A Common Variant in the Patatin-Like Phospholipase 3 Gene... : Hepatology (original) (raw)

Steatohepatitis/ Metabolic Liver Disease

A Common Variant in the Patatin-Like Phospholipase 3 Gene ( PNPLA3 ) Is Associated with Fatty Liver Disease in Obese Children and Adolescents

Santoro, Nicola1; Kursawe, Romy1; D'Adamo, Ebe1,4; Dykas, Daniel J.2; Zhang, Clarence K.5; Bale, Allen E.2; Calí, Anna M.1; Narayan, Deepak3; Shaw, Melissa M.1; Pierpont, Bridget1; Savoye, Mary1; Lartaud, Derek1; Eldrich, Samuel1; Cushman, Samuel W.6; Zhao, Hongyu5; Shulman, Gerald I.7; Caprio, Sonia1,*

1_Department of Pediatrics, Yale University School of Medicine, New Haven, CT_

2_Department of Genetics, Yale University School of Medicine, New Haven, CT_

3_Department of Plastic Surgery, Yale University School of Medicine, New Haven, CT_

4_Department of Pediatrics, University of Chieti, Chieti, Italy_

5_Yale Center for Statistical Genomics and Proteomics, New Haven, CT_

6_NIDDK/NIH Diabetes Branch, New Haven, CT_

7_Departments of Internal Medicine and Cellular and Molecular Physiology, Howard Hughes Medical Institute, New Haven, CT_

*Address reprint requests to: Yale University School of Medicine, Department of Pediatrics, 330 Cedar Street, P.O. Box 208064, New Haven, CT 06520. E-mail:[email protected]; fax: 203-785-6421

Received 18 February 2010; accepted 26 June 2010

This study was supported by grants from the National Institutes of Health (NIH): (R01-HD40787, R01-HD28016, and K24-HD01464 to S.C., R01 DK-49230 to G.I.S.), and by CTSA Grant Number UL1 RR0249139 from the National Center for Research Resources (NCRR), a component of NIH; and R01-EB006494 (Bioimage Suite), and Distinguished Clinical Scientist Awards from the American Diabetes Association (to S.C.). S.W.C. is supported by the Intramural Research Program of the NIH, NIDDK.

This publication was and its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH

View this article online atwileyonlinelibrary.com.

Potential conflict of interest: Dr. Shulman is a consultant for Pfizer, Sarnoff, GlaxoSmithKline, LG Life Sciences, Rigel, Sanofi-Aventis, Roche, Well State Therapeutics, Arete, Eli Lilly, and Forest labs.

Additional Supporting Information may be found in the online version of this article.

Abstract

The genetic factors associated with susceptibility to nonalcoholic fatty liver disease (NAFLD) in pediatric obesity remain largely unknown. Recently, a nonsynonymous single-nucleotide polymorphism (rs738409), in the patatin-like phospholipase 3 gene ( PNPLA3 ) has been associated with hepatic steatosis in adults. In a multiethnic group of 85 obese youths, we genotyped the PNLPA3 single-nucleotide polymorphism, measured hepatic fat content by magnetic resonance imaging and insulin sensitivity by the insulin clamp. Because PNPLA3 might affect adipogenesis/lipogenesis, we explored the putative association with the distribution of adipose cell size and the expression of some adipogenic/lipogenic genes in a subset of subjects who underwent a subcutaneous fat biopsy. Steatosis was present in 41% of Caucasians, 23% of African Americans, and 66% of Hispanics. The frequency of PNPLA3 (rs738409) G allele was 0.324 in Caucasians, 0.183 in African Americans, and 0.483 in Hispanics. The prevalence of the G allele was higher in subjects showing hepatic steatosis. Surprisingly, subjects carrying the G allele showed comparable hepatic glucose production rates, peripheral glucose disposal rate, and glycerol turnover as the CC homozygotes. Carriers of the G allele showed smaller adipocytes than those with CC genotype ( P = 0.005). Although the expression of PNPLA3, PNPLA2, PPARγ2 (peroxisome proliferator-activated receptor gamma 2), SREBP1c (sterol regulatory element binding protein 1c), and ACACA (acetyl coenzyme A carboxylase) was not different between genotypes, carriers of the G allele showed lower leptin ( LEP )( P = 0.03) and sirtuin 1 ( SIRT1 ) expression ( P = 0.04).

Conclusion:

A common variant of the PNPLA3 gene confers susceptibility to hepatic steatosis in obese youths without increasing the level of hepatic and peripheral insulin resistance. The rs738409 PNPLA3 G allele is associated with morphological changes in adipocyte cell size. (Hepatology 2010.)