Dataset Information

Exclusion of polymorphisms in carnosinase genes (CNDP1 and CNDP2) as a cause of diabetic nephropathy in type 1 diabetes: results of large case-control and follow-up studies.

ABSTRACT: Recently, an association was found between diabetic nephropathy and the D18S880 microsatellite, located in the carnosinase gene (CNDP1) on chromosome 18q. Alleles of this microsatellite encode for a variable number of leucine residues (from four to seven) in the leader peptide of the carnosinase precursor. The frequency of subjects homozygous for the five leucines was higher in control subjects than in case subjects in studies focusing on type 2 diabetic patients. To test whether this finding can be extended to type 1 diabetic patients, we carried out a comprehensive study on association between diabetic nephropathy and the D18S880 microsatellite and 21 additional SNPs that tagged the genomic region containing CNDP1 and CNDP2.Overall, 1,269 Caucasian patients with type 1 diabetes were included in the study, including 613 patients with normoalbuminuria and a long duration of diabetes, 445 patients with persistent proteinuria, and 211 patients with end-stage renal disease (ESRD). All patients were genotyped for selected polymorphisms, the associations with diabetic nephropathy were tested by a chi(2) test, and odds ratios were calculated.We did not find any significant association between diabetic nephropathy and any examined genetic markers. The negative findings of the case-control study were supported further by negative findings obtained from the 6-year follow-up study of 445 patients with persistent proteinuria, during which 135 patients developed ESRD.Our large, comprehensive study did not find an association between the D18S880 microsatellite or any other polymorphisms in the CNDP2-CNDP1 genomic region and susceptibility for diabetic nephropathy in type 1 diabetes.

SUBMITTER: Wanic K

PROVIDER: S-EPMC2518509 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

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Exclusion of polymorphisms in carnosinase genes (CNDP1 and CNDP2) as a cause of diabetic nephropathy in type 1 diabetes: results of large case-control and follow-up studies.

Wanic Krzysztof K Placha Grzegorz G Dunn Jonathon J Smiles Adam A Warram James H JH Krolewski Andrzej S AS

Diabetes 20080901 9

<h4>Objectives</h4>Recently, an association was found between diabetic nephropathy and the D18S880 microsatellite, located in the carnosinase gene (CNDP1) on chromosome 18q. Alleles of this microsatellite encode for a variable number of leucine residues (from four to seven) in the leader peptide of the carnosinase precursor. The frequency of subjects homozygous for the five leucines was higher in control subjects than in case subjects in studies focusing on type 2 diabetic patients. To test whet ...[more]

PMID: 18753673

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Project description:Type 2 diabetes mellitus (T2DM) is associated with a high incidence of nephropathy. The aim of this study was to investigate the association of a genetic polymorphism of carnosinase (CNDP1-D18S880 and -rs2346061), endothelial nitric oxide synthase (NOS3-rs1799983), and manganese superoxide dismutase (MnSOD-rs4880) genes with the development of diabetic nephropathy among Malaysian type 2 diabetic patients. A case-control association study was performed using 652 T2DM patients comprising 227 Malays (without nephropathy = 96 and nephropathy = 131), 203 Chinese (without nephropathy = 95 and nephropathy = 108), and 222 Indians (without nephropathy = 136 and nephropathy = 86). DNA sequencing was performed for the D18S880 of CNDP1, while the rest were tested using DNA Sequenom MassARRAY to identify the polymorphisms. DNA was extracted from the secondary blood samples taken from the T2DM patients. The alleles and genotypes were tested using four genetic models, and the best mode of inheritance was chosen based on the least p value. The rs2346061 of CNDP1 was significantly associated with diabetic nephropathy among the Indians only with OR = 1.94 and 95% CI = (1.76-3.20) and fitted best the multiplicative model, while D18S880 was associated among all the three major races with the Malays having the strongest association with OR = 2.46 and 95% CI = (1.48-4.10), Chinese with OR = 2.26 and 95% CI = (1.34-3.83), and Indians with OR = 1.77 and 95% CI = (1.18-2.65) in the genotypic multiplicative model. The best mode of inheritance for both MnSOD and NOS3 was the additive model. For MnSOD-rs4880, the Chinese had OR = 2.8 and 95% CI = (0.53-14.94), Indians had OR = 2.4 and 95% CI = (0.69-2.84), and Malays had OR = 2.16 and 95% CI = (0.54-8.65), while for NOS3-rs1799983, the Indians had the highest risk with OR = 3.16 and 95% CI = (0.52-17.56), followed by the Chinese with OR = 3.55 and 95% CI = (0.36-35.03) and the Malays with OR = 2.89 and 95% CI = (0.29-28.32). The four oxidative stress-related polymorphisms have significant effects on the development of nephropathy in type 2 diabetes patients. The genes may, therefore, be considered as risk factors for Malaysian subjects who are predisposed to T2DM nephropathy.

