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. 2013;75(1):34-43.
doi: 10.1159/000346195. Epub 2013 Apr 10.

Genetic variation at NCAN locus is associated with inflammation and fibrosis in non-alcoholic fatty liver disease in morbid obesity

Alexis Gorden  1 , Rongze Yang, Laura M Yerges-Armstrong, Kathleen A Ryan, Elizabeth Speliotes, Ingrid B Borecki, Tamara B Harris, Xin Chu, G Craig Wood, Christopher D Still, Alan R Shuldiner, Glenn S Gerhard; GOLD Consortium
Collaborators, Affiliations

Genetic variation at NCAN locus is associated with inflammation and fibrosis in non-alcoholic fatty liver disease in morbid obesity

Alexis Gorden et al. Hum Hered. 2013.

Abstract

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.

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Conflict of interest statement

Disclosures

Drs. Shuldiner, Gerhard, Chu, Yerges-Armstrong, Speliotes, Yang, and Gorden and Mr. Wood have no conflicts to report.

Figures

Figure 1
Figure 1
Spectrum of NAFLD represented in the bariatric cohort (n=1,092).
Figure 2
Figure 2
Proportions of bariatric surgery patients with varying degrees of hepatic steatosis (n=1,092). Grading was performed by experienced pathologists using the criteria of Brunt (1).
Figure 3
Figure 3
Liver histology features (lobular inflammation, hepatocyte ballooning and perivenular fibrosis) in bariatric patients with NASH (n=187). Grading was performed by experienced pathologists using the criteria of Brunt (1).
Figure 4
Figure 4
Association between SNP genotype and liver steatosis in all bariatric patients (n=1,092).
Figure 5
Figure 5
Association of NCAN rs2228603 genotype with features of NASH and cirrhosis in all bariatric patients (n=1,092).
See this image and copyright information in PMC

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