Relationship between PNPLA3 rs738409 polymorphism and decreased kidney function in children with NAFLD

Emerging evidence suggests that patatin‐like phospholipase domain‐containing protein‐3 (PNPLA3) rs738409 genotype (the major genetic variant associated with susceptibility to non‐alcoholic fatty liver disease [NAFLD]) is associated with decreased kidney function in adults. Currently, it is uncertain whether this association also occurs in children/adolescents and whether any association is independent of liver disease severity. We enrolled a sample of 142 consecutive Caucasian children and adolescents with biopsy‐proven NAFLD, presenting to the Liver Unit of the “Bambino Gesù” Children's Hospital. Glomerular filtration rate (e‐GFR) was estimated using the Bedside Schwartz equation, whereas 24‐hour proteinuria was measured with a radioimmunoassay method. Genotyping for PNPLA3 rs738409 genotype was undertaken using the TaqMan SNP genotyping allelic discrimination method. Overall, forty‐five children had G/G, 56 had G/C and 41 had C/C PNPLA3 rs738409 genotype, respectively. Children with G/G genotype had significantly lower e‐GFR (107.5±20 vs. 112.8±18 vs. 125.3±23 mL/min/1.73 m2, p=0.002) and higher 24‐hour proteinuria (58.5±21 vs. 53.9±22 vs. 42.9±20 mg/day, p=0.012) compared to those with either G/C or C/C genotypes. After adjustment for age, sex, systolic blood pressure, measures of adiposity, HOMA‐estimated insulin resistance and biopsy‐confirmed non‐alcoholic steatohepatitis (NASH) and stage of liver fibrosis, the presence of rs738409 G/G genotype was independently associated with both lower e‐GFR (β coefficient: ‐23.6, 95% CI ‐36.3 to ‐10.8, p<0.001) and higher 24‐hour proteinuria (β coefficient: 15.3, 95% CI 1.12 to 30.5, p=0.046)

Clinical impact of sexual dimorphism in non‐alcoholic fatty liver disease (NAFLD) and non‐alcoholic steatohepatitis (NASH)

: NAFLD/NASH is a sex-dimorphic disease, with a general higher prevalence in men. Women are at reduced risk of NAFLD compared to men in fertile age, whereas after menopause women have a comparable prevalence of NAFLD as men. Indeed, sexual category, sex hormones and gender habits interact with numerous NAFLD factors including cytokines, stress and environmental factors and alter the risk profiles and phenotypes of NAFLD. In the present review, we summarized the last findings about the influence of sex on epidemiology, pathogenesis, progression in cirrhosis, indication for liver transplantation and alternative therapies, including lifestyle modification and pharmacological strategies. We are confident that an appropriate consideration of sex, age, hormonal status and sociocultural gender differences will lead to a better understanding of sex differences in NAFLD risk, therapeutic targets and treatment responses and will aid in achieving sex-specific personalized therapies