Review
Copyright ©The Author(s) 2015.
World J Gastroenterol. Oct 21, 2015; 21(39): 11088-11111
Published online Oct 21, 2015. doi: 10.3748/wjg.v21.i39.11088
Table 1 Genetic variants involved in susceptibility and/or progression of nonalcoholic fatty liver disease identified by genome-wide association studies
GeneSNPAssociation with
PNPLA3, patatine-like phospholipase domain containing 3rs738409Steatosis
NASH/necroinflammation
Severity of fibrosis
HCC development
TM6SF2, transmembrane 6 superfamily member 2rs58542926Steatosis
NASH/necroinflammation
Severity of fibrosis
Reduced cardiovascular risk
NCAN, neurocanrs2228603Steatosis
PPP1R3B, protein phosphatase 1 regulatory subunit 3brs4240624Steatosis
GCKR, glucokinase regulatory proteinrs780094Steatosis
Severity of fibrosis
LYPLAL1, lysophospholipase-like 1rs12137855Steatosis
FDFT1, farnesyl diphosphate farnesyl transferase 1rs2645424NAFLD activity score
PDGFA, platelet-derived growth factor alphars343062Severity of fibrosis
COL13A1, collagen type XIII alpha1rs1227756Lobular inflammation
LTBP3, latent transforming growth factor-beta-protein 3rs6591182Lobular inflammation
EFCAB4B, EF-hand calcium binding domain 4Brs887304Lobular inflammation
Table 2 Genes influencing glucidic or lipid metabolism with a potential role in nonalcoholic fatty liver disease pathogenesis evaluated by candidate gene studies
GeneFunctions of encoded proteinSNP
ENPP1, ectonucleotide pyrophosphatase/phosphodiesterase1 or PC-1Interaction with the insulin receptor with consequent reduction of insulin receptor activityrs1044498
IRS-1, insulin receptor substrate 1Part of the machinery involved in insulin pathway as transductor of insulin receptor signalingrs1801278
ADIPOQ, adiponectinRelevant adipocytokine associated with insulin resistance, type 2 diabetes, and NAFLD pathogenesisrs2241766 rs1501299
LEPR, leptin receptorReceptor of leptin, a hormone synthesized by adipocytes that regulates food intake, insulin action, thermogenesis, and immune systemrs62589000
rs6700986
rs1137100
rs1137101
rs8179183
RETN, ResistinAdipocytokine involved in lipid metabolism, hepatic insulin resistance, inflammatory cascade reactions, and fibrogenesisrs3745367
PEMT, phosphatidylethanolamine N-methyltransferaseEnzyme involved in the de novo synthesis of phosphatidylcholine in the liver, a biochemical pathway essential for VLDL formationrs7946
FATP5, Fatty Acid Transport Protein 5Transporter involved in the hepatic uptake of fatty acidsrs56225452
ADRB2 and ADRB3, β-adrenergic receptor 2 and 3β-adrenergic receptors, with several functions including regulation of basal metabolism and induction of lipolysisrs4994
rs1042714
rs2053044
rs11168070
rs11959427
rs1042711
PPARα, peroxisome proliferative activated receptor αTranscription factor whose activation improves steatosis, inflammation, and fibrosis in pre-clinical models of NAFLDrs1800206
PPARGC1A, peroxisome proliferator-activated receptor γ coactivator 1-αPGC-1α, involved in mitochondrial functions, oxidative stress, gluconeogenesis, and lipogenesisrs8192678
rs2290602
PPARγ, peroxisome proliferative activated receptor γTranscription factor whose activation improves IR, restores adipose tissue insulin sensitivity, and decreases fatty free acids flux to the liverrs1801282
APOE, apolipoprotein EMediator of remnant lipoprotein binding to LDL receptors to favor the clearance of chylomicrons and VLDLN/A
APOC3, apolipoprotein C-IIIA constituent of plasma VLDL, chylomicrons, and HDL-C that inhibits lipoprotein lipase and triglycerides clearancers2854116
rs2854117
MTTP, microsomal triglyceride transfer proteinTransfer protein involved in apoB-lipoprotein assemblyrs1800591
rs1800804
rs1057613 rs3805335
LPIN1, lipin 1Phosphatase specifically involved in metabolic pathways between adipose tissue and liverrs13412852
Table 3 Genes potentially involved in mechanisms of liver injury in nonalcoholic fatty liver disease evaluated by candidate gene studies
GeneFunctions of encoded proteinSNP
TNF-α, tumor necrosis factor-αProinflammatory cytokine also involved in the regulation of insulin resistance, release of free fatty acids, and apoptosis in hepatocytesrs1800629
rs361525
rs1799964
rs1800630
TRAIL, TNF-related apoptosis -inducing ligandProtein functioning as a ligand that induces celluar apoptosisrs6763816 rs4491934
IL-6, interleukin-6Proinflammatory cytokine produced by adipocytes, hepatocytes, and immune cells also involved in the modulation of insulin resistancers1800795
IL-1β, interleukin-1βMember of IL-1 family cytokine, mainly produced by adipose tissuers16944
TLR4, toll-like receptor 4Receptor involved in the interaction with bacterial endotoxins capable to favor hepatic injury and a proinflammatory systemic statusrs4986790
IL28B, interleukin-28BCytokine belonging to the type III Interferon familyrs12979860
SOD2, superoxide dismutase 2Manganese-dependent mitochondrial enzyme involved in protection from cellular injury induced by superoxide radicalsrs4880
CYP2E1, cytochrome P450 2E1Part of the cytochrome P450 complexrs2031920
UCP3, uncoupling protein 3Mitochondrial anion carrier involved in the metabolism of superoxide radicals and in the modulation of lipid homeostasisrs1800849 rs11235972
UCP2, uncoupling protein 2Similar to uncoupling protein 3rs695366
MTHFR, methylenetetrahydrofolate reductaseEnzyme involved in the methylation of homocysteine to methioniners1801133
rs1801131
GCLC, Glutamate-cysteine ligase catalytic subunitLimiting enzyme in the formation of glutathione, a relevant endogen antioxidantrs17883901
HFE, hemochromatosisCrucial protein for the regulation of iron homeostasis via the modulation of the expression of hepcidinrs1800562
rs1799945
TMPRSS6, trans-membrane protease serine 6Matriptase-2, which cleaves the membrane-bound hemojuvelin, the co-receptor required for hepcidin expression in the liverrs855791
KLF6, kruppel-like factor 6One of the Kruppel-like factors, a family of transcriptional factors that regulate cellular proliferation, differentiation, and apoptosisrs3750861
TGF-β1, transforming growth factor β1In the liver, a promoter of hepatic fibrosis via the activation of hepatic stellate cellsrs1800471
ATII, angiotensin IIPart of the renin-angiotensin system, also advocated as an inducer of TGF-β1 production and accumulation of extracellular matrix in the liverrs699
AGTR1, Angiotensin II Type 1 ReceptorType 1 Receptor of Angiotensin IIrs3772622 rs3772633 rs2276736 rs3772630 rs3772627