Cholesteryl ester transfer protein gene polymorphisms increase the risk of fatty liver in females independent of adiposity

Abstract

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. 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. 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. 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.