👤 Michael I Goran

Genetic variation in six genes has been associated with elevated liver fat and nonalcoholic fatty liver disease in adults. The influence of these genes on liver fat and whether a genetic risk score (GRS) would improve upon the ability of common clinical risk factors to predict elevated liver fat content (ELF) in Hispanic children was determined. 223 obese Hispanic children were genotyped for six SNPs. MRI was used to measure liver fat. A GRS was tested for association with ELF using multivariate linear regression. Predictors were assessed via ROC curves and pair-wise analysis was used to determine significance alone and combined with clinical markers. Only variants in PNPLA3 and APOC3 genes were associated with liver fat (P < 0.001, P = 0.01, respectively). Subjects with a GRS = 4 had ∼3-fold higher liver fat content than subjects with GRS of 0 (15.1 ± 12.7 vs. 5.1 ± 3.7%, P = 0.03). While the addition of the GRS to a model containing BMI and liver enzymes increased ROC AUC from 0.83 to 0.85 [95% CI, 0.79-0.89], (P = 0.01), it does not improve detection of ELF from a clinical perspective. Only PNPLA3 and APOC3 were related to ELF and a GRS comprised of these susceptibility alleles did not add to the discriminatory power of traditional biomarkers for clinical assessment of liver fat. Show less

To summarize recent findings that have examined dietary, genetic and gene-diet interactions that contribute to fat accumulation in the liver during growth and development, with particular focus on contributions relating to dietary carbohydrate and sugar consumption. In addition, this review highlights how some of these contributions to liver fat vary across the population in terms of ethnic-specific effects. Dietary carbohydrate, and especially sugars contribute to increased liver fat accumulation due to the lipogenic potential of fructose during liver metabolism. In addition, recent genome-wide studies have identified several polymorphisms that contribute to increased liver fat accumulation, with some of these genes relating to dietary carbohydrate and sugar consumption. In particular, the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene, which is highly prevalent in Hispanics, contributes to excessive liver fat beginning at a young age, especially in the context of high sugar consumption. Dietary sugar contributes to liver fat accumulation, with this being explained by de-novo lipogenesis from fructose in the liver. Certain genetic factors, including PNPLA3, glucokinase regulatory protein and APOC3 contribute to increased liver fat accumulation, with these effects being manifested at an early age. Hispanics in particular are at elevated risk for liver fat accumulation because of the higher frequency of genetic variants such as PNPLA3 and glucokinase regulatory protein as well as an interaction between the PNPLA3 and dietary sugar. Show less