Project description:Diabetic nephropathy (DN) is one of the major complications of diabetes and contributes significantly towards end-stage renal disease. Previous studies have identified the gene encoding carnosinase (CN-1) as a predisposing factor for DN. Despite this fact, the relationship of the level of serum CN-1 and the progression of DN remains uninvestigated. Thus, the proposed study focused on clarifying the relationship among serum CN-1, indicators of renal function and tissue injury, and the progression of DN. A total of 14 patients with minimal changes disease (MCD) and 37 patients with DN were enrolled in the study. Additionally, 20 healthy volunteers were recruited as control. Further, DN patients were classified according to urinary albumin excretion rate into two groups: DN with microalbuminuria (n = 11) and DN with macroalbuminuria (n = 26). Clinical indicators including urinary protein components, serum carnosine concentration, serum CN-1 concentration and activity, and renal biopsy tissue injury indexes were included for analyzation. The serum CN-1 concentration and activity were observed to be the highest, but the serum carnosine concentration was the lowest in DN macroalbuminuria group. Moreover, within DN group, the concentration of serum CN-1 was positively correlated with uric acid (UA, r = 0.376, p = 0.026) and serum creatinine (SCr, r = 0.399, p = 0.018) and negatively correlated with serum albumin (Alb, r = - 0.348, p = 0.041) and estimated glomerular filtration rate (eGRF, r = - 0.432, p = 0.010). Furthermore, the concentration of serum CN-1 was discovered to be positively correlated with indicators including 24-h urinary protein-creatinine ratio (24 h-U-PRO/CRE, r = 0.528, p = 0.001), urinary albumin-to-creatinine ratio (Alb/CRE, r = 0.671, p = 0.000), urinary transferrin (TRF, r = 0.658, p = 0.000), retinol-binding protein (RBP, r = 0.523, p = 0.001), N-acetyl-glycosaminidase (NAG, r = 0.381, p = 0.024), immunoglobulin G (IgG, r = 0.522, p = 0.001), cystatin C (Cys-C, r = 0.539, p = 0.001), beta-2-microglobulin (β2-MG, r = 0.437, p = 0.009), and alpha-1-macroglobulin (α1-MG, r = 0.480, p = 0.004). Besides, in DN with macroalbuminuria group, serum CN-1 also showed a positive correlation with indicators of fibrosis, oxidative stress, and renal tubular injury. Taken together, our data suggested that the level of CN-1 was increased as clinical DN progressed. Thus, the level of serum CN-1 might be an important character during the occurrence and progression of DN. Our study will contribute significantly to future studies focused on dissecting the underlying mechanism of DN.

Dataset Information

Exclusion of polymorphisms in carnosinase genes (CNDP1 and CNDP2) as a cause of diabetic nephropathy in type 1 diabetes: results of large case-control and follow-up studies.

Publications

Exclusion of polymorphisms in carnosinase genes (CNDP1 and CNDP2) as a cause of diabetic nephropathy in type 1 diabetes: results of large case-control and follow-up studies.

Similar Datasets

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