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

Abstract

Background Recently the SNP identified as rs1260326, in the glucokinase regulatory protein (GCKR) was associated with hypertriglyceridemia in adults. Since accumulation of triglycerides in hepatocytes represents the hallmark of the steatosis, we aimed to investigate whether this variant might be associated with fatty liver (hepatic fat content, HFF%). Moreover, since recently rs738409 in the PNPLA3 and rs2854116 in the APOC3 were associated with fatty liver recently, we explored how the GCKR SNP and these two variants jointly influence hepatosteatosis. Methods and Results We studied 455 obese children and adolescents (181 Caucasians, 139 African Americans and 135 Hispanics). All underwent an OGTT and fasting lipoprotein subclasses measurement by proton NMR. A subset of 142 children underwent a fast gradient MRI to measure the HFF%. The rs1260326 was associated with elevated triglycerides (Caucasians p=0.00014; African Americans p=0.00417) large 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 triglycerides levels. There was a joint effect between the PNPLA3 and GCKR SNPs, explaining 32% of HFF% variance 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 triglycerides levels. GCKR and PNPLA3 act together to convey susceptibility to fatty liver in obese youths.

Proteomic and genomic studies of non-alcoholic fatty liver disease - clues in the pathogenesis

“…Given the essential contribution of lipogenesis pathway, another common gene variant, glucokinase regulatory protein (GCKR) gene has been studied extensively [108][109][110] . GCKR regulates glucokinase, a phosphorylating enzyme that responsible for hepatic glucose metabolism and activates hepatic lipogenesis [108] .…”

“…GCKR regulates glucokinase, a phosphorylating enzyme that responsible for hepatic glucose metabolism and activates hepatic lipogenesis [108] . Polymorphism of GCKR was found to be significantly associated with increased risk of T2DM, particularly in Asian population [109,110] .…”

“…Polymorphism of GCKR was found to be significantly associated with increased risk of T2DM, particularly in Asian population [109,110] . Furthermore, polymorphism of GCKR (rs780094 and rs1260326) has been shown to be associated with NAFLD in Chinese people and obese youth respectively [108,111] . In addition, Tan et al [112] further suggested that the interactions of GCKR and PNPLA3 genes can increase susceptibility to NAFLD.…”

“…Hyysalo et al [107] 2012 ApoC3 polymorphism does not associated with NAFLD in Finnish populations GCKR Santora et al [108] 2012 GCKR polymorphism is associated with NAFLD Lipogenesis pathway plays a role in NAFLD pathogenesis Tan et al [112] 2013…”

Стеатоз Підшлункової Залози В Дітей. Частина 1. Етіологія, Епідеміологія Та Патогенез

“…3) генів, відповідальних за печінковий метаболізм вільних жирних кислот (печінкової ліпази, лептину, ре-цептора лептину, адипонектину мікросомального білка-транспортера тригліцеридів (ММТР), фосфатидилетанол-амінметилтрансферази (РЕМТ)) [24]; 4) цитокінасоційованих генів (туморнекротизуючо-го фактора α, інтерлейкіну-10); 5) генів, асоційованих із розвитком й прогресуван-ням стеатозу печінки (інсулінрегульованої фосфоліпази (PNPLA3), білка-регулятора глюкокінази (GCKR), аполі-попротеїну С3 (АРОСЗ), лізофосфоліпази-1 (LYPLAL1) [24,27,28].…”