Lifelong reduction of LDL-cholesterol related to a common variant in the LDL-receptor gene decreases the risk of coronary artery disease--a Mendelian Randomisation study.
BACKGROUND
Rare mutations of the low-density lipoprotein receptor gene (LDLR) cause familial hypercholesterolemia, which increases the risk for coronary artery disease (CAD). Less is known about the implications of common genetic variation in the LDLR gene regarding the variability of cholesterol levels and risk of CAD.


METHODS
Imputed genotype data at the LDLR locus on 1 644 individuals of a population-based sample were explored for association with LDL-C level. Replication of association with LDL-C level was sought for the most significant single nucleotide polymorphism (SNP) within the LDLR gene in three European samples comprising 6 642 adults and 533 children. Association of this SNP with CAD was examined in six case-control studies involving more than 15 000 individuals.


RESULTS
Each copy of the minor T allele of SNP rs2228671 within LDLR (frequency 11%) was related to a decrease of LDL-C levels by 0.19 mmol/L (95% confidence interval (CI) [0.13-0.24] mmol/L, p = 1.5x10(-10)). This association with LDL-C was uniformly found in children, men, and women of all samples studied. In parallel, the T allele of rs2228671 was associated with a significantly lower risk of CAD (Odds Ratio per copy of the T allele: 0.82, 95% CI [0.76-0.89], p = 2.1x10(-7)). Adjustment for LDL-C levels by logistic regression or Mendelian Randomisation models abolished the significant association between rs2228671 with CAD completely, indicating a functional link between the genetic variant at the LDLR gene locus, change in LDL-C and risk of CAD.


CONCLUSIONS
A common variant at the LDLR gene locus affects LDL-C levels and, thereby, the risk for CAD.
Linsel-Nitschke
Patrick
P
Medizinische Klinik II, Universität zu Lübeck, Lübeck, Germany.
Götz
Anika
A
Erdmann
Jeanette
J
Braenne
Ingrid
I
Braund
Peter
P
Hengstenberg
Christian
C
Stark
Klaus
K
Fischer
Marcus
M
Schreiber
Stefan
S
El Mokhtari
Nour Eddine
NE
Schaefer
Arne
A
Schrezenmeir
Jürgen
J
Schrezenmeier
Jürgen
J
Rubin
Diana
D
Hinney
Anke
A
Reinehr
Thomas
T
Roth
Christian
C
Ortlepp
Jan
J
Hanrath
Peter
P
Hall
Alistair S
AS
Mangino
Massimo
M
Lieb
Wolfgang
W
Lamina
Claudia
C
Heid
Iris M
IM
Doering
Angela
A
Gieger
Christian
C
Peters
Annette
A
Meitinger
Thomas
T
Wichmann
H-Erich
HE
König
Inke R
IR
Ziegler
Andreas
A
Kronenberg
Florian
F
Samani
Nilesh J
NJ
Schunkert
Heribert
H
D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D016022:Case-Control Studies; D008078:Cholesterol, LDL / Q000097:blood* / Q000187:drug effects / Q000235:genetics; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10; D003327:Coronary Disease / Q000235:genetics* / Q000517:prevention & control*; D014644:Genetic Variation; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011897:Random Allocation; D011973:Receptors, LDL / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors
D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D011973:Receptors, LDL