Abstract
Non-alcoholic fatty liver disease (NAFLD) is a common liver disease; the histological spectrum of which ranges from steatosis to steatohepatitis. Nonalcoholic steatohepatitis (NASH) often leads to cirrhosis and development of hepatocellular carcinoma. To better understand pathogenesis of NAFLD, we performed the pathway of distinction analysis (PoDA) on a genome-wide association study dataset of 250 non-Hispanic white female adult patients with NAFLD, who were enrolled in the NASH Clinical Research Network (CRN) Database Study, to investigate whether biologic process variation measured through genomic variation of genes within these pathways was related to the development of steatohepatitis or cirrhosis. Pathways such as Recycling of eIF2:GDP, biosynthesis of steroids, Terpenoid biosynthesis and Cholesterol biosynthesis were found to be significantly associated with NASH. SNP variants in Terpenoid synthesis, Cholesterol biosynthesis and biosynthesis of steroids were associated with lobular inflammation and cytologic ballooning while those in Terpenoid synthesis were also associated with fibrosis and cirrhosis. These were also related to the NAFLD activity score (NAS) which is derived from the histological severity of steatosis, inflammation and ballooning degeneration. Eukaryotic protein translation and recycling of eIF2:GDP related SNP variants were associated with ballooning, steatohepatitis and cirrhosis. Il2 signaling events mediated by PI3K, Mitotic metaphase/anaphase transition, and Prostanoid ligand receptors were also significantly associated with cirrhosis. Taken together, the results provide evidence for additional ways, beyond the effects of single SNPs, by which genetic factors might contribute to the susceptibility to develop a particular phenotype of NAFLD and then progress to cirrhosis. Further studies are warranted to explain potential important genetic roles of these biological processes in NAFLD.
Highlights
Nonalcoholic fatty liver disease (NAFLD) affects almost a third of the adult population in North America [1]
This report represents an independent analysis of the genome wide association study (GWAS) dataset to identify genetic variations in biologic pathways associated with cirrhosis, nonalcoholic steatohepatitis (NASH) and the severity of the individual histologic features of NAFLD
The collections of single nucleotide polymorphisms (SNPs) in genes contained in Pathway Interaction Database (PID) [11] were examined for association with the following histological features of NAFLD that were recorded from Central Pathology Review: diagnosis of definite steatohepatitis, presence of cirrhosis, stage of fibrosis, grade of
Summary
Nonalcoholic fatty liver disease (NAFLD) affects almost a third of the adult population in North America [1]. NAFLD is a risk factor for the development of hepatocellular cancer which can develop with or without cirrhosis [5] It is a public health priority to better understand the pathogenesis of the disease as well as factors that drive disease progression. Since the discovery of the association between the PNPLA3 mutation and steatosis and steatohepatitis, several additional single nucleotide polymorphisms (SNPs) have been identified to be associated with NASH [7]. Despite these individual SNP associations, the biologic mechanisms that distinguish alternative clinical outcomes or disease progression are largely unknown
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