因组显著变异;其中23个还与
使用肝脏成像在7600个个体中评估了肝脏脂肪变性的增加。我们展示
来自ALT的多基因风险评分(PRS)而不是AST或ALP基因组范围内的显著性差异,
变异能够预测脂肪变性、肝硬化和HCC。在这里,我们聚集了世界上最大的
收集多种族肝脂肪变性样本,通过肝脏成像或NAFLD测量
根据国际疾病分类代码诊断,也可获得全基因组数据。
我们假设(1)常见和低频变异有助于NAFLD变异,
风险(2)总体上确定的变异将改善肝脂肪变性、肝硬化的风险预测
和HCC相比,单一变异和(3)GWAS NAFLD优先基因,当靶向,
将在肝细胞中自主发挥作用以引起脂肪变性。本申请的目的是
在影像学或ICD诊断的NAFLD中进行NAFLD的GWAS Meta分析。的PRS
将根据经验证的NAFLD相关变体效应创建,并评估其
预测脂肪变性肝硬化肝癌。我们将注释经验证的NAFLD相关变体,
鉴定靶基因,用于单独对脂肪变性的作用和
组合.这项工作的结果将有助于确定遗传和代谢机制,
导致NAFLD,并为开发新的生物标志物和潜在的治疗方法提供信息。
这个条件。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Elizabeth K Speliotes其他文献
Elizabeth K Speliotes的其他文献
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{{ truncateString('Elizabeth K Speliotes', 18)}}的其他基金
Human population based genetic studies to elucidate the biology of NAFLD
基于人群的遗传学研究阐明 NAFLD 的生物学
- 批准号:
9009526 - 财政年份:2016
- 资助金额:
$ 68.31万 - 项目类别:
Human population based genetic studies to elucidate the biology of NAFLD
基于人群的遗传学研究阐明 NAFLD 的生物学
- 批准号:
9549051 - 财政年份:2016
- 资助金额:
$ 68.31万 - 项目类别:
Human population based genetic studies to elucidate the biology of NAFLD
基于人群的遗传学研究阐明 NAFLD 的生物学
- 批准号:
10020952 - 财政年份:2016
- 资助金额:
$ 68.31万 - 项目类别:
Human population based genetic studies to elucidate the biology of NAFLD
基于人群的遗传学研究阐明 NAFLD 的生物学
- 批准号:
9348637 - 财政年份:2016
- 资助金额:
$ 68.31万 - 项目类别:
Identification and functional impact of NAFLD associated genetic variants
NAFLD 相关基因变异的鉴定和功能影响
- 批准号:
9506752 - 财政年份:2015
- 资助金额:
$ 68.31万 - 项目类别:
Identification and functional impact of NAFLD associated genetic variants
NAFLD 相关基因变异的鉴定和功能影响
- 批准号:
8945536 - 财政年份:2015
- 资助金额:
$ 68.31万 - 项目类别:
Analysis of Fatty Liver in the Framingham Heart Study Cohort
弗雷明汉心脏研究队列中的脂肪肝分析
- 批准号:
7361956 - 财政年份:2008
- 资助金额:
$ 68.31万 - 项目类别:
Analysis of Fatty Liver in the Framingham Heart Study Cohort
弗雷明汉心脏研究队列中的脂肪肝分析
- 批准号:
8018094 - 财政年份:2008
- 资助金额:
$ 68.31万 - 项目类别:
Analysis of Fatty Liver in the Framingham Heart Study Cohort
弗雷明汉心脏研究队列中的脂肪肝分析
- 批准号:
7570647 - 财政年份:2008
- 资助金额:
$ 68.31万 - 项目类别:
Analysis of Fatty Liver in the Framingham Heart Study Cohort
弗雷明汉心脏研究队列中的脂肪肝分析
- 批准号:
7784451 - 财政年份:2008
- 资助金额:
$ 68.31万 - 项目类别:
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