Genetic insights into the interaction between chronic hepatitis B virus infection and metabolic syndrome

The association between chronic hepatitis B virus (HBV) infection and metabolic syndrome (MetS) remains controversial. We aimed to analyze the causal effects of chronic HBV infection on MetS components and vice versa. Mendelian randomization (MR) was applied to explore the genetic association of chronic HBV infection with both metabolic risk factors and metabolic diseases using summary-level data from GWAS. Further colocalization and mediation analyses were performed for traits with significant causal relationships. The effect of HBV on lipid metabolism was validated by <i>in vitro</i> assays. In European populations, the MR analyses did not support causal relationships between chronic HBV infection and metabolic traits. In East Asian populations, chronic HBV infection was associated with decreased low-density lipoprotein (LDL) and reduced risk of coronary artery disease (CAD). Reversely, CAD showed negative causal effects on chronic HBV infection risk. Colocalization analysis revealed that the association between chronic HBV infection and CAD was most likely driven by distinct rather than shared causal variants. Mediation analysis identified LDL as a major mediator in the causal effect of chronic HBV infection on CAD and aspirin use as the primary mediator in the causal effect of CAD on chronic HBV infection. <i>In vitro</i> experiments suggested that HBV may inhibit glucose plus insulin-induced lipogenesis in hepatocytes. Our results provide genetic evidence of chronic HBV infection as a protective factor against dyslipidemia and CAD and reveal the potential causal effect of CAD on genetically proxied chronic HBV infection via aspirin treatment in East Asian populations.