Table 1.
Main genetic determinants of NAFLD.
| Gene | Variants/SNPs/Protein Variants | Relative Effects/Association with | |
|---|---|---|---|
| Major and most common genetic determinants of MAFLD | PNPLA3 | rs738409 (I148M) |
Disruption of triglycerides and phospholipids turnover and remodelling: increased hepatic fat accumulation; Disruption of retinol storage in HSCs leading to higher risk of inflammation, fibrosis, and HCC progression. |
| MBOAT 7 | rs641738 | Higher risk of MAFLD development, inflammation, fibrosis, and HCC progression. | |
| TM6SF2 | rs58542926 | Favouring liver fat accumulation;Protection against the development of cardiovascular diseases. | |
| Other genetic determinants involved in lipid metabolism | GCKR | rs1260326 | Increased de novo lipogenesis and worsened hepatic steatosis. |
| PPP1R3B | rs4841132 | Reduction of de novo lipogenesis and thus protection from hepatic fat accumulation. | |
| APOB | Several and different | Reduced VLDL export from hepatocytes. | |
| Other genetic determinants involved in oxidative stress imbalance | SOD2 | rs4880 | Higher oxidative stress and more advanced fibrosis. |
| UCP3 | rs1800849 | IR worsening, increased adiponectin levels, and NASH development. | |
| UCP2 | rs695366 | Higher insulin sensitivity and protection against liver damage. | |
| MARC1 | A165T | Lower hepatic fat accumulation and decreased levels of several biomarkers of liver disease. | |
| HFE | rs1800562 (C282Y) | Iron overload and related oxidative stress imbalance. | |
| Other genetic determinants involved in inflammation and fibrosis | TLR4 | D299G and T399I | Protection against fibrosis (in animal models). |
| IFNL4 | rs368234815 | Induction of severe inflammation. | |
| IFN/IL-28 | rs12979860 | Promotes inflammation and fibrosis (it is predictive for advanced stage of the disease). | |
| PCSK7 | rs236918 | Liver damage and altered fibrogenesis association. | |
| MERTK | rs4374383 | Protection against fibrosis. | |
| HSD17B13 | rs72613567 | Reduced risk of NASH (but not steatosis). |
Genetic variants identified as associated with MAFLD (Metabolic (dysfunction) associated fatty liver disease) and NASH (Non-alcoholic steatohepatitis) encodes for genes involved in several metabolism pathways. Some variants seem able to protect from MAFLD onset and progression to NASH; unfortunately, many others promote hepatic steatosis and its worsening in severe inflammation and fibrosis. PNPLA3, Patatin-like phospholipase domain-containing 3; MBOAT 7, Membrane-bound O-acyltransferase domain-containing 7; TM6SF2, Transmembrane 6 superfamily member 2; GCKR, glucokinase regulator; PPP1R3B, protein phosphatase 1 regulatory subunit 3B; APOB, APOB100; SOD2, manganese-dependent superoxide dismutase; UCP2, Uncoupling protein 2; UCP3, Uncoupling protein 3; MARC1, Mitochondrial Amidoxime Reducing Component 1; TLR4, toll-like receptor 4; IFNL4, Interferon Lambda 4; PCSK7, Proprotein convertase subtilisin/Kexin type 7; MERTK, Mer T kinase; HSCs, Hepatic stellate cells; HCC, Hepatocellular carcinoma; VLDL, Very-low-density lipoproteins.