RGD Reference Report - The CCR2 promoter polymorphism T-960A, but not the serum MCP-1 level, is associated with endothelial function in prediabetic individuals. - Rat Genome Database

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The CCR2 promoter polymorphism T-960A, but not the serum MCP-1 level, is associated with endothelial function in prediabetic individuals.

Authors: Rittig, K  Peter, A  Baltz, KM  Tschritter, O  Weigert, C  Andreozzi, F  Perticone, F  Siegel-Axel, DI  Stefan, N  Fritsche, A  Salih, HR  Schleicher, E  Machicao, F  Sesti, G  Haring, HU  Balletshofer, BM 
Citation: Rittig K, etal., Atherosclerosis. 2008 Jun;198(2):338-46. Epub 2007 Dec 21.
RGD ID: 2313557
Pubmed: PMID:18096169   (View Abstract at PubMed)
DOI: DOI:10.1016/j.atherosclerosis.2007.10.028   (Journal Full-text)

Monocyte-chemoattractant-protein (MCP)-1 and its receptor CCR2 have been shown to play a pivotal role in vascular inflammation and atherosclerotic plaque formation. However, it is currently unclear whether MCP-1/CCR2 triggered inflammation affects nitric oxide (NO)-bioavailability, hence influencing vascular function, a sign of early atherosclerosis. Therefore, we sought to investigate the association between serum levels of MCP-1 and NO-bioavailability, expressed as flow mediated dilation (FMD) in vivo, and the impact of CCR2 gene variations on FMD. We studied a German population of 242 prediabetic individuals (144 women, 98 men; mean age 45+/-0.8 years) via FMD by high-resolution ultrasound (13MHz). In order to replicate our findings, a second, independent population (n=115; 44 women, 77 men; mean age 48+/-1.0 years) (total=357 individuals) from Italy was studied. Vascular function in the Italian population was studied via intra-arterial application of acetylcholine. MCP-1 serum-levels were assessed by ELISA and CCR2 polymorphisms were determined by sequencing. MCP-1 serum levels showed no association with FMD (p=0.90), whereas the CCR2 promoter polymorphism was associated with elevated FMD (T/T: 5.6+/-0.3%; T/A: 6.7+/-0.4%; A/A: 8.3+/-0.8%; p=0.01) after adjusting for possible confounders. These results were confirmed in the independent Italian population (A/A: 97.1+/-20.3 vs. T/T: 60.5+/-5.6% forearm blood-flow increase; p<0.05). When testing for the functional relevance of the T-960A (rs3918359) polymorphism, we found that the A/A-genotype was associated with moderately increased protein binding in EMSA, increased promoter activity in luciferase assays and reduced transendothelial monocyte migration. In conclusion, MCP-1 serum levels do not reflect endothelial function in vivo in prediabetic individuals. However, the functionally relevant CCR2 promoter polymorphism T-960A (rs3918359) is associated with elevated vascular function. This might be due to reduced subendothelial inflammation, mediated by reduced transendothelial monocyte-migration ability.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CCR2Humanprediabetes syndrome  IAGP DNA:polymorphism:promoter:-960T>A (rs3918359) (human)RGD 
Ccr2Ratprediabetes syndrome  ISOCCR2 (Homo sapiens)DNA:polymorphism:promoter:-960T>A (rs3918359) (human)RGD 
Ccr2Mouseprediabetes syndrome  ISOCCR2 (Homo sapiens)DNA:polymorphism:promoter:-960T>A (rs3918359) (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ccr2  (C-C motif chemokine receptor 2)

Genes (Mus musculus)
Ccr2  (C-C motif chemokine receptor 2)

Genes (Homo sapiens)
CCR2  (C-C motif chemokine receptor 2)


Additional Information