Association of a polymorphism in the promoter of the cellular retinoic acid-binding protein II gene (CRABP2) with increased circulating low-density lipoprotein cholesterol

Abstract

The cellular retinoic acid-binding protein II (CRABP-II), together with nuclear receptors such as the retinoid X receptor (RXR) and retinoic acid receptor (RAR), is involved in the transcriptional regulation of genes that control lipid metabolism via the retinoid signaling pathway and, as such, may be associated with disorders of lipid metabolism. Interestingly, the gene for CRABP-II is located on chromosome 1q21-23, which is a region that has been linked with disorders such as familial combined hyperlipidemia (FCHL), type 2 diabetes mellitus, and partial lipodystrophy, all of which are characterized by dyslipidemia. We investigated the hypothesis that the CRABP2 gene is involved in the regulation of lipid metabolism. Using the promoter -394T>C polymorphism of the CRABP2 gene, we performed association studies in three different cohorts: 299 healthy males, 182 HIV-infected patients and 151 patients with familial hypercholesterolemia (FH). All cholesterol measurements were performed in the absence of any lipid-lowering agents. ANOVA was performed on data adjusted for age, body mass index (BMI), gender, and use of protease inhibitors. The frequency of the C allele was 0.03 in the three groups. Among healthy males, carriers of the C allele had 9% higher total plasma cholesterol (p=0.027) and 13% higher low-density lipoprotein cholesterol (LDL-C) concentrations (p=0.020). In HIV-infected patients, multivariate analysis of four measures over a 1-year period showed that carriers of the C allele had significantly higher LDL-C of between 10% and 31% (p=0.001) compared with non-carriers of the allele. FH patients who were carriers of the C allele had 16% higher LDL-C (p=0.038). The C allele was significantly over-represented among hypercholesterolemic patients (p=0.001). Our results show that the CRABP2 gene, a member of the retinoid signaling pathway, is associated with increased plasma LDL-C concentrations.