Hepatic Fat Accumulation Is Modulated by the Interaction between the rs738409 Variant in the PNPLA3 Gene and the Dietary Omega6/Omega3 PUFA Intake

A single nucleotide polymorphism (SNP), the rs738409, in the patatin like phospholipase 3 gene (PNPLA3) has been recently associated with increased hepatic steatosis and ALT levels in adults and children. Given the potential role of PNPLA3 in fatty liver development, we aimed to explore whether the influence of PNPLA3 genotype on hepatic fat in obese youth might be modulated by dietary factors such as essential omega polyunsaturated fatty acids (PUFA) intake.We studied 127 children and adolescents (56 boys, 71 girls; 58 Caucasians; 30 African Americans and 39 Hispanics; mean age 14.7±3.3; mean BMI 30.7±7.2). The dietary composition was assessed by the Nutrition Data System for Research (NDS-R version 2011). The patients underwent a MRI study to assess the liver fat content (HFF%), ALT measurement and the genotyping of the rs738409 SNP by automatic sequencing.As previously observed, HFF% and ALT levels varied according to the genotype in each ethnicity. ALT levels and HFF% were significantly influenced by the interaction between genotype and omega-6/omega-3 PUFA ratio (n-6/n-3), p = 0.003 and p = 0.002, respectively. HFF% and ALT levels were, in fact, related to the n-6/n-3 consumption only in subjects homozygote for the G allele of the rs738409 (r2 = 0.45, p =  0.001 and r2 = 0.40, p = 0.006, respectively).These findings suggest that the association of a high dietary n-6/n-3 PUFA with fatty liver and liver damage in obese youths may be driven by a predisposing genotype

Clinical features of the study population according to ethnicity and <i>PNPLA3</i> rs738409 genotype.

*<p> = log transformed and adjusted for age, gender, BMI, glucose tolerance. ** = Square root transformed and adjusted for age, gender, BMI, glucose tolerance. GT  =  glucose tolerance. NGT =  normal glucose tolerance, IGT =  impaired glucose tolerance, T2D  =  type 2 diabetes.</p

Interaction between <i>PNPLA3</i> rs738409 and n-6/n-3 PUFA in modulating ALT levels.

<p>The figure shows a different degree of regression between ALT (log10) and n-6/n-3 PUFA (log10) in the three genotypes. In the CC (Panel A) and CG (Panel B) group there was no association between ALT and n-6/n-3 PUFA (r2 = 0.0006, p = 0.91 and r2 = 0.015, p = 0.21 respectively). Only in the GG group (Panel C) there was a strong association between HFF% and n-6/n-3 PUFA (r2 =  0.40, p = 0.006).</p

Interaction between <i>PNPLA3</i> rs738409 and n-6/n-3 PUFA in modulating HFF%.

<p>The figure shows a different degree of regression between HFF% (square root) and n-6/n-3 PUFA (log10) in the three genotypes. In the CC (Panel A) and CG (Panel B) group there was no association between HFF% and n-6/n-3 PUFA (r2 = 0.0004, p = 0.86 and r2 = 0.018, p = 0.39, respectively). Only in the GG group (Panel C) there was a strong association between HFF% and n-6/n-3 PUFA (r2 =  0.45, p = 0.001).</p