title: The CCR2 promoter polymorphism T-960A, but not the serum MCP-1 level, is associated with endothelial function in prediabetic individuals.
abstract: 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.
authors: Department of Endocrinology, Diabetes, Vascular Medicine, Nephrology and Clinical Chemistry, University of Tübingen, Germany.
authors: Kilian
authors: K
authors: Rittig
authors: Andreas
authors: A
authors: Peter
authors: Katrin M
authors: KM
authors: Baltz
authors: Otto
authors: O
authors: Tschritter
authors: Cora
authors: C
authors: Weigert
authors: Francesco
authors: F
authors: Andreozzi
authors: Francesco
authors: F
authors: Perticone
authors: Dorothea I
authors: DI
authors: Siegel-Axel
authors: Norbert
authors: N
authors: Stefan
authors: Andreas
authors: A
authors: Fritsche
authors: Helmut R
authors: HR
authors: Salih
authors: Erwin
authors: E
authors: Schleicher
authors: Fausto
authors: F
authors: Machicao
authors: Giorgio
authors: G
authors: Sesti
authors: Hans-Ulrich
authors: HU
authors: Häring
authors: Bernd M
authors: BM
authors: Balletshofer
mesh_terms: D000328:Adult; D050197:Atherosclerosis / Q000235:genetics*; D001775:Blood Circulation / Q000235:genetics; D002465:Cell Movement; D024202:Electrophoretic Mobility Shift Assay; D004730:Endothelium, Vascular / Q000503:physiopathology*; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009000:Monocytes; D011110:Polymorphism, Genetic; D011236:Prediabetic State / Q000097:blood* / Q000503:physiopathology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D054390:Receptors, CCR2 / Q000097:blood* / Q000235:genetics*; D014664:Vasodilation / Q000235:genetics
chemical_list: C515334:CCR2 protein, human; D054390:Receptors, CCR2; D008156:Luciferases