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Abstract
Background
The 26S ubiquitin-proteasome system (UPS) is a principal proteolytic pathway of intracellular molecules regulating apoptosis, cell cycle, cell proliferation or differentiation, inflammation and etc. The recent study suggests that the rs1048990 (C/G) polymorphism of the proteasome subunit α type 6 (PSMA6) gene is associated with the increase of the risk of myocardial infarction by the dysregulation of IκB degradation. We hypothesized that 26S UPS is important in the development of insulin resistance and type 2 diabetes (T2DM) by controlling the degradation of IκB and insulin receptor substances as a substrate. We therefore investigated whether the rs1048990 (C/G) polymorphism of PSMA6 gene and the rs2230087 (G/A) polymorphism of proteasome subunit β type 5 gene (PSMB5), that is chymotrypsin-like protease determining the rate of proteolysis, are associated with susceptibility to T2DM in Korean subjects.
Methods
We examined the polymorphisms of these genes in 309 diabetic subjects and 170 non-diabetic controls. The polymorphisms of rs1048990 (C/G) and rs2230087 (G/A) were genotyped by real-time PCR.
Results
The frequency of the G allele of rs1048990 (C/G) and the A allele of rs2230087 (G/A) polymorphisms was significantly higher in diabetic patients (28% and 13%) compared to that in controls (13% and 1%; P = 0.000 and P = 0.000, respectively). Logistic regression analysis of the rs1048990 (C/G) polymorphism showed that the odds ratio (OR) (adjusted for age, smoking, waist circumference, fasting plasma glucose, systolic blood pressure, HDL-C, triglyceride, and total cholesterol) was 3.93 (95% confidence interval [CI], 2.35-6.59; P = 0.000) for the G allele and 5.09 (95% CI, 2.71-9.57; P = 0.000) for CG and GG genotype when compared with the CC genotype. Logistic regression analysis of the rs2230087 (G/A) polymorphism showed that the adjusted OR was 5.70 (95% CI, 1.63-19.98; P = 0.007) for the A allele and 6.08 (95% CI, 1.66-22.29; P = 0.006) for GA and AA genotype when compared with the GG genotype. In multiple logistic regression analysis with T2DM as the independent Variable rs1048990 (C/G) and rs2230087 (G/A) polymorphisms were the predictor for T2DM.
Figures and Tables
Table 1
Clinical and metabolic characteristics of study subjects
Values are presented as mean ± SD. BP, blood pressure; BMI, body mass index; FBS, fasting blood glucose; HBA1c glycosylated hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; s-Cr serum creatinine; T-chol, total cholesterol; TG, triglyceride; WHR waist-hip ratio.
Table 2
Genotype distribution of rs1048990 and rs2230087 polymorphisms in controls and diabetic patients
Table 3
Genotype distribution and allele frequency of rs1048990 and rs2230087 polymorphisms in controls and diabetic patients
Table 4
Age- and sex- adjusted or multivariate-adjusted ORs and 95% CIs of rs1048990 (A) and rs2230087 (B) polymorphisms in controls and diabetic patients
Table 6
Clinical and metabolic characteristics according to genotypes
Values are presented as mean ± SD. *P < 0.05. †P < 0.05, Significant even after adjustment for sex by binary logistic regression analysis. ‡Smoking: current or previous history of smoking. Other abbreviations see in Table 1.
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