Objective: Obesity-associated non-alcoholic fatty liver disease (NAFLD) may cause liver dysfunction and failure. In a previously reported genome-wide association meta-analysis, single nucleotide polymorphisms (SNPs) near PNPLA3, NCAN, GCKR, LYPLAL1 and PPP1R3B were associated with NAFLD and with distinctive serum lipid profiles. The present study examined the relevance of these variants to NAFLD in extreme obesity. Methods: In 1,092 bariatric surgery patients, the candidate SNPs were genotyped and association analyses with liver histology and serum lipids were performed. Results: We replicated the association of hepatosteatosis with PNPLA3 rs738409[G] and with NCAN rs2228603[T]. We also replicated the association of rs2228603[T] with hepatic inflammation and fibrosis. rs2228603[T] was associated with lower serum low-density lipoprotein, total cholesterol and triglycerides. After stratification by the presence or absence of NAFLD, these associations were present predominantly in the subgroup with NAFLD. Conclusion:NCAN rs2228603[T] is a risk factor for liver inflammation and fibrosis, suggesting that this locus is responsible for progression from steatosis to steatohepatitis. In this bariatric cohort, rs2228603[T] was associated with low serum lipids only in patients with NAFLD. This supports a NAFLD model in which the liver may sequester triglycerides as a result of either increased triglyceride uptake and/or decreased lipolysis.
© 2013 S. Karger AG, Basel
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Glenn S. Gerhard, MD
Department of Biochemistry and Molecular Biology, Institute for Personalized Medicine
Pennsylvania State University College of Medicine
Hershey, PA 17033 (USA)
Received: August 21, 2012
Accepted after revision: November 27, 2012
Published online: April 10, 2013
Number of Print Pages : 10
Number of Figures : 5, Number of Tables : 3, Number of References : 43
Additional supplementary material is available online - Number of Parts : 1
Human Heredity (International Journal of Human and Medical Genetics)
Vol. 75, No. 1, Year 2013 (Cover Date: May 2013)
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