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.
Interactions of allelic variance of PNPLA3 with nongenetic factors in predicting nonalcoholic steatohepatitis and nonhepatic complications of severe obesity
Article first published online: 29 MAY 2013
Copyright © 2013 The Obesity Society
Volume 21, Issue 9, pages 1935–1941, September 2013
How to Cite
Guichelaar, M.M.J., Gawrieh, S., Olivier, M., Viker, K., Krishnan, A., Sanderson, S., Malinchoc, M., Watt, K.D., Swain, J.M., Sarr, M. and Charlton, M.R. (2013), Interactions of allelic variance of PNPLA3 with nongenetic factors in predicting nonalcoholic steatohepatitis and nonhepatic complications of severe obesity. Obesity, 21: 1935–1941. doi: 10.1002/oby.20327
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.
- Issue published online: 23 SEP 2013
- Article first published online: 29 MAY 2013
- Accepted manuscript online: 18 FEB 2013 12:13AM EST
- Manuscript Accepted: 24 NOV 2012
- Manuscript Received: 14 OCT 2011
- Public Health Service. Grant Numbers: NIDDK RO1 DK41876, DK069757-05 (to M. R. C.), GCRC RR00585
Objective: Allelic variation (rs738409CG) 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.