Apolipoprotein A5 gene polymorphism (rs662799) and cardiovascular disease in end-stage kidney disease patients.

BACKGROUND: Plasma triglyceride (TG) levels are a significant risk factor for cardiovascular disease (CVD). The APOA5 gene is one of the crucial factors in plasma TG metabolism regulation. The rs662799 polymorphism in the APOA5 gene has been reported to be associated with cardiovascular disease. The goal of this study was to evaluate the potential association of this variant with CVD in patients with end-stage kidney disease.  METHODS: In this case-control study the polymorphism was analyzed using the PCR-RFLP method in 800 consecutive patients with ESKD and 500 healthy controls. The genotype and allele distribution was compared between subgroups of patients with CVD (552) versus those without CVD (248). RESULTS: The frequency of the minor allele (C) in the healthy individuals was 9% compared to 12% in ESRD group (p = 0.09). The difference between groups was slightly higher for CC homozygote (3.5% versus 1.6%, p = 0.042). The ESKD patient group was analyzed according to the presence or absence of CVD. The significant differences in the polymorphism distribution were revealed in this analysis. The frequency of the C allele in the CVD + subgroup was 14% compared to 6% in CVD- patients (p = 0.001). In the CVD + subgroup the ORs (95% CI) for the C allele and CC genotype were 2.41 (1.61-3.6), p < 0.001 and 3.13 (1.07-9.14), p = 0.036, respectively. This indicates to the association of the variant C allele with cardiovascular disease in ESKD patients. The CC homozygotes have a threefold higher odds of CVD compared to TT homozygotes. The highest frequency of the C allele (18%) was observed in subgroup of patients with diabetic nephropathy, with OR (95% CI) 3.40 (2.13-5.43), p < 0.001.The presence of minor allele (CC and CT genotypes) was significantly associated with increased plasma triglyceride levels (p < 0.001 for both CVD + and CVD- groups). CONCLUSION: The present study demonstrated the effect of rs662799 polymorphism on plasma TG levels and its association with the development of cardiovascular disease in ESKD patients.

LDLR gene polymorphism (rs688) affects susceptibility to cardiovascular disease in end-stage kidney disease patients.

BACKGROUND: The low-density lipoprotein receptor (LDLR) plays a significant role in maintaining the cellular cholesterol homeostasis. Mutations in the LDLR gene can lead to a significant rise in plasma LDL levels that may result in an increased risk of atherosclerosis and coronary heart disease. The purpose of this study was to assess the potential association of the LDLR rs688 polymorphism with cardiovascular disease (CVD) in patients with end-stage kidney disease (ESKD) undergoing hemodialysis. METHODS: In this case-control study the polymorphism was genotyped by the allele specific PCR method in 800 patients with ESKD and 500 healthy controls. The genotype and allele distribution was compared in subgroups of patients with CVD (552) versus those without CVD (248). RESULTS: A significant difference was observed in genotype distribution among ESKD patients and healthy controls. The frequencies of the T allele and TT genotype in ESKD group were significantly higher, with OR (95% CI) 2.2 (1.87-2.6), p <  0.0001 and 5.84 (3.94-8.65), p <  0.0001, respectively. In the he ESKD cohort the distribution of the rs688 was compared between CVD+ and CVD- subgroups. A strong association of the polymorphism with the CVD risk was observed in this analysis. The frequencies of the T allele and TT genotype were significantly higher in CVD+ subgroup, with OR (95% CI) 3.4 (2.71-4.26), p <  0.0001 and 13.2 (7.87-22.09), p <  0.0001, respectively. A multivariate logistic regression analysis was performed to estimate the association between rs688 T variant and risk of CVD. After adjustment for age, sex, BMI, hypertension and diabetes, both CT and TT genotypes were associated with an increased risk of developing CVD in the dominant, recessive and codominant models of inheritance. No significant differences in serum LDL cholesterol levels were found when compared between genotypes. CONCLUSIONS: The present study is the first to demonstrate the association of the LDLR gene polymorphism with increased susceptibility to cardiovascular disease in ESKD patients. This finding needs further investigation to confirm that LDLR rs688 might be a novel genetic risk factor with some prognostic capacity for CVD in ESKD patients.

