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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