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

Atherosclerosis. 2010 Jan;208(1):183-9. doi: 10.1016/j.atherosclerosis.2009.06.034. Epub 2009 Jul 8.


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 6605 individuals across a wide age spectrum and with CAD in four case-control studies comprising 4287 cases and 7572 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 x 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 four case-control samples and with a 13% decrease (90% CI 10-17%, p=2.18 x 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 multiligand 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=0.01).

Conclusions: Rs599839 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Vesicular Transport / genetics*
  • Cells, Cultured / metabolism
  • Cholesterol, LDL / blood
  • Cholesterol, LDL / metabolism*
  • Chromosomes, Human, Pair 1
  • Coronary Artery Disease / epidemiology*
  • Coronary Artery Disease / genetics*
  • Gene Expression Regulation*
  • Genetic Variation*
  • Humans
  • RNA, Messenger / biosynthesis*
  • Risk Factors


  • Adaptor Proteins, Vesicular Transport
  • Cholesterol, LDL
  • RNA, Messenger
  • sortilin