BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and adolescents today. In comparison with adult disease, paediatric NAFLD may show a periportal localization, which is associated with advanced fibrosis. This study aimed to assess the role of genetic risk variants for histological disease pattern and severity in childhood NAFLD. METHODS: We studied 14 single nucleotide polymorphisms (SNP) in a cohort of 70 adolescents with biopsy-proven NAFLD. Genotype was compared to an adult control cohort (n = 200) and analysed in relation to histological disease severity and liver tissue proteomics. RESULTS: Three of the 14 SNPs were significantly associated with paediatric NAFLD after FDR adjustment, rs738409 (PNPLA3, P = 2.80 × 10-06 ), rs1044498 (ENPP1, P = 0.0091) and rs780094 (GCKR, P = 0.0281). The severity of steatosis was critically associated with rs738409 (OR=3.25; 95% CI: 1.72-6.52, FDR-adjusted P = 0.0070). The strongest variants associated with severity of fibrosis were rs1260326, rs780094 (both GCKR) and rs659366 (UCP2). PNPLA3 was associated with a portal pattern of steatosis, inflammation and fibrosis. Proteome profiling revealed decreasing levels of GCKR protein with increasing carriage of the rs1260326/rs780094 minor alleles and downregulation of the retinol pathway in rs738409 G/G carriers. Computational metabolic modelling highlighted functional relevance of PNPLA3, GCKR and UCP2 for NAFLD development. CONCLUSIONS: This study provides evidence for the role of PNPLA3 as a determinant of portal NAFLD localization and severity of portal fibrosis in children and adolescents, the risk variant being associated with an impaired hepatic retinol metabolism.
BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and adolescents today. In comparison with adult disease, paediatric NAFLD may show a periportal localization, which is associated with advanced fibrosis. This study aimed to assess the role of genetic risk variants for histological disease pattern and severity in childhood NAFLD. METHODS: We studied 14 single nucleotide polymorphisms (SNP) in a cohort of 70 adolescents with biopsy-proven NAFLD. Genotype was compared to an adult control cohort (n = 200) and analysed in relation to histological disease severity and liver tissue proteomics. RESULTS: Three of the 14 SNPs were significantly associated with paediatric NAFLD after FDR adjustment, rs738409 (PNPLA3, P = 2.80 × 10-06 ), rs1044498 (ENPP1, P = 0.0091) and rs780094 (GCKR, P = 0.0281). The severity of steatosis was critically associated with rs738409 (OR=3.25; 95% CI: 1.72-6.52, FDR-adjusted P = 0.0070). The strongest variants associated with severity of fibrosis were rs1260326, rs780094 (both GCKR) and rs659366 (UCP2). PNPLA3 was associated with a portal pattern of steatosis, inflammation and fibrosis. Proteome profiling revealed decreasing levels of GCKR protein with increasing carriage of the rs1260326/rs780094 minor alleles and downregulation of the retinol pathway in rs738409 G/G carriers. Computational metabolic modelling highlighted functional relevance of PNPLA3, GCKR and UCP2 for NAFLD development. CONCLUSIONS: This study provides evidence for the role of PNPLA3 as a determinant of portal NAFLD localization and severity of portal fibrosis in children and adolescents, the risk variant being associated with an impaired hepatic retinol metabolism.
Authors: Simona Riccio; Rosa Melone; Caterina Vitulano; Pierfrancesco Guida; Ivan Maddaluno; Stefano Guarino; Pierluigi Marzuillo; Emanuele Miraglia Del Giudice; Anna Di Sessa Journal: World J Clin Pediatr Date: 2022-03-23
Authors: Kevin Teo; Kushala W M Abeysekera; Leon Adams; Elmar Aigner; Quentin M Anstee; Jesus M Banales; Rajarshi Banerjee; Priyadarshi Basu; Thomas Berg; Pallav Bhatnagar; Stephan Buch; Ali Canbay; Sonia Caprio; Ankita Chatterjee; Yii-Der Ida Chen; Abhijit Chowdhury; Ann K Daly; Christian Datz; Dana de Gracia Hahn; Johanna K DiStefano; Jiawen Dong; Amedine Duret; Connor Emdin; Madison Fairey; Glenn S Gerhard; Xiuqing Guo; Jochen Hampe; Matthew Hickman; Lena Heintz; Christian Hudert; Harriet Hunter; Matt Kelly; Julia Kozlitina; Marcin Krawczyk; Frank Lammert; Claudia Langenberg; Joel Lavine; Lin Li; Hong Kai Lim; Rohit Loomba; Panu K Luukkonen; Phillip E Melton; Trevor A Mori; Nicholette D Palmer; Constantinos A Parisinos; Sreekumar G Pillai; Faiza Qayyum; Matthias C Reichert; Stefano Romeo; Jerome I Rotter; Yu Ri Im; Nicola Santoro; Clemens Schafmayer; Elizabeth K Speliotes; Stefan Stender; Felix Stickel; Christopher D Still; Pavel Strnad; Kent D Taylor; Anne Tybjærg-Hansen; Giuseppina Rosaria Umano; Mrudula Utukuri; Luca Valenti; Lynne E Wagenknecht; Nicholas J Wareham; Richard M Watanabe; Julia Wattacheril; Hanieh Yaghootkar; Hannele Yki-Järvinen; Kendra A Young; Jake P Mann Journal: J Hepatol Date: 2020-08-31 Impact factor: 25.083