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Nonalcoholic fatty liver disease risk and histologic severity are associated with genetic polymorphisms in children
Nidhi P Goyal1,2, Sara B Rosenthal3, Chanod Nasamran3
1Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics , University of California, San Diego School of Medicine , San Diego , California , USA.
Insights
Pediatric nonalcoholic fatty liver disease (NAFLD) risk and severity are linked to specific genetic variations. The PNPLA3 gene variant strongly predicts NAFLD risk and liver fat accumulation in children.
Area of Science:
- Genetics
- Pediatric Gastroenterology
- Hepatology
Background:
- Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver condition in children.
- Limited pediatric research exists on genetic factors influencing NAFLD risk and disease progression.
- Understanding genetic associations is crucial for targeted interventions and treatment strategies in pediatric NAFLD.
Purpose of the Study:
- To identify single nucleotide polymorphisms (SNPs) associated with the risk of developing NAFLD in children using family-based trio analysis.
- To investigate the association between candidate gene variants and the histological severity of NAFLD in pediatric patients.
- To explore the genetic underpinnings of NAFLD development and progression in a pediatric cohort.
Main Methods:
- Enrolled 822 children with biopsy-confirmed NAFLD from the NASH Clinical Research Network.
- Conducted genotyping for 60 candidate SNPs using allele-specific primers and performed transmission disequilibrium tests in family trios.
- Utilized regression analysis to assess associations between genetic variants and histological features like steatosis, inflammation, and fibrosis, including NASH activity score.
Main Results:
- The PNPLA3 (rs738409) SNP showed the strongest association with NAFLD risk (p=2.24 × 10^-14).
- Specific genotypes of PNPLA3 rs738409 were linked to increased steatosis and lobular/portal inflammation.
- Several SNPs, including TM6SF2, GCKR, MTTP, PARVB rs6006473, NR1I2, ADIPOR2, and OXTR, were associated with varying degrees of steatosis, inflammation, and fibrosis severity.
Conclusions:
- Identified specific SNPs associated with NAFLD risk and histological severity in children.
- The rs6006473 variant of PARVB was strongly linked to advanced fibrosis.
- These findings provide a basis for future research into the mechanisms driving NAFLD complications and for developing novel therapeutic targets in pediatric populations.
Background And Aims:
NAFLD is the most common chronic liver disease in children. Large pediatric studies identifying single nucleotide polymorphisms (SNPs) associated with risk and histologic severity of NAFLD are limited. Study aims included investigating SNPs associated with risk for NAFLD using family trios and association of candidate alleles with histologic severity.
Approach And Results:
Children with biopsy-confirmed NAFLD were enrolled from the NASH Clinical Research Network. The Expert Pathology Committee reviewed liver histology. Genotyping was conducted with allele-specific primers for 60 candidate SNPs. Parents were enrolled for trio analysis. To assess risk for NAFLD, the transmission disequilibrium test was conducted in trios. Among cases, regression analysis assessed associations with histologic severity. A total of 822 children with NAFLD had mean age 13.2 years (SD 2.7) and mean ALT 101 U/L (SD 90). PNPLA3 (rs738409) demonstrated the strongest risk ( p = 2.24 × 10 -14 ) for NAFLD. Among children with NAFLD, stratifying by PNPLA3 s738409 genotype, the variant genotype associated with steatosis ( p = 0.005), lobular ( p = 0.03) and portal inflammation ( p = 0.002). Steatosis grade associated with TM6SF2 ( p = 0.0009), GCKR ( p = 0.0032), PNPLA3 rs738409 ( p = 0.0053), and MTTP ( p = 0.0051). Fibrosis stage associated with PARVB rs6006473 ( p = 0.0001), NR1I2 ( p = 0.0021), ADIPOR2 ( p = 0.0038), and OXTR ( p = 0.0065). PNPLA3 rs738409 ( p = 0.0002) associated with borderline zone 1 NASH.
Conclusions:
This study demonstrated disease-associated SNPs in children with NAFLD. In particular, rs6006473 was highly associated with severity of fibrosis. These hypothesis-generating results support future mechanistic studies of development of adverse outcomes such as fibrosis and generation of therapeutic targets for NAFLD in children.
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