Commentary: dissecting the PNPLA3 association with liver fat and stiffness, and interaction with diet

We read the article by Shen et al. with great interest, and highlighted some of the key features of this study.1 The authors conducted a prospective cohort study and reported that the rs738409 GG variant in patatin-like phospholipase domain-containing protein 3 (PNPLA3) genotype was associated with an increased risk of non-alcoholic fatty liver disease (NAFLD) by magnetic resonance spectroscopy (MRS) of the liver, and the presence of gene effect on trait was not explained by the diet history recorded by the food frequency questionnaire. In multivariable-adjusted analyses, metabolic syndrome was a much stronger correlate of presence of hepatic steatosis than PNPLA3 genotype. Incremental net reclassification rate (although not shown) by including PNPLA3 genotype in addition to clinical risk factors of NAFLD appeared modest, and not clinically significant, when these results are seen in context of the broader themes in the field at this time. This study provides validation that PNPLA3 genotype is associated with increased risk of NAFLD in an urban Asian population, predominantly of Chinese origin, residing in Hong Kong. The investigators also found that liver stiffness measured by transient elastography did not reveal any association with PNPLA3 genotype. These data suggest that liver stiffness in NAFLD is not affected by PNPLA3 genotype, and possibly other genetic variants may be associated with hepatic fibrosis and/or liver stiffness. Previous studies have shown that the association of the GG variant and hepatic lipid content is associated with the presence of other risk factors, such as severe obesity,2 visceral adiposity,3 increased intake of sugars4 and omega-6 poly-unsaturated fatty acids.5 However, the results presented by Shen and colleagues do not find an association. Most of the prior association studies were conducted in Caucasian populations in contrast to the study by Shen et al., which is derived from a biogeo-graphically distinct population compared with previous studies. However, the association between NAFLD and various metabolic traits was consistent across all previous studies, as well as this study, suggesting some generalis-ability between cohorts.6–10 Overall, the study provides four key messages. First, it confirms the association between PNPLA3 genotype and liver fat content by MRS in a Chinese population residing in Hong Kong. Second, PNPLA3 genotype effect on trait was not found to be influenced by diet in this study. Third, presence of metabolic syndrome trumps PNPLA3 genotype in it's association with the trait (i.e., NAFLD). Fourth, PNPLA3 genotype did not influence liver stiffness. These findings underscore the need to better understand the molecular mechanisms by which the GG variant is linked to fat accumulation in the liver, and further research is warranted to unravel the physiological role of the PNPLA3 in times of starvation and caloric excess. Improved understanding of the role of PNPLA3 could open new areas of investigations and may provide novel avenues for drug development and intervention studies to reverse NAFLD.