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01.04.2015 | Original Article

Genome-wide analysis of hepatic lipid content in extreme obesity

verfasst von: Johanna K. DiStefano, Christopher Kingsley, G. Craig Wood, Xin Chu, George Argyropoulos, Christopher D. Still, Stefania Cotta Doné, Christophe Legendre, Waibhav Tembe, Glenn S. Gerhard

Erschienen in: Acta Diabetologica | Ausgabe 2/2015

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Abstract

Aims

Individuals with type 2 diabetes have an increased risk of developing non-alcoholic fatty liver disease (NAFLD), and NAFLD patients are also at greater risk for developing type 2 diabetes. Although the relationship between type 2 diabetes and NAFLD is highly interconnected, the pathogenic mechanisms linking the two diseases are poorly understood. The goal of this study was to identify genetic determinants of hepatic lipid accumulation through association analysis using histological phenotypes in obese individuals.

Methods

Using the Illumina HumanOmniExpress BeadChip assay, we genotyped 2,300 individuals on whom liver biopsy data were available.

Results

We analyzed total bilirubin levels, which are linked to fatty liver in severe obesity, and observed the strongest evidence for association with rs4148325 in UGT1A (P < 5.0 × 10⁻⁹³), replicating previous findings. We assessed hepatic fat level and found strong evidence for association with rs4823173, rs2896019, and rs2281135, all located in PNPLA3 and rs10401969 in SUGP1. Analysis of liver transcript levels of 20 genes residing at the SUGP1/NCAN locus identified a 1.6-fold change in the expression of the LPAR2 gene in fatty liver. We also observed suggestive evidence for association between low-grade fat accumulation and rs10859525 and rs1294908, located upstream from SOCS2 and RAMP3, respectively. SOCS2 was differentially expressed between fatty and normal liver.

Conclusions

These results replicate findings for several hepatic phenotypes in the setting of extreme obesity and implicate new loci that may play a role in the pathophysiology of hepatic lipid accumulation.

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Titel: Genome-wide analysis of hepatic lipid content in extreme obesity
verfasst von: Johanna K. DiStefano
Christopher Kingsley
G. Craig Wood
Xin Chu
George Argyropoulos
Christopher D. Still
Stefania Cotta Doné
Christophe Legendre
Waibhav Tembe
Glenn S. Gerhard
Publikationsdatum: 01.04.2015
Verlag: Springer Milan
Erschienen in: Acta Diabetologica / Ausgabe 2/2015
Print ISSN: 0940-5429
Elektronische ISSN: 1432-5233
DOI: https://doi.org/10.1007/s00592-014-0654-3

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Abstract

Aims

Methods

Results

Conclusions

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