Genetic Loci associated with C-reactive protein levels and risk of coronary heart disease.
BACKGROUND
Plasma levels of C-reactive protein (CRP) are independently associated with risk of coronary heart disease, but whether CRP is causally associated with coronary heart disease or merely a marker of underlying atherosclerosis is uncertain.


OBJECTIVE
To investigate association of genetic loci with CRP levels and risk of coronary heart disease.


METHODS
We first carried out a genome-wide association (n = 17,967) and replication study (n = 13,615) to identify genetic loci associated with plasma CRP concentrations. Data collection took place between 1989 and 2008 and genotyping between 2003 and 2008. We carried out a mendelian randomization study of the most closely associated single-nucleotide polymorphism (SNP) in the CRP locus and published data on other CRP variants involving a total of 28,112 cases and 100,823 controls, to investigate the association of CRP variants with coronary heart disease. We compared our finding with that predicted from meta-analysis of observational studies of CRP levels and risk of coronary heart disease. For the other loci associated with CRP levels, we selected the most closely associated SNP for testing against coronary heart disease among 14,365 cases and 32,069 controls.


METHODS
Risk of coronary heart disease.


RESULTS
Polymorphisms in 5 genetic loci were strongly associated with CRP levels (% difference per minor allele): SNP rs6700896 in LEPR (-14.8%; 95% confidence interval [CI], -17.6% to -12.0%; P = 6.2 x 10(-22)), rs4537545 in IL6R (-11.5%; 95% CI, -14.4% to -8.5%; P = 1.3 x 10(-12)), rs7553007 in the CRP locus (-20.7%; 95% CI, -23.4% to -17.9%; P = 1.3 x 10(-38)), rs1183910 in HNF1A (-13.8%; 95% CI, -16.6% to -10.9%; P = 1.9 x 10(-18)), and rs4420638 in APOE-CI-CII (-21.8%; 95% CI, -25.3% to -18.1%; P = 8.1 x 10(-26)). Association of SNP rs7553007 in the CRP locus with coronary heart disease gave an odds ratio (OR) of 0.98 (95% CI, 0.94 to 1.01) per 20% lower CRP level. Our mendelian randomization study of variants in the CRP locus showed no association with coronary heart disease: OR, 1.00; 95% CI, 0.97 to 1.02; per 20% lower CRP level, compared with OR, 0.94; 95% CI, 0.94 to 0.95; predicted from meta-analysis of the observational studies of CRP levels and coronary heart disease (z score, -3.45; P < .001). SNPs rs6700896 in LEPR (OR, 1.06; 95% CI, 1.02 to 1.09; per minor allele), rs4537545 in IL6R (OR, 0.94; 95% CI, 0.91 to 0.97), and rs4420638 in the APOE-CI-CII cluster (OR, 1.16; 95% CI, 1.12 to 1.21) were all associated with risk of coronary heart disease.


CONCLUSIONS
The lack of concordance between the effect on coronary heart disease risk of CRP genotypes and CRP levels argues against a causal association of CRP with coronary heart disease.
Elliott
Paul
P
Faculty of Medicine, Imperial College London, London, United Kingdom. p.elliott@imperial.ac.uk
Chambers
John C
JC
Zhang
Weihua
W
Clarke
Robert
R
Hopewell
Jemma C
JC
Peden
John F
JF
Erdmann
Jeanette
J
Braund
Peter
P
Engert
James C
JC
Bennett
Derrick
D
Coin
Lachlan
L
Ashby
Deborah
D
Tzoulaki
Ioanna
I
Brown
Ian J
IJ
Mt-Isa
Shahrul
S
McCarthy
Mark I
MI
Peltonen
Leena
L
Freimer
Nelson B
NB
Farrall
Martin
M
Ruokonen
Aimo
A
Hamsten
Anders
A
Lim
Noha
N
Froguel
Philippe
P
Waterworth
Dawn M
DM
Vollenweider
Peter
P
Waeber
Gerard
G
Jarvelin
Marjo-Riitta
MR
Mooser
Vincent
V
Scott
James
J
Hall
Alistair S
AS
Schunkert
Heribert
H
Anand
Sonia S
SS
Collins
Rory
R
Samani
Nilesh J
NJ
Watkins
Hugh
H
Kooner
Jaspal S
JS
D000328:Adult; D000368:Aged; D002097:C-Reactive Protein / Q000235:genetics* / Q000378:metabolism; D003327:Coronary Disease / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D017720:Molecular Epidemiology; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
D002097:C-Reactive Protein