Atherosclerosis 193 (2007) 366–372 A monocyte chemoattractant protein-1 gene polymorphism is associated with occult ischemia in a high-risk asymptomatic population Min P. Kim a , Larry M. Wahl a , Lisa R. Yanek b , Diane M. Becker b , Lewis C. Becker c,∗ a Immunopathology Section, National Institute of Dental and Craniofacial Research, United States b Division of Internal Medicine, The Johns Hopkins Sibling and Family Heart Study, The Johns Hopkins University School of Medicine, United States c Division of Cardiology, The Johns Hopkins Sibling and Family Heart Study, The Johns Hopkins University School of Medicine, United States Received 2 November 2005; received in revised form 27 April 2006; accepted 25 June 2006 Available online 24 August 2006 Abstract Monocyte chemoattractant protein-1 (MCP-1) recruits monocytes into atherosclerotic plaques. A single nucleotide polymorphism in the MCP-1 gene promoter (-2578A > G) results in greater production of MCP-1 protein. We examined the association of this polymorphism with occult coronary artery disease (CAD) and its interaction with CAD risk factor burden, as assessed by the Framingham risk score (FRS) for hard events. We genotyped 679 apparently healthy 24–59-year-old siblings (SIBS) of people with premature CAD, tested for occult ischemia with exercise treadmill tests and thallium-201 single photon emission computed tomography, and assessed CAD risk factors to calculate the FRS. Occult ischemia occurred in 18% of SIBS and overall was somewhat more prevalent in those with the G allele (20.6%) compared to those without (15.6%), p = 0.095. In SIBS at higher risk (highest quartile of FRS, ≥6.8%), occult ischemia occurred significantly more frequently in those with the G allele (44.4% versus 26.1%, p = 0.017), while there was no significant difference in SIBS with lower FRS. After adjusting for individual risk factors included in the FRS, multivariate logistic regression modeling demonstrated that the G allele independently predicted occult ischemia in the entire study population (p = 0.014, OR = 1.86, 95% CI = 1.14–3.04). This study demonstrates for the first time that the MCP-1 gene -2578A > G polymorphism is associated with an excess risk of coronary atherosclerosis in an asymptomatic population and demonstrates an apparent interaction with CAD risk factor burden. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Atherosclerosis; Coronary disease; Genetics; Ischemia; Monocyte chemoattractant protein-1; Radionuclide perfusion imaging 1. Introduction Monocyte chemoattractant protein-1 (MCP-1), a chemokine involved in monocyte recruitment to sites of inflammation, may play an important role in the development of atherosclerosis. Following injury to vascular endothelium induced by common atherosclerosis risk factors, MCP-1 may contribute to accumulation of monocytes in injured areas, leading to chronic inflammation and smooth muscle ∗ Corresponding author at: Halsted 500, Johns Hopkins Hospital, 600 N. Wolfe Street, Baltimore, MD 21287, United States. Tel.: +1 410 955 5997; fax: +1 410 955 0852. E-mail address: lbecker@mail.jhmi.edu (L.C. Becker). cell proliferation [1]. MCP-1 protein has been detected in human atherosclerotic plaques [2] and mRNA for MCP-1, which is absent in normal arteries, has been detected in diseased arteries by in situ hybridization [3,4]. In mice with deficiency of low-density lipoprotein (LDL) receptors [5] or overexpression of apolipoprotein B [6], knock out of the MCP-1 gene leads to a decrease in the extent of atheroscle- rosis. Furthermore, absence of the receptor for MCP-1, C–C chemokine receptor (CCR)-2, or administration of propager- manium, an inhibitor of CCR-2 function, are associated with reduction of atherosclerosis in apolipoprotein E knockout mice [7,8]. In humans, the level of MCP-1 production is modified by a functional single nucleotide (A > G) polymorphism (SNP) 0021-9150/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2006.06.029