Does high C-reactive protein concentration increase atherosclerosis? The Whitehall II Study.
BACKGROUND
C-reactive protein (CRP), a marker of systemic inflammation, is associated with risk of coronary events and sub-clinical measures of atherosclerosis. Evidence in support of this link being causal would include an association robust to adjustments for confounders (multivariable standard regression analysis) and the association of CRP gene polymorphisms with atherosclerosis (Mendelian randomization analysis).


RESULTS
We genotyped 3 tag single nucleotide polymorphisms (SNPs) [+1444T>C (rs1130864); +2303G>A (rs1205) and +4899T>G (rs 3093077)] in the CRP gene and assessed CRP and carotid intima-media thickness (CIMT), a structural marker of atherosclerosis, in 4941 men and women aged 50-74 (mean 61) years (the Whitehall II Study). The 4 major haplotypes from the SNPs were consistently associated with CRP level, but not with other risk factors that might confound the association between CRP and CIMT. CRP, assessed both at mean age 49 and at mean age 61, was associated both with CIMT in age and sex adjusted standard regression analyses and with potential confounding factors. However, the association of CRP with CIMT attenuated to the null with adjustment for confounding factors in both prospective and cross-sectional analyses. When examined using genetic variants as the instrument for serum CRP, there was no inferred association between CRP and CIMT.


CONCLUSIONS
Both multivariable standard regression analysis and Mendelian randomization analysis suggest that the association of CRP with carotid atheroma indexed by CIMT may not be causal.
Kivimäki
Mika
M
Department of Epidemiology and Public Health, University College London, London, United Kingdom. m.kivimaki@ucl.ac.uk
Lawlor
Debbie A
DA
Smith
George Davey
GD
Kumari
Meena
M
Donald
Ann
A
Britton
Annie
A
Casas
Juan P
JP
Shah
Tina
T
Brunner
Eric
E
Timpson
Nicholas J
NJ
Halcox
Julian P J
JP
Miller
Michelle A
MA
Humphries
Steve E
SE
Deanfield
John
J
Marmot
Michael G
MG
Hingorani
Aroon D
AD
D000375:Aging; D050197:Atherosclerosis / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D001794:Blood Pressure; D015992:Body Mass Index; D002097:C-Reactive Protein / Q000235:genetics* / Q000378:metabolism; D003920:Diabetes Mellitus / Q000453:epidemiology; D003925:Diabetic Angiopathies / Q000235:genetics; D005260:Female; D005838:Genotype; D006801:Humans; D008019:Life Style; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic; D015995:Prevalence; D012044:Regression Analysis
D008055:Lipids; D002097:C-Reactive Protein