Age, BMI, and Type 2 Diabetes Modify the Relationship Between PNPLA3 and Advanced Fibrosis in Children and Adults With NAFLD

BACKGROUND AND AIMS:PNPLA3 G-allele is an important determinant of disease severity in NAFLD. Here, we investigated the effect of age, BMI, and type 2 diabetes mellitus (T2DM) on the relationship between PNPLA3 G-allele and advanced fibrosis in adults and children with histologically characterized NAFLD. METHODS:1,047 children and 2,057 adults were included. DNA was genotyped for rs738409 in duplicate. Primary outcome of interest was advanced fibrosis (fibrosis stage ≥ 3). Regression analyses were performed after controlling for relevant co-variates. An additive model was used to assess the effect of PNPLA3 G allele (CC vs CG vs GG). RESULTS:PNPLA3 G-allele was significantly associated with advanced fibrosis in both children (OR:1.55, 95% CI: 1.16-2.09) and adults (OR:1.55, 05% CI: 1.16-1.54). Across the cohort, older age significantly increased the risk for advanced fibrosis for PNPLA3 CC (OR: 1.019, 95% CI: 1.013-1.026), CG (OR: 1.024, 95% CI: 1.018-1.030), and GG (OR: 1.03, 95% CI: 1.023-1.037) genotypes. BMI significantly increased the relationship between PNPLA3 genotypes and advanced fibrosis in both children and adults. A BMI of 30kg/m2 was the cut-off beyond which PNPLA3 G-allele had exponential effect on the risk for advanced fibrosis in both children and adults. T2DM significantly worsened the relationship between PNPLA3 G-allele and advanced fibrosis in both children and adults (interaction P<0.01 for both). CONCLUSION:Age, BMI, and T2DM modify the risk of advanced fibrosis associated with PNPLA3 G-allele. Preventing or reversing T2DM and obesity in persons carrying PNPLA3 G-allele may lower the risk for advanced fibrosis in NAFLD.