Variant in the glucokinase regulatory protein (GCKR) gene... : Hepatology (original) (raw)

Steatohepatitis/Metabolic Liver Disease

Variant in the glucokinase regulatory protein ( GCKR ) gene is associated with fatty liver in obese children and adolescents

Santoro, Nicola1,†; Zhang, Clarence K.2; Zhao, Hongyu2; Pakstis, Andrew J.3; Kim, Grace1; Kursawe, Romy1; Dykas, Daniel J.3; Bale, Allen E.3; Giannini, Cosimo1; Pierpont, Bridget1; Shaw, Melissa M.1; Groop, Leif4; Caprio, Sonia1,†

1 Department of Pediatrics, Yale University School of Medicine, New Haven, CT

2 Yale Center for Statistical Genomics and Proteomics, New Haven, CT

3 Department of Genetics, Yale University School of Medicine, New Haven, CT

4 Department of Clinical Sciences/Diabetes & Endocrinology and Lund University Diabetes Centre, Lund University, University Hospital, Malmoe, Malmoe, Sweden

†Address reprint requests to: Yale University School of Medicine, Department of Pediatrics, 330 Cedar Street, P.O. Box 208064, New Haven, CT 06520; Department of Pediatrics, Yale University School of Medicine, New Haven, CT

Email:[email protected]

Received 20 September 2011; Accepted 7 November 2011

Grant sponsor: the American Hearth Association (AHA); Grant Number: 11CRP5620013; Grant sponsor: the National Institutes of Health (NIH); Grant Numbers: R01-HD-40787 R01-HD-28016 K24-HD-01464.

Potential conflict of interest: Nothing to report.

†fax: 203-785-6421

Abstract

Recently, the single nucleotide polymorphism (SNP) identified as rs1260326, in the glucokinase regulatory protein ( GCKR ), was associated with hypertriglyceridemia in adults. Because accumulation of triglycerides in hepatocytes represents the hallmark of steatosis, we aimed to investigate whether this variant might be associated with fatty liver (hepatic fat content, HFF%). Moreover, because recently rs738409 in the PNPLA3 and rs2854116 in the APOC3 were associated with fatty liver, we explored how the GCKR SNP and these two variants jointly influence hepatosteatosis. We studied 455 obese children and adolescents (181 Caucasians, 139 African Americans, and 135 Hispanics). All underwent an oral glucose tolerance test and fasting lipoprotein subclasses measurement by proton nuclear magnetic resonance. A subset of 142 children underwent a fast gradient magnetic resonance imaging to measure the HFF%. The rs1260326 was associated with elevated triglycerides (Caucasians P = 0.00014; African Americans P = 0.00417), large very low-density lipoprotein (VLDL) (Caucasians P = 0.001; African Americans, P = 0.03), and with fatty liver (Caucasians P = 0.034; African Americans P = 0.00002; and Hispanics P = 0.016). The PNPLA3 , but not the APOC3 rs2854116 SNP, was associated with fatty liver but not with triglyceride levels. There was a joint effect between the PNPLA3 and GCKR SNPs, explaining 32% of HFF% variance in Caucasians ( P = 0.00161), 39.0% in African Americans ( P = 0.00000496), and 15% in Hispanics ( P = 0.00342).

Conclusion:

The rs1260326 in GCKR is associated with hepatic fat accumulation along with large VLDL and triglyceride levels. GCKR and PNPLA3 act together to convey susceptibility to fatty liver in obese youths.

Abbreviations: APOC3, apolipoprotein C3; DNL, de novo lipogenesis; GCKR, glucokinase regulatory protein; GWAS, genome-wide association studies; HFF, hepatic fat content; NAFLD, nonalcoholic fatty liver disease; SNP, single nucleotide polymorphism; TG, triglyceride; VLDL, very low-density lipoprotein.