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

基本信息

项目摘要

 DESCRIPTION (provided by applicant): Nonalcoholic fatty liver disease (NAFLD) is caused by hepatic steatosis (lipid accumulation), affects up to 29 million adults in the U.S. and will become the leading cause of liver disease worldwide by 2020. There are few effective ways to prevent or treat NAFLD. A better understanding of NAFLD etiology is needed to improve its diagnosis and treatment. We previously determined that NAFLD is heritable (genetically influenced) and identified common (minor allele frequency (MAF) >5%) single nucleotide polymorphisms (SNPs) at 5 loci that associate with hepatic steatosis, first in ~7,000 individuals of European ancestry and then across ancestries. Variants at the 5 loci explain ~20% of heritability, suggesting the existence of more influential causal variants. We now aim to identify 1. causal genetic variants 2. gene(s) they work through to exert their effects, and 3. mechanism(s) by which they lead to disease. We tripled the sample size and ancestral diversity of our discovery sample, thus improving our ability to identify and fine-map causal variants. We will impute genome- wide genotypes to new denser and ancestrally diverse imputation panels, increasing our ability to identify causal common and now low-frequency (MAF 1-5%) variants across ancestries. We will use new analytical methods to perform not only single variant but also conditional and gene-based analyses across ancestries allowing us to efficiently identify causal single variants and genes. We will use new variant and gene annotations algorithms to prioritize variants and genes for functional follow up. Using this approach we identify new putative causal NAFLD variants and genes missed by previous analyses. Finally, we developed a human cell line model of NAFLD that we use to show that altering the function of three genes prioritized by the above approaches results in increased liver triglyceride accumulation, suggesting this as a common mechanism by which these genes cause NAFLD. We hypothesize that causal NAFLD-promoting human genetic variants have effects across ancestries and exert their effects in a cell-autonomous manner in hepatocytes to increase triglyceride accumulation. To test this hypothesis, we will harmonize the computed tomography hepatic steatosis phenotype and genotypes from 10 discovery cohorts (n>21K), impute genotypes to the 1000 Genomes cosmopolitan reference panel, and perform single variant, gene-based, and conditional meta- analyses across groups to identify, fine-map, and annotate putative causal variants and genes. We will follow- up top associating variants in >4,000 histologically confirmed NAFLD cases and ~3,000 controls to replicate our findings. We will knockdown and overexpress putative causal genes (wild-type and variant) in human liver cell lines and determine their effect on triglyceride accumulation and genetic mechanism of action. We will begin with three genes prioritized from our previous NAFLD meta-analysis and proceed to new genes identified from the 1000 Genomes meta-analysis. 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.


项目成果

期刊论文数量(17)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Genome-wide association study of serum liver enzymes implicates diverse metabolic and liver pathology.
  • DOI:
    10.1038/s41467-020-20870-1
  • 发表时间:
    2021-02-05
  • 期刊:
  • 影响因子:
    16.6
  • 作者:
    Chen VL;Du X;Chen Y;Kuppa A;Handelman SK;Vohnoutka RB;Peyser PA;Palmer ND;Bielak LF;Halligan B;Speliotes EK
  • 通讯作者:
    Speliotes EK
Thwart your destiny; effect of nonacoholic fatty liver disease genes on steatosis, liver injury and cirrhosis varies by body mass index.
  • DOI:
    10.1002/hep.29739
  • 发表时间:
    2018-07
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Speliotes EK
  • 通讯作者:
    Speliotes EK
Hepatic decompensation is accelerated in patients with cirrhosis and alpha-1 antitrypsin Pi∗MZ genotype.
  • DOI:
    10.1016/j.jhepr.2022.100483
  • 发表时间:
    2022-06
  • 期刊:
  • 影响因子:
    8.3
  • 作者:
    Chen, Vincent L.;Burkholder, Daniel A.;Moran, Isabel J.;V. DiBattista, Jacob;Miller, Matthew J.;Chen, Yanhua;Du, Xiaomeng;Oliveri, Antonino;Cushing, Kelly C.;Lok, Anna S.;Speliotes, Elizabeth K.
  • 通讯作者:
    Speliotes, Elizabeth K.
Recent Advances in Human Genetics and Epigenetics of Adiposity: Pathway to Precision Medicine?
人类遗传学和肥胖表观遗传学的最新进展:精密医学途径?
  • DOI:
    10.1053/j.gastro.2017.01.054
  • 发表时间:
    2017-05
  • 期刊:
  • 影响因子:
    29.4
  • 作者:
    Fall T;Mendelson M;Speliotes EK
  • 通讯作者:
    Speliotes EK
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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

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
  • 批准号:
    10598159
  • 财政年份:
    2022
  • 资助金额:
    $ 62.82万
  • 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:
    9009526
  • 财政年份:
    2016
  • 资助金额:
    $ 62.82万
  • 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:
    $ 62.82万
  • 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:
    $ 62.82万
  • 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:
    $ 62.82万
  • 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:
    $ 62.82万
  • 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:
    $ 62.82万
  • 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:
    $ 62.82万
  • 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:
    $ 62.82万
  • 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:
    $ 62.82万
  • 项目类别:

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