title: 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.
abstract: 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.
authors: Medizinische Klinik 2, Universität zu Lübeck, Ratzeburger Allee 160, Lübeck, Germany. p.linsel-nitschke@cardiogenics.eu
authors: Patrick
authors: P
authors: Linsel-Nitschke
authors: Jörg
authors: J
authors: Heeren
authors: Zouhair
authors: Z
authors: Aherrahrou
authors: Petra
authors: P
authors: Bruse
authors: Christian
authors: C
authors: Gieger
authors: Thomas
authors: T
authors: Illig
authors: Holger
authors: H
authors: Prokisch
authors: Katharina
authors: K
authors: Heim
authors: Angela
authors: A
authors: Doering
authors: Annette
authors: A
authors: Peters
authors: Thomas
authors: T
authors: Meitinger
authors: H-Erich
authors: HE
authors: Wichmann
authors: Anke
authors: A
authors: Hinney
authors: Thomas
authors: T
authors: Reinehr
authors: Christian
authors: C
authors: Roth
authors: Jan R
authors: JR
authors: Ortlepp
authors: Mouhidien
authors: M
authors: Soufi
authors: Alexander M
authors: AM
authors: Sattler
authors: Jürgen
authors: J
authors: Schaefer
authors: Klaus
authors: K
authors: Stark
authors: Christian
authors: C
authors: Hengstenberg
authors: Arne
authors: A
authors: Schaefer
authors: Stefan
authors: S
authors: Schreiber
authors: Florian
authors: F
authors: Kronenberg
authors: Nilesh J
authors: NJ
authors: Samani
authors: Heribert
authors: H
authors: Schunkert
authors: Jeanette
authors: J
authors: Erdmann
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics*; D002478:Cells, Cultured / Q000378:metabolism; D008078:Cholesterol, LDL / Q000097:blood / Q000378:metabolism*; D002878:Chromosomes, Human, Pair 1; D003324:Coronary Artery Disease / Q000453:epidemiology* / Q000235:genetics*; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006801:Humans; D012333:RNA, Messenger / Q000096:biosynthesis*; D012307:Risk Factors; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D008078:Cholesterol, LDL; D012333:RNA, Messenger; D000099183:Sortilin