Circulating MCP-1 levels shows linkage to chemokine receptor gene cluster on chromosome 3: the NHLBI Family Heart Study follow-up examination

Abstract

Atherogenesis is a chronic inflammatory process. Critical in the inflammation process is monocyte chemoattractant protein-1 (MCP-1). To locate genomic regions that affect circulating MCP-1 levels, a genome-wide linkage scan was conducted in a sample of whites and blacks. Phenotype and genetic marker data were available for 2501 white and 513 black participants in the National Heart Lung Blood Institute Family Heart Study follow-up examination. Heritability for MCP-1 was 0.37 in whites and 0.47 in blacks after adjusting for the effects of sex, age, age-sex interaction, smoking status, lifetime smoking exposure (pack-years) and field center. Significant linkage was observed for MCP-1 in a combined black and white sample on chromosome 3 (logarithm of the odds ratio (LOD) ¼ 3.5 at 78 cM, P ¼ 0.0001) and suggestive linkage was observed in whites on chromosome 5 (LOD ¼ 1.8 at 128 cM, P ¼ 0.002). Located under the linkage peak on chromosome 3 is the chemokine receptor gene cluster, including CCR2, the receptor for MCP-1. This study provides preliminary evidence linking genetic variation in a receptor to circulating levels of its ligand, as previously demonstrated for the low-density lipoprotein receptor. Further characterization of these chromosomal regions is needed to identify the functional mutations associated with circulating levels of MCP-1.

Duffy antigen receptor for chemokines (Darc) polymorphism regulates circulating concentrations of monocyte chemoattractant protein-1 and other inflammatory mediators

“…13 It is notable that DARC is a trans-acting variant and is not on the same chromosome as the gene coding for MCP-1 (CCL2). As observed before, 14 family-based genetic linkage for serum MCP-1 confirms our GWA results with a convincingly high LOD score of greater than 14. The single SNP, rs12075, located under the peak explains most of this linkage signal.…”

“…Our results are strengthened by a recent linkage scan that showed a peak for plasma MCP-1 concentrations on chromosome 3 with a LOD score of 3.5 at 78cM, which coincides with the same chemokine receptor cluster. 14 In the FHS linkage study, we did not observe a relevant peak in this area even with a larger sample compared with the original publication, a finding which may be due to the small effect size. 15 CCR2 resides in this region and codes for 2 isoforms of the MCP-1 receptor, 4 which mediate the biologic effects of MCP-1; thus, CCR2 is a good candidate for further exploration.…”

“…Multivariable-adjusted heritability of MCP-1 concentrations in whites of European descent has been reported to be 0.37 in plasma and 0.44 in serum. 14,15 Initial linkage studies showed peaks of genome-wide significance on chromosome 1 and 3. 14,15 Multiple single nucleotide polymorphisms (SNPs) in the MCP-1 gene (CCL2) have been reported to be related to blood concentrations of MCP-1, but to date, only rs1024611 (Ϫ2518 A/G) has been replicated.…”

“…14,15 Initial linkage studies showed peaks of genome-wide significance on chromosome 1 and 3. 14,15 Multiple single nucleotide polymorphisms (SNPs) in the MCP-1 gene (CCL2) have been reported to be related to blood concentrations of MCP-1, but to date, only rs1024611 (Ϫ2518 A/G) has been replicated. 16,17 To identify the genetic basis of the proinflammatory cytokine MCP-1, we used family-based genetic linkage and genome-wide association (GWA) studies.…”

Association of Monocyte Chemoattractant Protein‐1 (MCP‐1)‐2518A>G Polymorphism with Susceptibility to Coronary Artery Disease: A Meta‐Analysis

“…The human MCP-1 gene maps to chromosome 17q11.2-q21.1 (Bielinski et al, 2007). More than 10 polymorphisms in the regulatory region of MCP-1 have been reported to lead to variability in MCP-1 expression and serum levels, whereas the rs1024611G (dbSNP database; originally designated as -2518G or -2578G) variant is recognized as the most common one (Pham et al, 2012;Pan et al, 2013).…”