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 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.
Linsel-Nitschke
Patrick
P
Medizinische Klinik 2, Universität zu Lübeck, Ratzeburger Allee 160, Lübeck, Germany. p.linsel-nitschke@cardiogenics.eu
Heeren
Jörg
J
Aherrahrou
Zouhair
Z
Bruse
Petra
P
Gieger
Christian
C
Illig
Thomas
T
Prokisch
Holger
H
Heim
Katharina
K
Doering
Angela
A
Peters
Annette
A
Meitinger
Thomas
T
Wichmann
H-Erich
HE
Hinney
Anke
A
Reinehr
Thomas
T
Roth
Christian
C
Ortlepp
Jan R
JR
Soufi
Mouhidien
M
Sattler
Alexander M
AM
Schaefer
Jürgen
J
Stark
Klaus
K
Hengstenberg
Christian
C
Schaefer
Arne
A
Schreiber
Stefan
S
Kronenberg
Florian
F
Samani
Nilesh J
NJ
Schunkert
Heribert
H
Erdmann
Jeanette
J
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
D033942:Adaptor Proteins, Vesicular Transport; D008078:Cholesterol, LDL; D012333:RNA, Messenger; D000099183:Sortilin