Genetic predeterminants and recent advancements in steatotic liver disease: A roadmap toward precision hepatology

Table 1 Genetic variants and their impact on steatotic liver disease

Major genes	Variant	Functional impact of mutation	Outcome	Therapeutic target
PNPLA3	rs738409 (I148M)	Impairs triglyceride hydrolysis resulting in elevated hepatic triglyceride content	Hepatic steatosis	rs738409 (I148M)
			12 X risk of HCC
			18 X risk of liver-related mortality
TM6SF2	rs58542926	Impaired secretion of VLDL	Hepatic steatosis	E167K
			Progression of MASLD and MASH
GCKR	rs1260326 and rs780094	Disturbs glucokinase pathway	Elevated serum triglycerides	rs1260326
			Hepatic fibrosis
			Hepatic steatosis
GCKR	rs641738	Disrupts the phospholipid pathway by reducing levels of arachidonic acid-containing phosphatidylcholines	Increase in free polyunsaturated fatty acids	rs641738
			Increased hepatic fat content
			More severe liver damage
			Higher risk of fibrosis

HCC: Hepatocellular carcinoma; VLDL: Very low-density lipoprotein; MASLD: Metabolic dysfunction-associated steatotic liver disease; MASH: Metabolic dysfunction-associated steatohepatitis.

Table 2 Ethnic predominance of major genes involved in metabolic dysfunction-associated steatotic liver disease

Gene	Ethnic predominance
PNLPA3	Hispanics, Asians
TM6SF2	Caucasians and African Americans
GCKR	European Americans and Middle East
HSD17B13	Europeans

Table 3 Stages of metabolic associated fatty liver disease

Stage	Brief description
Stage 0	Normal connective tissue of the liver with no scarring or fibrosis
Stage 1	Mild fibrosis
Stage 2	Moderate fibrosis
Stage 3	Advanced fibrosis
Stage 4	Cirrhosis