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). CONCLUSION: Regardless of established renal risk factors and the histological severity of NAFLD, the PNPLA3 G/G genotype was strongly associated with decreasing kidney function and increasing 24-hour proteinuria in children/adolescents with histologically confirmed NAFLD. This article is protected by copyright. All rights reserved.