Genetic and Genomic Insights Across the SLD Spectrum

Chronic liver disease is a rapidly growing cause of morbidity and mortality worldwide, and this increase is largely driven by steatotic liver disease (SLD) comprising metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), and MASLD and increased alcohol intake (MetALD). Hepatic steatosis and fibrosis are highly heritable and genetic variation has also associated with risk of hepatocellular carcinoma and hepatic decompensation. This review summarizes the state of the art of genetics and genomics in SLD, with particular emphasis on potential clinical utility. Variants in/near genes including PNPLA3, TM6SF2, and HSD17B13 have been associated with cirrhosis and hepatocellular carcinoma (HCC) in both MASLD and ALD, while others such as those in GCKR, TRIB1, and GPAM have been consistently associated with greater risk of hepatic steatosis in MASLD with much weaker effects if any on cirrhosis and hepatocellular carcinoma. While data on MetALD genetics are limited, we believe that the genetic risk factors for liver steatosis, cirrhosis, and HCC will be similar in MetALD compared to MASLD and ALD based on the largely shared genetic risk factors for MASLD and ALD. Finally, we discuss future directions in SLD genetics, notably genetically-defined disease subtypes, gene-environment interactions and its implications for therapy, and utility of genetics in clinical risk stratification. Genetic studies have provided insight into important disease processes in SLD and may have an upcoming role in clinical care.