Association between liver-specific gene polymorphisms and their expression levels with nonalcoholic fatty liver disease

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dc.contributor.authorAdams, L.
dc.contributor.authorWhite, S.
dc.contributor.authorMarsh, J.
dc.contributor.authorLye, S.
dc.contributor.authorConnor, K.
dc.contributor.authorMaganga, R.
dc.contributor.authorAyonrinde, O.
dc.contributor.authorOlynyk, J.
dc.contributor.authorMori, T.
dc.contributor.authorBeilin, L.
dc.contributor.authorPalmer, L.
dc.contributor.authorHamdorf, J.
dc.contributor.authorPennell, C.
dc.date.issued2013
dc.description.abstractGenetic factors account for a significant proportion of the phenotypic variance of nonalcoholic fatty liver disease (NAFLD); however, very few predisposing genes have been identified. We aimed to (1) identify novel genetic associations with NAFLD by performing a genome-wide association study (GWAS), and (2) examine the biological expression of the strongest genetic associations in a separate cohort. We performed GWAS of a population-based cohort (Raine Study) of 928 adolescents assessed for NAFLD by ultrasound at age 17. Expression of genes with single nucleotide polymorphisms (SNPs) that were associated with NAFLD at a significance level of P < 10−5 was examined in adults with NAFLD and controls by quantifying hepatic messenger RNA (mRNA) expression and serum levels of protein. After adjustment for sex and degree of adiposity, SNPs in two genes expressed in liver were associated with NAFLD adolescents: group-specific component (GC) (odds ratio [OR], 2.54; P = 1.20 × 10−6) and lymphocyte cytosolic protein-1 (LCP1) (OR, 3.29; P = 2.96 × 10−6). SNPs in two genes expressed in neurons were also associated with NAFLD: lipid phosphate phosphatase-related protein type 4 (LPPR4) (OR, 2.30; P = 4.82 × 10−6) and solute carrier family 38 member 8 (SLC38A8) (OR, 3.14; P = 1.86 × 10−6). Hepatic GC mRNA was significantly reduced (by 83%) and LCP1 mRNA was increased (by 300%) in liver biopsy samples from patients with NAFLD compared to controls (P < 0.05). Mean serum levels of GC protein were significantly lower in patients with NAFLD than controls (250 ± 90 versus 298 ± 90, respectively; P = 0.004); GC protein levels decreased with increasing severity of hepatic steatosis (P < 0.01). Conclusion: The association between GC and LCP1 SNPs and NAFLD as well as altered biological expression implicate these genes in the pathogenesis of NAFLD.
dc.description.statementofresponsibilityLeon A. Adams, Scott W. White, Julie A. Marsh, Stephen J. Lye, Kristin L. Connor, Richard Maganga, Oyekoya T. Ayonrinde, John K. Olynyk, Trevor A. Mori, Lawrence J. Beilin, Lyle J. Palmer, Jeffrey M. Hamdorf, and Craig E. Pennell
dc.identifier.citationHepatology, 2013; 57(2):590-600
dc.identifier.doi10.1002/hep.26184
dc.identifier.issn0270-9139
dc.identifier.issn1527-3350
dc.identifier.orcidPalmer, L. [0000-0002-1628-3055]
dc.identifier.urihttp://hdl.handle.net/2440/86445
dc.language.isoen
dc.publisherJohn Wiley & Sons
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/634445
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/403981
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/572613
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/353514
dc.rights© 2012 American Association for the Study of Liver Diseases
dc.source.urihttps://doi.org/10.1002/hep.26184
dc.subjectHumans
dc.subjectFatty Liver
dc.subjectMicrofilament Proteins
dc.subjectPhosphatidate Phosphatase
dc.subjectAmino Acid Transport Systems, Neutral
dc.subjectVitamin D-Binding Protein
dc.subjectPolymorphism, Single Nucleotide
dc.subjectAdolescent
dc.subjectAdult
dc.subjectGenome-Wide Association Study
dc.subjectNon-alcoholic Fatty Liver Disease
dc.titleAssociation between liver-specific gene polymorphisms and their expression levels with nonalcoholic fatty liver disease
dc.typeJournal article
pubs.publication-statusPublished

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