The Association of Genetic Variability in PNPLA3 with Histological Severity of Non-Alcoholic Fatty Liver Disease

Background—Genome wide association (GWA) studies identified single nucleotide polymorphisms (SNPs) that are associated with increased hepatic fat or elevated liver enzymes, presumably reflecting nonalcoholic fatty liver disease (NAFLD). Aim—To investigate whether these SNPs are associated with histological severity in a large cohort of NAFLD patients. Methods—1117 (894 adults/223 children) individuals enrolled in NASH-Clinical Research Network and National Institutes of Health Clinical Center studies with histologically-confirmed NAFLD were genotyped for six SNPs that are associated with hepatic fat or liver enzymes in GWA studies. Results—In adults, 3 SNPs on chromosome 22 showed associations with histological parameters of nonalcoholic steatohepatitis (NASH). After adjustment for age, gender, diabetes and alcohol consumption, the minor allele of rs738409C/G, a nonsynonymous coding SNP in the PNPLA3 (adiponutrin) gene encoding an I148M change, was associated with steatosis (p=0.03), portal inflammation (p=2.5×10−4), lobular inflammation (p=0.005), Mallory-Denk bodies (p=0.015), NAFLD activity score (NAS, p=0.004) and fibrosis (p=7.7×10−6). Two other SNPs in the SAMM50-PNPLA3 cluster demonstrated similar associations. Three SNPs on chromosome 10 in the CPN1-ERLIN1-CHUK region were independently associated with fibrosis (p=0.010). In children, no SNP was associated with histological severity. However, the rs738409 G allele was associated with younger age at the time of biopsy in multivariate analysis (p=0.045). Conclusions—In this large cohort of histologically-proven NAFLD, we confirm the association of the rs738409G allele with steatosis and describe its association with histological severity. In pediatric patients, the high-risk rs738409G allele is associated with an earlier presentation of disease. We also describe a hitherto unknown association between SNPs at a chromosome 10 locus and the severity of NASH fibrosis. †Corresponding author: T. Jake Liang, NIH, NIDDK, Liver Diseases Branch, 10 Center Drive, Building 10, Room 9B16, Bethesda, MD, 20892-1800, [email protected]. *Both authors contributed equally to this work NIH Public Access Author Manuscript Hepatology. Author manuscript; available in PMC 2011 September 1. Published in final edited form as: Hepatology. 2010 September ; 52(3): 894–903. doi:10.1002/hep.23759. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript