title: Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents.
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).
  
  
  CONCLUSIONS
  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.
authors: Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520, USA. nicola.santoro@yale.edu
authors: Nicola
authors: N
authors: Santoro
authors: Clarence K
authors: CK
authors: Zhang
authors: Hongyu
authors: H
authors: Zhao
authors: Andrew J
authors: AJ
authors: Pakstis
authors: Grace
authors: G
authors: Kim
authors: Romy
authors: R
authors: Kursawe
authors: Daniel J
authors: DJ
authors: Dykas
authors: Allen E
authors: AE
authors: Bale
authors: Cosimo
authors: C
authors: Giannini
authors: Bridget
authors: B
authors: Pierpont
authors: Melissa M
authors: MM
authors: Shaw
authors: Leif
authors: L
authors: Groop
authors: Sonia
authors: S
authors: Caprio
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D001741:Black or African American; D053305:Apolipoprotein C-III / Q000235:genetics; D002648:Child; D005234:Fatty Liver / Q000453:epidemiology* / Q000208:ethnology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000453:epidemiology* / Q000208:ethnology / Q000235:genetics*; D006239:Haplotypes; D006630:Hispanic or Latino; D006801:Humans; D008049:Lipase / Q000235:genetics; D008079:Lipoproteins, VLDL / Q000097:blood; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009765:Obesity / Q000097:blood / Q000150:complications*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D014280:Triglycerides / Q000097:blood; D044465:White People; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D053305:Apolipoprotein C-III; D008049:Lipase; D008079:Lipoproteins, VLDL; D008565:Membrane Proteins; D014280:Triglycerides; C485100:GCKR protein, human; C533682:PNPLA3 protein, human; D000217:Acyltransferases; D054512:Phospholipases A2, Calcium-Independent