Genetic risk of steatotic liver disease: Pathogenesis, prognosis, and implications for treatment.

Steatotic liver disease (SLD) is a leading cause of liver-related morbidity and mortality worldwide. Obesity, insulin resistance, and chronic alcohol intake are its major risk factors, but genetic differences strongly influence disease susceptibility. Human genetic studies have identified key genetic modifiers of SLD risk, thereby deepening our understanding of disease pathogenesis. All major SLD-associated variants localize to genes involved in hepatic lipid metabolism, underscoring the fundamental role of lipid imbalance in SLD development. Nearly all risk and protective variants are associated with the full spectrum of SLD-from steatosis and steatohepatitis to cirrhosis and hepatocellular carcinoma-with effects on progression proportional to their impact on hepatic triglyceride (TG) levels. These findings have challenged the earlier notion that hepatic steatosis is benign. Furthermore, most variants exert similar effects on metabolic dysfunction-associated SLD (MASLD) and alcohol-associated liver disease (ALD), pointing to shared pathogenic mechanisms of these 2 SLD etiologies. The effects of genetic variants are strongly influenced by nongenetic factors, such as obesity, insulin resistance, and alcohol intake. The advent of GLP-1 receptor agonists for treating obesity and insulin resistance has transformed the therapeutic landscape for SLD. These agents are predicted to become the first-line therapy for SLD, even among individuals at the highest genetic risk. In addition, genetic studies have paved the way for the development of several targeted therapies. Here, we review the major insights into SLD pathogenesis gleaned from over 20 years of human genetic studies, and their implications for the treatment and prevention of SLD.