Pediatric fatty liver disease: Role of ethnicity and genetics

Table 1 Gene variants associated with fatty liver disease identified by Genome Wide Association Studies

Ref.	Gene	Polymorphisms	Chromosome	Number of subjects studied
Romeo et al[35]	PNPLA3	rs738409	22	3383
Speliotes et al[71]	GCKR	rs1260326	2	7176
Petersen et al[60]	APOC3	rs2854116	11	258
		rs2854117
Speliotes et al[71]	NCAN	rs2228603	19	7176
Speliotes et al[71]	LYPLAL1	rs12137855	1	7176
Speliotes et al[71]	PPP1R3B	rs4240624	8	7176
Adams et al[73]	GC	rs222054	4	928
Adams et al[73]	LCP1	rs7324845	13	928
Adams et al[73]	SLC38A8	rs11864146	16	928
Adams et al[73]	LPPR4	rs12743824	1	928
Kitamoto et al[72]	SAMM50	rs2143571	22	1326
Kitamoto et al[72]	PARVB	rs6006473	22	1326
		rs5764455
		rs6006611
Chalasani et al[66]	FDFT1	rs2645424	8	236

Table 2 Proposed mechanism of action of each genetic variant associated with fatty liver disease

Gene	Proposed mechanism of action
PNPLA3	The PNPLA3 encodes for the adiponutrin, an enzyme expressed in the liver and adipose tissue showing both a lipogenic and lipolytic activity. This variant could cause both a gain of function of the enzyme (which could have a lipogenic activity in the liver) and a loss of function (that could predispose to steatosis by decreasing triglyceride hydrolysis in hepatocytes)
GCKR	The gene product is a regulatory protein that inhibits glucokinase in liver and pancreatic islet cells. The polymorphism could lead to increased hepatic glucokinase activity. This enhance the glycolytic flux and then promotes hepatic glucose metabolism and elevates the concentrations of malonyl coenzyme A, a substrate for de novo lipogenesis
APOC3	APOC3 variants could increase the plasma concentrations of apolipoprotein C3. The apolipoprotein C3 could then inhibit the lipoprotein lipase reducing the clearance of triglycerides. Consequence of reduced clearance of triglycerides is the increase of chylomicron-remnant particles that confer a predisposition to both fasting and postprandial hypertriglyceridemia. Higher circulating levels of chylomicron-remnant particles are then especially cleared by the liver through a receptor-mediated process, resulting in NAFLD and hepatic insulin resistance
NCAN	NCAN encodes for a chondroitin sulfate proteoglycan thought to be involved in the modulation of cell adhesion and migration. NCAN is a risk factor for liver inflammation and fibrosis, suggesting that this locus is responsible for progression from steatosis to steatohepatitis
LYPLAL1	LYPLAL1 encodes for a lysophospholipase and it is associated with increased hepatic steatosis probably preventing breakdown of triglycerides
PPP1R3B	This gene encodes the catalytic subunit of the serine/theonine phosphatase, protein phosphatase-1. The encoded protein is expressed in liver. It is associated with computer tomography–assessed liver attenuation but not histology-proven NAFLD
GC	GC gene is expressed predominately in the hepatocytes where it encodes for VDBP. VDBP is the main vitamin D carrier, which has been implicated in the development of obesity and diabetes. In fact, low vitamin D concentrations could increase adipocyte intracellular calcium, stimulating lipogenesis, whereas vitamin D supplementation improves insulin resistance and down-regulates inflammatory cytokines such as tumor necrosis factor-a and interleukin-6 in cell models. Vitamin D levels are influenced by GC genetic polymorphisms
LCP1	LCP-1 is an actin bundling protein expressed especially in hematopoietic cells and is involved in leukocyte activation and tumor cell proliferation. Its pathogenic role in NAFLD is unknown
SLC38A8 LPPR4	SLC38A8 protein product is a putative sodium-coupled neutral amino acid transporter whose expression is limited to the brain, whereas LPPR4 catalyzes the dephosphorylation of biologically active lipids and is expressed especially in the hypothalamus. While the functional significance of neuronally expressed genes such as SLC38A8 and LPPR4 with NAFLD is not apparent, there is convincing evidence that the nervous system and particularly the hypothalamus play an important role in lipid homeostasis in the liver
SAMM50	SAMM50 gene encodes for Sam50 a protein that may be involved in mitochondrial dysfunction. The subsequent decreased removal of reactive oxygen species could lead to progression of NAFLD
PARVB	The PARVB gene encodes parvin-b, which forms integrin-linked kinase-pinch-parvin complex. Integrins are a large family of heterodimeric cell surface receptors that act as mechanoreceptors by relaying information between cells and from the ECM to the cell interior. Since integrin receptors directly bind to ECM components to control remodeling, they are thought to play a crucial role in the evolution and progression of liver fibrosis. Overexpression of parvin-b leads to a concomitant increase in lipogenic gene expression
FDFT1	The FDFT1 gene, situated on chromosome 8, is an important modulator of cholesterol biosynthesis[67,68]. It codifies for the Squalene Synthase, an enzyme which converts two molecules of farnesyl pyrophosphate into squalene, a precursor to cholesterol. An hypothesis could be that this SNP is in linkage disequilibrium with a variant in the promoter of squalene synthase gene that through the enhancement of its expression, could lead to an increased activation of the enzyme and to the intra-hepatic accumulation of cholesterol

VDBP: Vitamin D binding protein; NAFLD: Non-alcoholic fatty liver disease; ECM: Extracellular matrix; LCP-1: Lymphocyte cytosolic protein-1; SLC38A8: Solute carrier family 38 member 8; LPPR4: Lipid phosphate phosphatase-related protein type 4 gene; GC: Group-specific component.