Shared genetic effects between hepatic steatosis and fibrosis: A prospective twin study.
Nonalcoholic fatty liver disease is associated with metabolic risk factors including hypertension and dyslipidemia and may progress to liver fibrosis. Studies have shown that hepatic steatosis and fibrosis are heritable, but whether they have a significant shared gene effect is unknown. This study examined the shared gene effects between hepatic steatosis and fibrosis and their associations with metabolic risk factors. This was a cross-sectional analysis of a prospective cohort of well-characterized, community-dwelling twins (45 monozygotic, 20 dizygotic twin pairs, 130 total subjects) from southern California. Hepatic steatosis was assessed with magnetic resonance imaging-proton density fat fraction and hepatic fibrosis with magnetic resonance elastography. A standard bivariate twin additive genetics and unique environment effects model was used to estimate the proportion of phenotypic variance between two phenotypes accounted for by additive genetic effects and individual-specific environmental effects. Genetic correlations estimated from this model represent the degree to which the genetic determinants of two phenotypes overlap. Mean (± standard deviation) age and body mass index were 47.1 (±21.9) years and 26.2 (±5.8) kg/m2, respectively. Among the cohort, 20% (26/130) had hepatic steatosis (magnetic resonance imaging-proton density fat fraction ≥5%), and 8.2% (10/122) had hepatic fibrosis (magnetic resonance elastography ≥3 kPa). Blood pressure (systolic and diastolic), triglycerides, glucose, homeostatic model assessment of insulin resistance, insulin, hemoglobin A1c, and low high-density lipoprotein had significant shared gene effects with hepatic steatosis. Triglycerides, glucose, homeostatic model assessment of insulin resistance, insulin, hemoglobin A1c, and low high-density lipoprotein had significant shared gene effects with hepatic fibrosis. Hepatic steatosis and fibrosis had a highly significant shared gene effect of 0.756 (95% confidence interval 0.716-1, P < 0.0001).



Genes involved with steatosis pathogenesis may also be involved with fibrosis pathogenesis. (Hepatology 2016;64:1547-1558).
NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, CA.
Jeffrey
J
Cui
Department of Radiology, University of California at San Diego, La Jolla, CA.
Chi-Hua
CH
Chen
Department of Radiology, University of California at San Diego, La Jolla, CA.
Min-Tzu
MT
Lo
Human Biology, J. Craig Venter Institute, La Jolla, CA.
Nicholas
N
Schork
NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, CA.|Division of Epidemiology, Department of Family and Preventive Medicine, University of California at San Diego, La Jolla, CA.
Ricki
R
Bettencourt
NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, CA.
Monica P
MP
Gonzalez
NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, CA.
Archana
A
Bhatt
Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, CA.
Jonathan
J
Hooker
NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, CA.|Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA.
Katherine
K
Shaffer
J. Craig Venter Institute, La Jolla, CA.
Karen E
KE
Nelson
Division of Gastroenterology, Department of Medicine, Boston University School of Medicine, Boston, MA.
Michelle T
MT
Long
Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA.
David A
DA
Brenner
Liver Imaging Group, Department of Radiology, University of California at San Diego, La Jolla, CA.
Claude B
CB
Sirlin
NAFLD Research Center, Department of Medicine, University of California at San Diego, La Jolla, CA. roloomba@ucsd.edu.|Division of Epidemiology, Department of Family and Preventive Medicine, University of California at San Diego, La Jolla, CA. roloomba@ucsd.edu.|Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA. roloomba@ucsd.edu.
Rohit
R
Loomba
For The Genetics Of Nafld In Twins Consortium
D003430:Cross-Sectional Studies; D004200:Diseases in Twins / Q000235:genetics* / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012307:Risk Factors