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
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The 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.
The 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 4 year changes in body weight on liver steatosis and glucose metabolism.
The PNPLA3 homozygous GG genotype dissociated the changes in the LFC and OGTT 2 h post-load blood glucose (PBG) in relation to 4 year 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 pinteraction = 0.044) and ALT (FDR-adjusted pinteraction = 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.
The 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.
KeywordsBody weight Diabetes Gene–environment interaction NAFLD PNPLA3 gene variant
Fasting blood glucose
False discovery rate
Proton magnetic resonance spectroscopy
Liver fat content
Non-alcoholic fatty liver disease
Post-load blood glucose
Patatin-like phospholipase domain containing 3
The authors thank S. Conte (American Journal Experts, Durham, NC, USA) for providing an editing service for this article.
MX and HL designed and performed the study and drafted the manuscript. LC, LW, HM, QL and QA performed the study, collected data and revised the manuscript. WH conducted the ultrasound examination, interpreted data and revised the manuscript. JG analysed and interpreted the data and wrote the statistical methods section of the manuscript. YH and HB interpreted the data and revised the discussion section of the manuscript. XL designed the study and revised the manuscript. XG designed the study, provided funding and revised the manuscript. All authors approved the final version. XG is the guarantor of this work and, as such, has full access to all of the data, takes responsibility for the integrity of the data, and controlled the decision to publish.
This work was supported by the National Key Research Program of China (grant no. 2012CB524906 to XG), the National Natural Science Foundation of China (grant no. 81873660 to MX), the Shanghai Municipal Science and Technology Committee (grant no. 16411954800 to XG) and the Shanghai Health and Family Planning Commission Foundation (grant no. 15GWZK0801 to XG and HL and 20164Y0029 to MX).
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
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