"Not all forms of NAFLD were created equal". Do metabolic syndrome-related NAFLD and PNPLA3-related NAFLD exert a variable impact on the risk of early carotid atherosclerosis?

On this background of evidence, the results of the study by Di Costanzo et al. [8] provide further support to the view that the aetiology of NAFLD is multifactorial and this disease may be caused by common genetic variants. One of these, the PNPLA-3 variant, is associated with higher liver fat content and increased risk of NASH, but is not systematically associated with insulin resistance and MetS traits [4,5]. This study adds a further critical piece of information by suggesting that the MetS-related NAFLD and the PNPLA3-related NAFLD may differentially affect the risk of subclinical atherosclerosis and perhaps of clinical CVD [8]. However, it does not detract from the notion that NAFLD, especially NASH with varying degrees of fibrosis, may directly contribute to the development and progression of CVD [2,3,9], because genetic NAFLD is a subtly different disease and less than 15% of European patients with NAFLD have the PNPLA3 GG genotype [4,5]. Furthermore, as previously mentioned, the few observational studies that have assessed the association between the PNPLA3 rs738409 gene polymorphism and risk of atherosclerosis have provided conflicting results (as summarized in Table 1)