Association between Monocyte Chemoattractant Protein-1 -2518 (A/G) Single Nucleotide Polymorphism and Chronic Periodontitis in End-stage Renal Disease Patients - A Case-control Study.

Monocyte chemoattractant protein 1 (MCP-1) plays an important role in the development of periodontitis. The purpose of this investigation was to evaluate association of the  MCP-1 gene polymorphism with chronic periodontitis in patients with end-stage renal disease (ESRD). One hundred fifty ESRD patients with chronic periodontitis (CP), 100 without CP and 190 healthy controls were included in this study. Genomic DNA from all participants was genotyped for the -2518 (A/G) polymorphism by a polymerase chain reaction - restriction fragment length polymorphism (PCR--RFLP) assay. Significant differences were observed in the genotype and allele frequencies between patients with ESRD and CP and controls.  The G allele frequency was significantly higher in patients than in control subjects, with odds ratio 1.77 (95 % CI 1.2-2.5), p = 0.0014. For the GG genotype the OR was 3.63 (95 % CI 1.5-8.76), p = 0.041.  No significant differences in the polymorphism distribution were observed between ESRD patients  without CP and control subjects. Comparison of the MCP-1 gene polymorphism distribution in ESRD patients with various primary diseases leading to ESRD did not show any significant differences. The mean MCP-1 serum levels were compared between subgroups. They were significantly higher in ESRD patients with CP (582 ± 112 pg/ml) than in patients without CP (309 ± 103 pg/ml) and controls (265 ± 85 pg/ml). Our results suggest that the MCP-1-2518 A/G  polymorphism might be a novel risk factor for developing chronic periodontitis in patients with ESRD.

Interleukin-1ß Gene (IL1B) Polymorphism and Risk of Developing Diabetic Nephropathy.

Objective: Cytokines play an important role in the pathogenesis of type 2 diabetes (T2DM) and its complications. The aim of the study was to evaluate an association of the -511 (C/T) polymorphism in the IL1B gene with diabetic nephropathy (DN). Methods: The study population included 860 patients with T2DM (506 with diabetic nephropathy and 354 without nephropathy) as well as 505 healthy individuals. Genomic DNA was genotyped for the IL1B -511 (C/T) polymorphism using PCR-RFLP technique. Results: The IL1B -511 C/T polymorphism was genotyped in 860 T2DM patients with or without DN and 505 healthy individuals. The average age of patients was 65.3 years in DN+ and 62.2 years in DN- subgroups. The genotype distribution did not differ significantly between patients and controls. Only a tendency to a slight increase of T allele frequency was observed in patient group. Genotype and allele frequencies of -511 C/T polymorphism were compared in patients with DN and those without it. The minor allele (T) and homozygote TT frequencies were significantly different between subgroups. The T allele was more frequent in DN+ patients, with odds ratio 1.45 (95% CI 1.2-1.8), p = 0.0003. The TT genotype frequency was also higher in DN+, with OR 1.76 (96% CI 1.1-2.7), p = 0.01. Conclusion: In a studied population the -511 C/T polymorphism in the IL1B gene is associated with diabetic nephropathy in dialyzed T2DM patients. Further studies are required to confirm the clinical significance of this finding.

IL4 gene VNTR polymorphism in chronic periodontitis in end-stage renal disease patients.

OBJECTIVE: Interleukin-4 gene polymorphisms were found to be associated with periodontitis. The purpose of this case-control study was to evaluate association of IL4 VNTR polymorphism with periodontitis in patients with end-stage renal disease (ESRD). SUBJECTS AND METHODS: We examined 180 ESRD patients with chronic periodontitis, 82 without CP and 180 healthy controls. Genomic DNA from all subjects was genotyped for the IL4 VNTR polymorphism by polymerase chain reaction (PCR). RESULTS: Genotype distribution in all groups followed Hardy-Weinberg equilibrium. