Single nucleotide polymorphisms in monocyte chemoattractant protein-1 and its receptor act synergistically to increase the risk of carotid atherosclerosis.
BACKGROUND
Monocyte chemoattractant protein 1 (MCP-1), acting in concert with its receptor chemokine receptor 2 (CCR2), promotes recruitment of macrophages into atherosclerotic plaque. We examined whether single nucleotide polymorphism (SNP) variants in the MCP-1 or CCR2 genes independently or in combination are associated with carotid artery atherosclerosis in an African American population at increased risk of vascular disease.


METHODS
Four SNPs in MCP-1 and 1 in CCR2 were genotyped. Carotid artery duplex ultrasonography was used to identify the presence or absence of carotid plaque >1 mm. The study population included 325 apparently healthy 30- to 59-year-old black siblings of 185 probands with premature coronary artery disease (<60 years old). Associations between each independent SNP and the presence of carotid plaque were examined using multivariate logistic regression models adjusted for age, sex, educational level, diabetes, smoking, hypertension, obesity, low-density lipoprotein cholesterol and non-independence within families. Interactions between SNPs in the MCP-1 gene and the SNP in the CCR2 gene were examined by multivariate analysis.


RESULTS
Siblings were 32% males, with a mean age of 46 +/- 7 years, and 77 (24%) demonstrated carotid plaque. In multivariate analyses, the CC genotype of MCP-1 SNP rs2857656 was independently associated with plaque (p = 0.05). Subjects who had both the MCP-1 CC genotype and were heterozygotic or homozygotic for the CCR2 V64I genotype (rs1799864; n = 12) had an even higher risk of carotid atherosclerosis (odds ratio 6.14, 95% confidence interval 1.82-20.73; p = 0.0037).


CONCLUSIONS
The MCP-1 rs2857656 CC genotype is independently associated with carotid artery plaque in African American from families with premature coronary artery disease. The combination of the MCP-1 CC homozygous genotype and the homozygotic or heterozygote CCR2 V64I genotype is associated with a particularly high prevalence of carotid artery plaque.
Nyquist
Paul A
PA
Department of Anesthesiology/Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA. pnyquis1@jhmi.edu
Winkler
Cherie A
CA
McKenzie
Louise M
LM
Yanek
Lisa R
LR
Becker
Lewis C
LC
Becker
Diane M
DM
D000328:Adult; D001741:Black or African American / Q000235:genetics*; D002340:Carotid Artery Diseases / Q000000981:diagnostic imaging / Q000208:ethnology / Q000235:genetics*; D018932:Chemokine CCL2 / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D054390:Receptors, CCR2 / Q000235:genetics*; D018570:Risk Assessment; D012307:Risk Factors; D018616:Ultrasonography, Doppler, Duplex
C111835:CCL2 protein, human; C515334:CCR2 protein, human; D018932:Chemokine CCL2; D054390:Receptors, CCR2