Interactions of allelic variance of PNPLA3 with nongenetic factors in predicting nonalcoholic steatohepatitis and nonhepatic complications of severe obesity

Authors

  • M.M.J. Guichelaar,

    1. Division of Gastroenterology and Hepatology, Medical Spectrum Twente, Enschede, The Netherlands
    2. Liver Transplantation, Mayo Clinic, Rochester, Minnesota, USA
    Search for more papers by this author
    • Author contributions: MMJ Guichelaar: acquisition of data, analysis and interpretation of data, and drafting of the manuscript; S Gawrieh, M Oliver, M Viker, A Krishnan, KD Watt, JM Swain, and M Sarr: acquisition of data and critical revision of the manuscript; S Sanderson: acquisition of data and critical revision of the manuscript for important intellectual content; M Malinchoc: statistical analyses and critical revision of the manuscript for important intellectual content; MR Charlton: acquisition of data, analysis and interpretation of data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content.

  • S. Gawrieh,

    1. Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
    Search for more papers by this author
  • M. Olivier,

    1. Biotechnology and Bioengineering Center, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
    Search for more papers by this author
  • K. Viker,

    1. Liver Transplantation, Mayo Clinic, Rochester, Minnesota, USA
    Search for more papers by this author
  • A. Krishnan,

    1. Liver Transplantation, Mayo Clinic, Rochester, Minnesota, USA
    Search for more papers by this author
  • S. Sanderson,

    1. Division of Pathology, Mayo Clinic, Rochester, Minnesota, USA
    Search for more papers by this author
  • M. Malinchoc,

    1. Division of Biostatistics, Mayo Clinic, Rochester, Minnesota, USA
    Search for more papers by this author
  • K.D. Watt,

    1. Liver Transplantation, Mayo Clinic, Rochester, Minnesota, USA
    Search for more papers by this author
  • J.M. Swain,

    1. Department of Surgery, Mayo Clinic, Rochester, Minnesota, USA
    Search for more papers by this author
  • M. Sarr,

    1. Department of Surgery, Mayo Clinic, Rochester, Minnesota, USA
    Search for more papers by this author
  • M.R. Charlton

    Corresponding author
    1. Liver Transplantation, Mayo Clinic, Rochester, Minnesota, USA
    • Division of Gastroenterology and Hepatology, Medical Spectrum Twente, Enschede, The Netherlands
    Search for more papers by this author

  • Disclosure: The authors declared no conflict of interest.

  • Funding agencies: This work has been supported by Public Health Service grants NIDDK RO1 DK41876, DK069757-05 (to M. R. C.), and GCRC RR00585.

Correspondence: M.R. Charlton (charlton.michael@mayo.edu)

Abstract

Objective: Allelic variation (rs738409C→G) in adiponutrin (patatin-like phospholipase domain-containing protein 3, PNPLA3) has been associated with hepatic steatosis and liver fibrosis. The physiologic impact of the PNPLA3 G allele may be exacerbated in patients with severe obesity. In this study, we investigated the interactions of PNPLA3 rs738409 with a broad panel of metabolic and histologic characteristics of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH) in patients with medically complicated obesity.

Design and Methods: Consecutive patients undergoing bariatric surgery were selected for a prospective study. They underwent extensive laboratory and histologic (liver biopsy) assessment, as well as evaluation of rs738409 polymorphism by TaqMan assay.

Results: Only 12 (8.3%) of the 144 patients had normal liver histology, with 72 (50%) NASH, of whom 15 (10.4% of total patients) had fibrosis stage 2-3. PNPLA3 GG genotype correlated positively (P < 0.05) with serum levels of alanine aminotransferase (ALT), asparate aminotransferase (AST), glucose, fibrinogen, and insulin-dependent diabetes mellitus, homeostasis model assessment—insulin resistance, and presence of NASH. Multivariate analysis indicated that PNPLA3 rs738409 G versus C allele remained an (independent) risk factor for NASH, in addition to CK-18 >145 IU/l, glucose >100 mg/dl, and C-reactive protein (CRP) >0.8 mg/dl. The probability of NASH increased from 9% (no risk factor) to 82% if all four risk factors were present.

Conclusions: In this cohort of patients with medically complicated obesity, PNPLA3 rs738409 G allelic expression is associated with hepatic (NASH) and nonhepatic complications of obesity, such as insulin resistance. These novel findings may be related to a greater impact of PNPLA3 variant in magnitude and scope in patients with severe obesity than in less obese populations. Further studies are needed to characterize the nature of these associations.

Ancillary