Genetic background in nonalcoholic fatty liver disease: A comprehensive review

Table 1 Genetic variants involved in susceptibility and/or progression of nonalcoholic fatty liver disease identified by genome-wide association studies

Gene	SNP	Association with
PNPLA3, patatine-like phospholipase domain containing 3	rs738409	Steatosis
		NASH/necroinflammation
		Severity of fibrosis
		HCC development
TM6SF2, transmembrane 6 superfamily member 2	rs58542926	Steatosis
		NASH/necroinflammation
		Severity of fibrosis
		Reduced cardiovascular risk
NCAN, neurocan	rs2228603	Steatosis
PPP1R3B, protein phosphatase 1 regulatory subunit 3b	rs4240624	Steatosis
GCKR, glucokinase regulatory protein	rs780094	Steatosis
		Severity of fibrosis
LYPLAL1, lysophospholipase-like 1	rs12137855	Steatosis
FDFT1, farnesyl diphosphate farnesyl transferase 1	rs2645424	NAFLD activity score
PDGFA, platelet-derived growth factor alpha	rs343062	Severity of fibrosis
COL13A1, collagen type XIII alpha1	rs1227756	Lobular inflammation
LTBP3, latent transforming growth factor-beta-protein 3	rs6591182	Lobular inflammation
EFCAB4B, EF-hand calcium binding domain 4B	rs887304	Lobular inflammation

SNP: Single nucleotide polymorphism; NASH: Nonalcoholic steatohepatitis; NAFLD: Nonalcoholic fatty liver disease; HCC: Hepatocellular carcinoma.

Table 2 Genes influencing glucidic or lipid metabolism with a potential role in nonalcoholic fatty liver disease pathogenesis evaluated by candidate gene studies

Gene	Functions of encoded protein	SNP
ENPP1, ectonucleotide pyrophosphatase/phosphodiesterase1 or PC-1	Interaction with the insulin receptor with consequent reduction of insulin receptor activity	rs1044498
IRS-1, insulin receptor substrate 1	Part of the machinery involved in insulin pathway as transductor of insulin receptor signaling	rs1801278
ADIPOQ, adiponectin	Relevant adipocytokine associated with insulin resistance, type 2 diabetes, and NAFLD pathogenesis	rs2241766 rs1501299
LEPR, leptin receptor	Receptor of leptin, a hormone synthesized by adipocytes that regulates food intake, insulin action, thermogenesis, and immune system	rs62589000
		rs6700986
		rs1137100
		rs1137101
		rs8179183
RETN, Resistin	Adipocytokine involved in lipid metabolism, hepatic insulin resistance, inflammatory cascade reactions, and fibrogenesis	rs3745367
PEMT, phosphatidylethanolamine N-methyltransferase	Enzyme involved in the de novo synthesis of phosphatidylcholine in the liver, a biochemical pathway essential for VLDL formation	rs7946
FATP5, Fatty Acid Transport Protein 5	Transporter involved in the hepatic uptake of fatty acids	rs56225452
ADRB2 and ADRB3, β-adrenergic receptor 2 and 3	β-adrenergic receptors, with several functions including regulation of basal metabolism and induction of lipolysis	rs4994
		rs1042714
		rs2053044
		rs11168070
		rs11959427
		rs1042711
PPARα, peroxisome proliferative activated receptor α	Transcription factor whose activation improves steatosis, inflammation, and fibrosis in pre-clinical models of NAFLD	rs1800206
PPARGC1A, peroxisome proliferator-activated receptor γ coactivator 1-α	PGC-1α, involved in mitochondrial functions, oxidative stress, gluconeogenesis, and lipogenesis	rs8192678
		rs2290602
PPARγ, peroxisome proliferative activated receptor γ	Transcription factor whose activation improves IR, restores adipose tissue insulin sensitivity, and decreases fatty free acids flux to the liver	rs1801282
APOE, apolipoprotein E	Mediator of remnant lipoprotein binding to LDL receptors to favor the clearance of chylomicrons and VLDL	N/A
APOC3, apolipoprotein C-III	A constituent of plasma VLDL, chylomicrons, and HDL-C that inhibits lipoprotein lipase and triglycerides clearance	rs2854116
		rs2854117
MTTP, microsomal triglyceride transfer protein	Transfer protein involved in apoB-lipoprotein assembly	rs1800591
		rs1800804
		rs1057613 rs3805335
LPIN1, lipin 1	Phosphatase specifically involved in metabolic pathways between adipose tissue and liver	rs13412852

