PNPLA3 rs738409 risk genotype decouples TyG index from HOMA2-IR and intrahepatic lipid content

Abstract

AbstractBackgroundRecent reports suggested a different predictive value for TyG index compared to HOMA-IR in coronary artery calcification (CAC) and other atherosclerotic outcomes, despite that both indices are proposed as surrogate markers of insulin resistance. We hypothesized a key role for liver pathology as an explanation and therefore assessed the relationship among the two indices and the intrahepatic lipid content stratified byPNPLA3rs738409 genotypes as a known non-alcoholic fatty liver disease (NAFLD) genetic risk.MethodsThirty-nine women from a prior GDM-genetic study were recalled withPNPLA3rs738409CCandGGgenotypes for metabolic phenotyping and to assess hepatic triglyceride content (HTGC). 75 g OGTT was performed, fasting lipid, glucose, insulin levels and calculated insulin resistance indices (TyG and HOMA2-IR) were used. HTGC was measured by MR based methods. Mann–Whitney-U, χ2and for the correlation analysis Spearman rank order tests were applied.ResultsThePNPLA3rs738409 genotype had a significant effect on the direct correlation between the HOMA2-IR and TyG index: the correlation (R = 0.52, p = 0.0054) found in theCCgroup was completely abolished in those with theGG(NAFLD) risk genotype. In addition, the HOMA2-IR correlated with HTGC in the entire study population (R = 0.69, p < 0.0001) and also separately in both genotypes (CCR = 0.62, p = 0.0006,GG: R = 0.74, p = 0.0058). In contrast, the correlation between TyG index and HTGC was only significant in rs738409CCgenotype group (R = 0.42, p = 0.0284) but not inGGgroup. A similar pattern was observed in the correlation between TG and HTGC (CC: R = 0.41, p = 0.0335), when the components of the TyG index were separately assessed.ConclusionsPNPLA3rs738409 risk genotype completely decoupled the direct correlation between two surrogate markers of insulin resistance: TyG and HOMA2-IR confirming our hypothesis. The liver lipid content increased in parallel with the HOMA2-IR independent of genotype, in contrast to the TyG index where the risk genotype abolished the correlation. This phenomenon seems to be related to the nature of hepatic fat accumulation and to the different concepts establishing the two insulin resistance markers.