Author information

¹Division of Pediatric Gastroenterology, Hepatology and Nutrition, Indiana University School of Medicine, Indianapolis, Indiana.

²Division of Gastroenterology, and Hepatology, Indiana University School of Medicine, Indiana University Health, Indianapolis, Indiana.

³Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland.

⁴Division of Gastroenterology, and Hepatology, Saint Louis University, St Louis, Missouri.

⁵Division of Gastroenterology, Hepatology, and Nutrition, University of California, San Diego School of Medicine, La Jolla, California.

⁶Division of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana.

⁷Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia.

⁸Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.

⁹Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California, San Diego School of Medicine, La Jolla, California; Department of Gastroenterology, Rady Children's Hospital San Diego, San Diego, California.

¹⁰Division of Gastroenterology, and Hepatology, Virginia Commonwealth University, Richmond, Virginia.

¹¹Department of Biostatistics and Epidemiology, Johns Hopkins University, Baltimore, Maryland.

¹²Division of Gastroenterology, and Hepatology, Indiana University School of Medicine, Indiana University Health, Indianapolis, Indiana. Electronic address: nchalasa@iu.edu.

Abstract

Background & aims: PNPLA3 G-allele is an important determinant of disease severity in nonalcoholic fatty liver disease (NAFLD). Here, we investigated the effect of age, body mass index (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: A total of 1047 children and 2057 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 covariates. 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 children (odds ratio [OR], 1.55; 95% confidence interval [CI], 1.16-2.09) and adults (OR, 1.55; 95% 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 children and adults. A BMI of 30 kg/m² was the cutoff beyond which PNPLA3 G-allele had exponential effect on the risk for advanced fibrosis in children and adults. T2DM significantly worsened the relationship between PNPLA3 G-allele and advanced fibrosis in children and adults (interaction P < .01 for both).

Conclusions: 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.