Genetic determinants of steatosis and fibrosis progression in paediatric non‐alcoholic fatty liver disease

Abstract

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.

Insights into paediatric non‐alcoholic fatty liver disease from genetic variants

“…Over the past decade, there has been much investigation into genetic variants associated with NAFLD in adults, but there have been only a handful of studies focusing on children . In this issue, Hudert et al combine candidate single nucleotide polymorphism (SNP) testing with proteomics and computational modelling in a cohort of 70 children with biopsy‐proven NAFLD to deepen our understanding of these genetic variants. Exploring the role of genetic variants in paediatric NAFLD is particularly important due to its unique histology with periportal/zone 1‐predominant localisation of steatosis and inflammation, which is associated with more advanced fibrosis …”

“…Hudert et al selected 14 SNPs previously associated with adult NAFLD, of which three were significantly associated with disease in paediatric NAFLD compared to a control group: rs738409C>G in PNPLA3, rs1044498A>C in ENPP1 and rs780094C>T in GCKR, but not rs58542926C>T near TM6SF2 or rs641738C>T near TMC4‐MBOAT7.…”

“…Unlike adult NASH, paediatric NAFLD shows periportal predominant histology with a lack of ballooning, particularly in prepubertal children. Hudert et al found common genetic variants in several genes to correlate with periportal histological features. Other variants were associated with histology without a zonal pattern…”

“…Exploring the role of genetic variants in paediatric NAFLD is particularly important due to its unique histology with periportal/zone 1-predominant localisation of steatosis and inflammation, which is associated with more advanced fibrosis. 4 Hudert et al 3 When SNP-histology associations were examined, rs738409C>G in PNPLA3 and rs13412852C>T near lipin 1 (LPIN1) were significantly associated with the severity of steatosis. Critically, PNPLA3 was associated with periportal/zone 1-predominant steatosis ( Figure 1).…”

“…et al3 found common genetic variants in several genes to correlate with periportal histological features. Other variants were associated with histology without a zonal pattern…”