rs2143571

A comprehensive review of the pathogenesis of non-alcoholic fatty liver disease (NAFLD) in children and adolescents, examining the evolution from the 'two-hit theory' to the 'multiple-hit model'. The paper discusses genetic factors including PNPLA3 rs738409 and GCKR rs1260326 polymorphisms, which together account for up to one-third of variability in liver fat content in obese children, along with contributions from MBOAT7, SAMM50, PARVB, TM6SF2, and other genes involved in lipid metabolism.

Genome-wide association study in Japanese population identified nine SNPs in PNPLA3 (rs738409, rs2896019, rs3810622), SAMM50 (rs738491, rs3761472, rs2143571, rs6006473), and PARVB (rs5764455, rs6006611) genes strongly associated with nonalcoholic fatty liver disease (NAFLD) development and progression. rs738409 showed the strongest association (P = 6.8×10⁻¹⁴, OR = 2.05); other SNPs had P < 2.0×10⁻¹⁰ and ORs of 1.84–2.02. These variants were associated with decreased serum triglycerides, increased liver enzymes (AST/ALT), and histological features including steatosis grade and fibrosis.

In a cohort of 894 adults with histologically-confirmed NAFLD, the rs738409 minor allele in PNPLA3 (I148M) was associated with increased steatosis (p=0.03, OR 1.46), portal inflammation (p=2.5×10⁻⁴, OR 1.57), lobular inflammation (p=0.005, OR 1.84), Mallory-Denk bodies (p=0.015, OR 1.55), and fibrosis (p=7.7×10⁻⁶, OR 1.50 per G allele). Three SNPs on chromosome 10 (rs11591741, rs11597086, rs11597390) in the CPN1-ERLIN1-CHUK region were independently associated with fibrosis severity (p=0.010). In pediatric patients, rs738409 G allele was associated with younger age at biopsy (p=0.045).