Abstract 1879: Genetic Variation at Chromosome 1p13.3 Affects Sortilin mRNA Expression, Cellular LDL Uptake and Serum LDL Levels Which Translates to the Risk of Coronary Artery Disease
Background: A single nucleotide polymorphism (SNP) rs599839 located at chromosome 1p13.3 has previously been associated with risk of coronary artery disease (CAD) and with serum levels of low-density-lipoprotein cholesterol (LDL-C). A functional link explaining the association of SNP rs599839 with LDL-C levels and CAD risk has not yet been elucidated.
Methods: We analyzed the association of rs599839 with LDL-C in 6,605 individuals across a wide age-spectrum and with CAD in four case-control studies comprising 4,287 cases and 7,572 controls. Genome wide expression array data was used to assess the association of SNP rs599839 with gene expression at chromosome 1p13. Finally, we overexpressed sortilin in transfected cells to study LDL-uptake in-vitro.
Results: Each copy of the G-allele of rs599839 associated with a decrease of serum LDL-C by 0.14 mmol/L (90% confidence interval (CI) 0.09 – 0.17 mmol/L, p=2.6×10 –11). Moreover, each copy of the G allele associated with a 9% decrease of CAD risk (90% CI 4 –14%) in the presently studied 4 case-control samples and with a 13% decrease (90%CI 10 –17%, p=2.18×10 –9) in a pooled meta-analysis including recent genome-wide association studies on CAD. The same allele was associated with higher mRNA expression levels of the multi-ligand receptor sortilin (log transformed mRNA AA vs. GG = 8.31 vs. 8.55; p = 0.01). Overexpression of SORT1 cDNA resulted in a significant increase in LDL-particle uptake (+23%, p = 4.8×10 – 4).
Conclusions: Genetic variation at chromosome 1p13 associates with decreased LDL-C and a lower risk of CAD. Effects appear to be mediated by increased sortilin expression and subsequently enhanced LDL-uptake into cells.