rs2281135

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).

A case-control study examining genetic variants associated with liver function tests and steatosis and their relationship to histologically-defined nonalcoholic fatty liver disease (NAFLD). The rs738409 PNPLA3 variant showed the strongest association with NAFLD (OR = 3.26, 95% CI 2.11-7.21, p = 3.60E-43), and displayed significant associations with severe histologic features including fibrosis, ballooning, and inflammation within the NAFLD cohort. Other genetic variants at CPN1, ABO, GPLD1, JMJD1C, GGT1, and HNF1A loci did not show significant associations with NAFLD, suggesting PNPLA3 genetic variation specifically confers increased risk for histologic NAFLD without strong effects on metabolic traits.