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Genome-wide analysis of hepatic lipid content in extreme obesity

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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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Abbreviations

NAFLD:

Non-alcoholic fatty liver disease

PNPLA3 :

Patatin-like phospholipase domain containing 3 gene

UGT1A :

Uridine 5′-diphospho-glucuronosyltransferase

SUGP1 :

SURP and G patch domain containing 1 gene

NCAN :

Neurocan

LPAR2 :

Lysophosphatidic acid receptor 2

RAMP3 :

Receptor (G protein-coupled) activity modifying protein 3

SOCS2 :

Suppressor of cytokine signaling 2

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Acknowledgments

The authors would like to thank the staff of the TGen Collaborative Sequencing Center for their assistance. This work was supported by the National Institutes of Health DK091601 (JKD and GSG), P30 DK072488 (GSG and CDS), Translational Genomics Research Institute, and the Geisinger Obesity Institute.

Conflict of interest

Johanna K. DiStefano, Christopher Kingsley, G. Craig Wood, Xin Chu, George Argyropoulos, Christopher D. Still, Stefania Cotta Doné, Christophe Legendre, Waibhav Tembe, and Glenn S. Gerhard declare that they have no conflict of interest.

Human and animal rights

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2008 (5).

Informed consent

Informed consent was obtained from all patients for being included in the study.

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Authors and Affiliations

  1. Diabetes, Cardiovascular and Metabolic Diseases Division, Translational Genomics Research Institute, 445 North Fifth Street, Phoenix, AZ, 85004, USA

    Johanna K. DiStefano, Christopher Kingsley, Stefania Cotta Doné, Christophe Legendre & Waibhav Tembe

  2. Geisinger Obesity Institute, Geisinger Clinic, 100 N. Academy Ave., Danville, PA, 17822, USA

    G. Craig Wood, Xin Chu, George Argyropoulos, Christopher D. Still & Glenn S. Gerhard

  3. Department of Biochemistry and Molecular Biology, Institute for Personalized Medicine, Pennsylvania State University College of Medicine, Room C5750, 500 University Drive, MC-H171, Hershey, PA, 17033, USA

    Glenn S. Gerhard

  4. Department of Pathology and Laboratory Medicine, Pennsylvania State University College of Medicine, Room C5750, 500 University Drive, MC-H171, Hershey, PA, 17033, USA

    Glenn S. Gerhard

Authors
  1. Johanna K. DiStefano
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  2. Christopher Kingsley
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  3. G. Craig Wood
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  4. Xin Chu
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  5. George Argyropoulos
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  7. Stefania Cotta Doné
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  8. Christophe Legendre
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  9. Waibhav Tembe
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  10. Glenn S. Gerhard
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Corresponding authors

Correspondence to Johanna K. DiStefano or Glenn S. Gerhard.

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DiStefano, J.K., Kingsley, C., Craig Wood, G. et al. Genome-wide analysis of hepatic lipid content in extreme obesity. Acta Diabetol 52, 373–382 (2015). https://doi.org/10.1007/s00592-014-0654-3

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