Genetically elevated C-reactive protein and ischemic vascular disease.
BACKGROUND
Elevated levels of C-reactive protein (CRP) are associated with increased risks of ischemic heart disease and ischemic cerebrovascular disease. We tested whether this is a causal association.


METHODS
We studied 10,276 persons from a general population cohort, including 1786 in whom ischemic heart disease developed and 741 in whom ischemic cerebrovascular disease developed. We examined another 31,992 persons from a cross-sectional general population study, of whom 2521 had ischemic heart disease and 1483 had ischemic cerebrovascular disease. Finally, we compared 2238 patients with ischemic heart disease with 4474 control subjects and 612 patients with ischemic cerebrovascular disease with 1224 control subjects. We measured levels of high-sensitivity CRP and conducted genotyping for four CRP polymorphisms and two apolipoprotein E polymorphisms.


RESULTS
The risk of ischemic heart disease and ischemic cerebrovascular disease was increased by a factor of 1.6 and 1.3, respectively, in persons who had CRP levels above 3 mg per liter, as compared with persons who had CRP levels below 1 mg per liter. Genotype combinations of the four CRP polymorphisms were associated with an increase in CRP levels of up to 64%, resulting in a theoretically predicted increased risk of up to 32% for ischemic heart disease and up to 25% for ischemic cerebrovascular disease. However, these genotype combinations were not associated with an increased risk of ischemic vascular disease. In contrast, apolipoprotein E genotypes were associated with both elevated cholesterol levels and an increased risk of ischemic heart disease.


CONCLUSIONS
Polymorphisms in the CRP gene are associated with marked increases in CRP levels and thus with a theoretically predicted increase in the risk of ischemic vascular disease. However, these polymorphisms are not in themselves associated with an increased risk of ischemic vascular disease.
Zacho
Jeppe
J
Department of Clinical Biochemistry, Herlev Hospital, Faculty of Health Sciences, University of Copenhagen, Copenhagen.
Tybjaerg-Hansen
Anne
A
Jensen
Jan Skov
JS
Grande
Peer
P
Sillesen
Henrik
H
Nordestgaard
Børge G
BG
D050197:Atherosclerosis / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000032:analysis / Q000235:genetics*; D002561:Cerebrovascular Disorders / Q000097:blood* / Q000235:genetics; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D017202:Myocardial Ischemia / Q000097:blood* / Q000235:genetics; D011110:Polymorphism, Genetic; D012307:Risk Factors
D015415:Biomarkers; D002097:C-Reactive Protein