title: Cholesteryl ester transfer protein gene polymorphisms increase the risk of fatty liver in females independent of adiposity.
abstract: OBJECTIVE
  Environmental factors including excessive caloric intake lead to disordered lipid metabolism and fatty liver disease (FLD). However, FLD demonstrates heritability suggesting genetic factors are also important. We aimed to use a candidate gene approach to examine the association between FLD and single nucleotide polymorphisms (SNPs) in lipid metabolism genes in the adolescent population-based Western Australian Pregnancy (Raine) Cohort.
  
  
  METHODS
  A total 951 seventeen year-olds underwent hepatic ultrasound, anthropometric and biochemical characterization, DNA extraction and genotyping for 57 SNPs in seven lipid metabolism genes (ApoB100, ATGL, ABHD5, MTTP, CETP, SREBP-1c, PPARα). Associations were adjusted for metabolic factors and Bonferroni corrected.
  
  
  RESULTS
  The prevalence of FLD was 16.2% (11.4% male vs 21.2% female, P=0.001). Multivariate analysis of metabolic factors found suprailiac skinfold thickness (SST) to be the major predictor of FLD in females and males (odds ratio [OR] 1.11, 95% confidence interval [CI] 1.08-1.15, P=1.7×10(-10) and OR 1.17, 95%CI 1.13-1.22, P=2.4×10(-11) , respectively). In females, two SNPs in linkage disequilibrium from the CETP gene were associated with FLD: rs12447924 (OR 2.16, 95%CI 1.42-3.32, P=0.0003) and rs12597002 (OR=2.22, 95%CI 1.46-3.41 P=0.0002). In lean homozygotes, the probability of FLD was over 30%, compared with 10-15% in lean heterozygotes and 3-5% in lean wild-types. However, these associations were modified by SST, such that for obese individuals, the probability of FLD was over 30% in all genotype groups.
  
  
  CONCLUSIONS
  Cholesteryl ester transfer protein gene polymorphisms are associated with an increased risk of FLD in adolescent females. The effect is independent of adiposity in homozygotes, thereby placing lean individuals at a significant risk of FLD.
authors.affiliation: School of Medicine and Pharmacology, The University of Western Australia (UWA), Australia. leon.adams@uwa.edu.au
authors.forename: Leon A
authors.initials: LA
authors.lastname: Adams
authors.forename: Julie A
authors.initials: JA
authors.lastname: Marsh
authors.forename: Oyekoya T
authors.initials: OT
authors.lastname: Ayonrinde
authors.forename: John K
authors.initials: JK
authors.lastname: Olynyk
authors.forename: Wei Q
authors.initials: WQ
authors.lastname: Ang
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Beilin
authors.forename: Trevor
authors.initials: T
authors.lastname: Mori
authors.forename: Lyle J
authors.initials: LJ
authors.lastname: Palmer
authors.forename: Wendy W
authors.initials: WW
authors.lastname: Oddy
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Lye
authors.forename: Craig E
authors.initials: CE
authors.lastname: Pennell
mesh_terms: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000235:genetics; D050154:Adiposity; D000293:Adolescent; D000886:Anthropometry; D053299:Apolipoprotein B-100 / Q000235:genetics; D001315:Australia; D001794:Blood Pressure; D002352:Carrier Proteins / Q000235:genetics; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics*; D016001:Confidence Intervals; D005234:Fatty Liver / Q000097:blood / Q000000981:diagnostic imaging / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007333:Insulin Resistance; D008049:Lipase / Q000235:genetics; D008099:Liver / Q000000981:diagnostic imaging; D008297:Male; D015999:Multivariate Analysis; D016017:Odds Ratio; D047493:PPAR alpha / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D012737:Sex Factors; D012885:Skinfold Thickness; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics; D014463:Ultrasonography; D000217:Acyltransferases
chemical_list: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; D053299:Apolipoprotein B-100; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008049:Lipase; D047493:PPAR alpha; D051780:Sterol Regulatory Element Binding Protein 1; C106092:microsomal triglyceride transfer protein; C439972:ABHD5 protein, human; C494794:PNPLA2 protein, human; D000217:Acyltransferases