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(Circulation. 2005;112:1113-1120.)
© 2005 American Heart Association, Inc.

Epidemiology

CCL2 Polymorphisms Are Associated With Serum Monocyte Chemoattractant Protein-1 Levels and Myocardial Infarction in the Framingham Heart Study

David H. McDermott, MD; Qiong Yang, PhD; Sekar Kathiresan, MD; L. Adrienne Cupples, PhD; Joseph M. Massaro, PhD; John F. Keaney, Jr, MD; Martin G. Larson, ScD; Ramachandran S. Vasan, MD; Joel N. Hirschhorn, MD, PhD; Christopher J. O’Donnell, MD, MPH; Philip M. Murphy, MD; Emelia J. Benjamin, MD, ScM

From the Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md (D.H.M., P.M.M.); Department of Biostatistics, School of Public Health (Q.Y., L.A.C.), Department of Mathematics (J.M.M., M.G.L.), and School of Medicine (J.F.K., R.S.V., E.J.B.), Boston University, Boston, Mass; Cardiology Division, Massachusetts General Hospital (S.K., C.J.O.) and Department of Genetics (J.N.H.), Harvard Medical School, Boston, Mass; Broad Institute, Cambridge, Mass (S.K., C.J.O.); National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Md (C.J.O.); and National Heart, Lung and Blood Institute’s Framingham Heart Study, Framingham, Mass (S.K., R.S.V., C.J.O., E.J.B.).

Correspondence to David H. McDermott, MD, NIAID, NIH Bldg 10, Room 11N111, Bethesda, MD 20892-1886 (e-mail dmcdermott{at}niaid.nih.gov); or Emelia J. Benjamin, MD, ScM, Framingham Heart Study, 73 Mt Wayte Ave, Suite 2, Framingham, MA 01702-5827 (e-mail emelia@bu.edu).

Received February 8, 2005; revision received April 21, 2005; accepted May 5, 2005.

Background— Monocyte chemoattractant protein-1 (MCP-1) is a chemokine strongly implicated in promoting atherosclerosis in animal models, but human genetic evidence is contradictory.

Methods and Results— We analyzed the association of genetic variation in the MCP-1 gene (CCL2) with prevalent myocardial infarction and serum MCP-1 levels in the community-based Framingham Heart Study Offspring Cohort (50% women; mean age, 62 years). MCP-1 levels and CCL2 genotypes were determined in 3236 and 1797 individuals, respectively. Significant clinical correlates of MCP-1 levels were age, cigarette smoking, triglycerides, body mass index, and waist-to-hip ratio. The MCP-1-2578G allele located in the CCL2 regulatory region was significantly associated with both higher serum MCP-1 levels in a recessive genetic model (358±10 versus 328±3 pg/mL; P=0.002) and higher prevalence of myocardial infarction in a dominant genetic model (adjusted odds ratio, 2.0; 95% CI, 1.2 to 3.3; P=0.005). We also defined the linkage disequilibrium structure at the CCL2 locus and observed 6 common haplotypes in whites. We performed haplotype-based association analysis and found that only the most frequent haplotype, defined by the MCP-1-2578G allele, was associated with prevalent MI.

Conclusions— Our data are consistent with the hypothesis that MCP-1 is involved in the pathogenesis of human atherosclerosis and myocardial infarction.

Key Words: epidemiology • genetics • inflammation • myocardial infarction • risk factors

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