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

Chaowapong Jarasvaraparn, Eduardo Vilar-Gomez, Katherine P. Yates, Laura A. Wilson, Brent Neuschwander-Tetri, Rohit Loomba, Oscar Cummings, Miriam Vos, Stavra Xanthakos, Jeffrey Schwimmer, Jean P. Molleston, Arun Sanyal, James Tonascia, Naga Chalasani

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1024-1036.e2
JournalClinical Gastroenterology and Hepatology
Volume22
Issue number5
DOIs
StatePublished - May 2024

Keywords

  • Advanced Fibrosis
  • Genotypes
  • Modifier
  • PNPLA3

ASJC Scopus subject areas

  • Gastroenterology
  • Hepatology

Fingerprint

Dive into the research topics of 'Age, BMI, and Type 2 Diabetes Modify the Relationship Between PNPLA3 and Advanced Fibrosis in Children and Adults With NAFLD'. Together they form a unique fingerprint.

Cite this