Hepatic gene networks in morbidly obese patients with nonalcoholic fatty liver disease.
BACKGROUND
Genetic factors alter the risk for nonalcoholic fatty liver disease (NAFLD). We sought to identify NAFLD-associated genes and elucidate gene networks and pathways involved in the pathogenesis of NAFLD.


METHODS
Quantitative global hepatic gene expression analysis was performed on 53 morbidly obese Caucasian subjects undergoing bariatric surgery (27 with NAFLD and 26 controls). After standardization of data, gene expression profiles were compared between patients with NAFLD and controls. The set of genes that significantly correlated with NAFLD was further analyzed by hierarchical clustering and ingenuity pathways analyses.


RESULTS
There were 25,643 quantitative transcripts, of which 108 were significantly associated with NAFLD (p < 0.001). Canonical pathway analysis in the NAFLD-associated gene clusters showed that the hepatic fibrosis signaling was the most significant pathway in the up-regulated NAFLD gene cluster containing three (COL1A1, IL10, IGFBP3) significantly altered genes, whereas the endoplasmic reticulum stress and protein ubiquitination pathways were the most significant pathways in the down-regulated NAFLD gene cluster, with the first pathway containing one (HSPA5) and the second containing two (HSPA5, USP25) significantly altered genes. The four primary gene networks associated with NAFLD were involved in cell death, immunological disease, cellular movement, and lipid metabolism with several significantly altered "hub" genes in these networks.


CONCLUSIONS
This study reveals the canonical pathways and gene networks associated with NAFLD in morbidly obese Caucasians. The application of gene network analysis highlights the transcriptional relationships among NAFLD-associated genes and allows identification of hub genes that may represent high-priority candidates for NAFLD.
Gawrieh
Samer
S
Department of Medicine, Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI 53212, USA. sgawrieh@mcw.edu
Baye
Tesfaye M
TM
Carless
Melanie
M
Wallace
James
J
Komorowski
Richard
R
Kleiner
David E
DE
Andris
Deborah
D
Makladi
Bassem
B
Cole
Regina
R
Charlton
Michael
M
Curran
Joanne
J
Dyer
Thomas D
TD
Charlesworth
Jac
J
Wilke
Russell
R
Blangero
John
J
Kissebah
Ahmed H
AH
Olivier
Michael
M
D000328:Adult; D015897:Comorbidity; D003920:Diabetes Mellitus / Q000453:epidemiology / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP; D005234:Fatty Liver / Q000453:epidemiology / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D006801:Humans; D006973:Hypertension / Q000453:epidemiology / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D009767:Obesity, Morbid / Q000453:epidemiology / Q000235:genetics*; D044465:White People
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