Chemokine Receptor Genotype Is Associated With Diabetic Nephropathy in Japanese With Type 2 Diabetes

Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo, Japan.
Diabetes (Impact Factor: 8.1). 01/2002; 51(1):238-42. DOI: 10.2337/diabetes.51.1.238
Source: PubMed


Glomerular infiltration of monocytes/macrophages occurs in diabetic patients with nephropathy, and chemokine receptor signals are thought to play a key role in the development of nephropathy. Recently, polymorphism of the chemokine receptor (CCR)2 coding region V64I and the CCR5 promoter region 59029 (G/A) have been identified. Accordingly, we evaluated the effects of these genotypes on diabetic nephropathy. CCR2 V64I and CCR5 59029 (G/A) were detected by polymerase chain reaction-restriction fragment-length polymorphism in 401 patients with type 2 diabetes who had a serum creatinine <2.0 mg/dl. Although the CCR2 V64I genotype showed no association with nephropathy, the frequency of the CCR5 59029 A-positive genotype (G/A or A/A) was significantly higher in patients with microalbuminuria (urinary albumin-to-creatinine ratio [ACR] > or = 30 and <300 mg/gCre, 86%) and patients with macroalbuminuria (ACR > or = 300 mg/gCre, 87%) than in patients with normoalbuminuria (ACR <30 mg/gCre, 75%; P = 0.0095). Polytomic logistic regression analysis showed that the CCR5 59029 A-positive genotype was associated with nephropathy (odds ratio 2.243, P = 0.0074). These results suggest that the CCR5 promoter 59029 A genotype may be an independent risk factor for diabetic nephropathy in patients with type 2 diabetes.

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    • "Another study by Boger et al. suggested that up regulation of CCR5 could lead to accelerated atherosclerosis in type 2 diabetes mellitus patients on hemodialysis [26]. Also other CCR5 polymorphisms have been implicated in the development of diabetic complications [27] [28]. Together these findings support involvement of CCR5-mediated inflammatory processes in the outcome of diabetes. "
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    ABSTRACT: To test whether the genetic variant CCR5Delta32 in the CC-chemokine receptor 5, which is known to lead to CCR5 deficiency, is associated with mortality in type 2 diabetes patients. We examined the effect of presence or absence of the CCR5Delta32 on overall and cardiovascular mortality risk in the Zwolle Outpatient Diabetes project Integrating Available Care (ZODIAC) cohort, a type 2 diabetes patient cohort. We studied 756 patients with a mean duration of follow-up of 5.4 (+/- 1.4) years. 194 patients died during follow up of which 83 were cardiovascular deaths. 144 subjects (19%) carried the CCR5Delta32 deletion. CCR5Delta32 carriers had an adjusted hazard ratio of 0.62 (95%CI: 0.40-0.96; p=0.03) for all-cause mortality and 0.63 (95%CI: 0.33-1.19; p=0.16) for cardiovascular mortality. The presence of CCR5Delta32 is associated with better survival in type 2 diabetes patients. These data suggest that it is worthwhile to explore the protective potential of pharmacological blockade of CCR5 in type 2 diabetic patients.
    Diabetes research and clinical practice 10/2009; 86(2):140-5. DOI:10.1016/j.diabres.2009.08.013 · 2.54 Impact Factor
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    • "Recently, RANTES promoter single nucleotide polymorphism (SNP) -28G genotype and its major receptor, chemotactic cytokine receptor 5 (CCR5) promoter 59029A genotype were shown to be associated with diabetic nephropathy in patients with type 2 diabetes (7, 8). However, effects of MCP-1 and its receptor CCR2 polymorphisms have not been fully assessed so far on diabetic nephropathy. "
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    ABSTRACT: Macrophage infiltration has been observed in the renal biopsy specimens of diabetic nephropathy (DN), and hyperglycemic state stimulates the renal expression of RANTES (regulated upon activation, normal T-cell expressed and secreted) and MCP- 1 (monocyte chemoattractant protein-1). Upregulation of RANTES and MCP-1 with infiltrating macrophages may play a crucial role in the development and progression of DN. Genetic polymorphisms of RANTES and its receptors were reported to be independent risk factors for DN. We genotyped single nucleotide polymorphism (SNPs) in the MCP-1 G-2518A, CCR2 G46295A, RANTES C-28G and G-403A in 177 diabetic end-stage renal disease (ESRD) patients and 184 patients without renal involvement (controls) in order to investigate the effects of these SNPs on DN in Korean patients with type 2 DM. There were no differences in the frequencies of SNPs and the distribution of haplotypes of RANTES promoter SNPs between two groups. In conclusion, there were no associations of MCP-1, CCR2 and RANTES promoter SNPs with diabetic ESRD in Korean population. Prospective studies with clearly-defined, homogenous cohorts are needed to confirm the effect of these genetic polymorphisms on DN.
    Journal of Korean Medical Science 09/2007; 22(4):611-5. DOI:10.3346/jkms.2007.22.4.611 · 1.27 Impact Factor
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    • "In addition, angiotensin II also activates PKC and MAPK pathways, which are abundantly implicated in activation of TGFβ1, TNFα and IL1, in various cells [8-11]. Over expression of TNFα and IL-1 stimulates the expression of chemokines like monocyte chemoattractant protein1 (MCP1) and "Regulated upon activation and normal T cell expressed and secreted" (RANTES) in human mesangial cells [12-14]. Up regulation of MCP1 and RANTES triggers recruitment of monocytes and macrophage infiltration in glomerulus of diabetic rats [15] and DN subjects [16]. "
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