SNP: Single nucleotide polymorphism; NAFLD: Nonalcoholic fatty liver disease; HDL-C: High-density lipoprotein-cholesterols; VLDL: Very low density lipoprotein; LDL: Low density lipoprotein.

Table 3 Genes potentially involved in mechanisms of liver injury in nonalcoholic fatty liver disease evaluated by candidate gene studies

Gene	Functions of encoded protein	SNP
TNF-α, tumor necrosis factor-α	Proinflammatory cytokine also involved in the regulation of insulin resistance, release of free fatty acids, and apoptosis in hepatocytes	rs1800629
		rs361525
		rs1799964
		rs1800630
TRAIL, TNF-related apoptosis -inducing ligand	Protein functioning as a ligand that induces celluar apoptosis	rs6763816 rs4491934
IL-6, interleukin-6	Proinflammatory cytokine produced by adipocytes, hepatocytes, and immune cells also involved in the modulation of insulin resistance	rs1800795
IL-1β, interleukin-1β	Member of IL-1 family cytokine, mainly produced by adipose tissue	rs16944
TLR4, toll-like receptor 4	Receptor involved in the interaction with bacterial endotoxins capable to favor hepatic injury and a proinflammatory systemic status	rs4986790
IL28B, interleukin-28B	Cytokine belonging to the type III Interferon family	rs12979860
SOD2, superoxide dismutase 2	Manganese-dependent mitochondrial enzyme involved in protection from cellular injury induced by superoxide radicals	rs4880
CYP2E1, cytochrome P450 2E1	Part of the cytochrome P450 complex	rs2031920
UCP3, uncoupling protein 3	Mitochondrial anion carrier involved in the metabolism of superoxide radicals and in the modulation of lipid homeostasis	rs1800849 rs11235972
UCP2, uncoupling protein 2	Similar to uncoupling protein 3	rs695366
MTHFR, methylenetetrahydrofolate reductase	Enzyme involved in the methylation of homocysteine to methionine	rs1801133
		rs1801131
GCLC, Glutamate-cysteine ligase catalytic subunit	Limiting enzyme in the formation of glutathione, a relevant endogen antioxidant	rs17883901
HFE, hemochromatosis	Crucial protein for the regulation of iron homeostasis via the modulation of the expression of hepcidin	rs1800562
		rs1799945
TMPRSS6, trans-membrane protease serine 6	Matriptase-2, which cleaves the membrane-bound hemojuvelin, the co-receptor required for hepcidin expression in the liver	rs855791
KLF6, kruppel-like factor 6	One of the Kruppel-like factors, a family of transcriptional factors that regulate cellular proliferation, differentiation, and apoptosis	rs3750861
TGF-β1, transforming growth factor β1	In the liver, a promoter of hepatic fibrosis via the activation of hepatic stellate cells	rs1800471
ATII, angiotensin II	Part of the renin-angiotensin system, also advocated as an inducer of TGF-β1 production and accumulation of extracellular matrix in the liver	rs699
AGTR1, Angiotensin II Type 1 Receptor	Type 1 Receptor of Angiotensin II	rs3772622 rs3772633 rs2276736 rs3772630 rs3772627

SNP: Single nucleotide polymorphism; TGF: Transforming growth factor.