The Association of Genetic Variability in Patatin-Like Phospholipase Domain-Containing Protein 3 (PNPLA3) with Histological Severity of Nonalcoholic Fatty Liver Disease†
Year: 2010
Type: article
Study design: Observational Study
Abstract: UNLABELLED: Genome-wide association studies identified single-nucleotide polymorphisms (SNPs) that are associated with increased hepatic fat or elevated liver enzymes, presumably reflecting nonalcoholic fatty liver disease (NAFLD). To investigate whether these SNPs are associated with histological severity of NAFLD, 1117 (894 adults/223 children) individuals enrolled in the Nonalcoholic Steatohepatitis (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 genome-wide association studies. In adults, three SNPs on chromosome 22 showed associations with histological parameters of NASH. After adjustment for age, sex, diabetes, and alcohol consumption, the minor allele of rs738409 C/G, a nonsynonymous coding SNP in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) (adiponutrin) gene encoding an Ile148Met change, was associated with steatosis (P = 0.03), portal inflammation (P = 2.5 x 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 x 10(-6)). Two other SNPs in the same region demonstrated similar associations. Three SNPs on chromosome 10 near the CHUK (conserved helix-loop-helix ubiquitous kinase) gene 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). CONCLUSION: In this large cohort of histologically proven NAFLD, we confirm the association of the rs738409 G allele with steatosis and describe its association with histological severity. In pediatric patients, the high-risk rs738409 G 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.
Source: Hepatology
DOI: 10.1002/hep.23759
Language: English
Subfield: Hepatology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Continuation of the Nonalcoholic Steatohepatitis Clinical Research Network, The Genetics of Disease Progression and Treatment Response in Hepatitis C, Clinical and Translational Science Institute, G2225345073, Case Western Reserve University/Cleveland Clinic CTSA (UL1), General Clinical Research Center, Institute for Translational Health Science (UL1), General Clinical Research Center, General Clinical Research Center, General Clinical Research Center, Nonalcoholic Steatohepatitis: Natural History and Therapy, The Genetics of Disease Progression and Treatment Response in Hepatitis C, General Clinical Research Center, Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN), Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN), Clinical Research Network in Nonalcoholic Steatohepatitis, Collaborative Clinical Research in Nonalcoholic Steatohepatitis, Nonalcoholic Steatohepatitis: Natural History, Pathogenesis and Therapy, Continuation of the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) Clinical Center-Cleveland site, Clinical Research on Nonalcoholic Fatty Liver Disease, The Saint Louis University Component of the NASH Clinical Research Network, Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN)
OpenAlex ID: W2054608703