Insight into the nature of the CRP-coronary event association using Mendelian randomization.
BACKGROUND
It is unclear wheather the association between C-reactive protein (CRP) and incident coronary events is free from bias and confounding. Individuals homozygous for a +1444C>T polymorphism in the CRP gene have higher circulating concentrations of CRP. Since the distribution of this polymorphism occurs at random during gamete formation, its association with coronary events should not be biased or confounded.


METHODS
We calculated the weighted mean difference in CRP between individuals with variants of the +1444C>T polymorphism in the CRP gene among 4,659 European men from six studies (genotype-intermediate phenotype studies). We used this difference together with data from previous observational studies to compute an expected odds ratio (OR) for non-fatal myocardial infarction (MI) among individuals homozygous for the T allele. We then performed four new genetic association studies (6,201 European men) to obtain a summary OR for the association between the +1444C>T polymorphism and non-fatal MI (genotype-disease studies).


RESULTS
CRP was 0.68 mg/l [95% confidence interval (95% CI) 0.31-1.10; P = 0.0001] higher among subjects homozygous for the +1444-T allele, with no confounding by a range of covariates. The expected ORs among TT subjects for non-fatal MI corresponding to this difference in CRP was 1.20 (95% CI 1.07-1.38) using the Reykjavik Heart study data and 1.25 (1.09-1.43) for all observational studies to 2004. The estimate for the observed adjusted-OR for non-fatal MI among TT subjects was 1.01 (95% CI 0.74-1.38), lower than both expected ORs.


CONCLUSIONS
A common CRP gene polymorphism is associated with important differences in CRP concentrations, free from confounding. The null association of this variant with coronary events suggests possible residual confounding (or reverse causation) in the CRP-coronary event association in observational studies, though the confidence limits are still compatible with a modest causal effect. Additional studies of genotype (or haplotype) and coronary events would help clarify whether or not the link between CRP and coronary events in observational studies is causal.
Centre for Clinical Pharmacology, Department of Medicine, BHF Laboratories at University College London, UCL, London, UK.
Juan P
JP
Casas
Tina
T
Shah
Jackie
J
Cooper
Emma
E
Hawe
Alex D
AD
McMahon
Dairena
D
Gaffney
Christopher J
CJ
Packard
Denis S
DS
O'Reilly
Irene
I
Juhan-Vague
John S
JS
Yudkin
Elena
E
Tremoli
Maurizio
M
Margaglione
Giovanni
G
Di Minno
Anders
A
Hamsten
Teake
T
Kooistra
Jeffrey W
JW
Stephens
Steven J
SJ
Hurel
Shona
S
Livingstone
Helen M
HM
Colhoun
George J
GJ
Miller
Leonelo E
LE
Bautista
Tom
T
Meade
Naveed
N
Sattar
Steve E
SE
Humphries
Aroon D
AD
Hingorani
D002097:C-Reactive Protein / Q000032:analysis / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006720:Homozygote; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D009203:Myocardial Infarction / Q000097:blood / Q000235:genetics*; D016017:Odds Ratio; D010641:Phenotype; D011110:Polymorphism, Genetic; D018570:Risk Assessment / Q000379:methods
D002097:C-Reactive Protein