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Identification and functional impact of NAFLD associated genetic variants

NAFLD 相关基因变异的鉴定和功能影响

基本信息

批准号：
9506752
负责人：
Elizabeth K Speliotes
金额：
$ 62.94万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-05 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9506752
关键词：
Adult Affect Amino Acid Sequence Biological Assay Biological Markers Candidate Disease Gene Cell Line Cell model Cells Code Collection Data Development Diagnosis Disease Etiology European Fatty Liver Frequencies Functional disorder Gene Frequency Genes Genetic Genetic study Genotype Hepatic Hepatocyte Heritability Histologic Histology Human Human Cell Line Individual Influentials Lipids Liver Liver diseases Measures Medical Meta-Analysis Metabolic Metabolic Diseases Methods Minor Modeling Mutation Phenotype Population Population Heterogeneity Prevention Proteins Public Health Resources Sample Size Sampling Single Nucleotide Polymorphism Testing Therapeutic Time Variant Work X-Ray Computed Tomography base bead chip cohort exome exome sequencing expression vector follow-up genetic variant genome sequencing genome wide association study improved knock-down mutant non-alcoholic fatty liver disease overexpression population based prevent protein function public health relevance rare variant whole genome

项目摘要

DESCRIPTION (provided by applicant): Nonalcoholic fatty liver disease (NAFLD) is caused by hepatic steatosis (lipid accumulation), is a common disease that affects up to 29 million adults in the U.S., and will become the number one cause of liver disease worldwide by 2020. There are few effective ways to prevent or treat this disease. A better understanding of its etiology is needed to improve diagnosis and treatment. We previously found 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 together explain ~20% of heritability suggesting that other influential variants remain to be discovered. We and others have now found that genes harboring functional coding (affecting protein sequence) common variants of small effect often can also harbor rare variants with large effects. At three of the five associated loci we have now identified putative functional coding variants across ancestries. Recent whole genome and exome sequencing studies identified many new coding variants but many are low frequency (MAF 1-5%) or rare (MAF < 1%) and neutral as opposed to damaging. These low frequency and rare variants have been underexplored in genome-wide association studies due to the limitations of imputation and small sample sizes. These variants can now be affordably assayed in large numbers of samples using the new Illumina Human Exome BeadChip. Further, we can test whether particular genes and variants affect hepatic lipid accumulation in a new cell based model of hepatic steatosis we have created. We hypothesize that low frequency (MAF 1-5%) and rare (MAF <1%) coding variants with effects on hepatic steatosis exist and if expressed in liver, affect liver lipid accumulation. To identify and characterize low and rare frequency variants for effects on NAFLD, we have now assembled the largest, most ancestrally diverse population based collection of individuals (>16,000 from 8 cohorts) with measures of hepatic steatosis and genotyped them with the Exome BeadChip. We will harmonize the hepatic steatosis phenotype and genotypes in our cohorts and carry out single variant, gene based, and conditional meta analyses across groups to identify putative causal variants. We will follow up top associating variants and genes from hepatic steatosis analyses in >4,000 histologically confirmed NAFLD cases and ~3,000 controls to replicate our findings. Using our cellular model of hepatic steatosis, we will overexpress and knockdown liver expressed genes harboring coding variants in human liver cell lines and characterize their genetic and lipidomic mechanisms of action. We will start with the three genes we have already identified that harbor coding variants that associate with NAFLD and then proceed to new genes identified and replicated from the proposed exome analyses. This work will begin to define the genetic and metabolic mechanisms which cause NAFLD to inform development of new biomarkers as well as potential therapeutics for this condition.