The PNPLA3 rs738409 C>G variant interacts with changes in body weight over time to aggravate liver steatosis, but reduces the risk of incident type 2 diabetes

Aims/hypothesisThe rs738409 C>G variant of the patatin-like phospholipase domain containing 3 gene (PNPLA3) increases the risk of non-alcoholic fatty liver disease (NAFLD) with no predisposition for insulin resistance. In this study, we aimed to investigate the influence of PNPLA3 polymorphisms on liver fat content (LFC) and glucose metabolic variables, and the associations between these, during the natural course of body weight changes in a Chinese adult cohort.MethodsThe LFC, measured using a quantitative ultrasound method, was prospectively monitored in 2189 middle-aged and elderly adults from the Shanghai Changfeng Study, together with changes in body weight and metabolic variables. General linear models were used to detect interactive effects between the PNPLA3 rs738409 genotype and 4year changes in body weight on liver steatosis and glucose metabolism.ResultsThe PNPLA3 homozygous GG genotype dissociated the changes in the LFC and OGTT 2h post-load blood glucose (PBG) in relation to 4year changes in body weight. PNPLA3 GG genotype carriers showed greater increases in the LFC and serum alanine aminotransferase (ALT) but lower PBG elevation and incident diabetes than PNPLA3 wild-type (CC) genotype carriers exhibiting the same degree of body weight increase. The interactions between the PNPLA3 genotype and changes in body weight on the LFC (false discovery rate [FDR]-adjusted p(interaction)=0.044) and ALT (FDR-adjusted p(interaction)=0.044) were significant. Subgroup analyses showed that the effect of the PNPLA3 GG genotype on changes in the LFC and PBG was only observed in metabolically unhealthy participants with insulin resistance or abdominal obesity.Conclusions/interpretationThe PNPLA3 GG genotype interacted with changes in body weight to aggravate liver steatosis but reduced the risk of incident type 2 diabetes in metabolically unhealthy participants.