In multivariable-adjusted Cox proportional hazards regression models that contained each possible combination of the 3 risk factors, we observed synergistic interactions between the PNPLA3 I148M variant, obesity, and excessive alcohol intake that were associated with the risk of incident cirrhosis, HCC, or liver disease–related death (Table 3; Figure 2A). This evidence concerns the gene PNPLA3 and obesity due to melanocortin 4 receptor deficiency.