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.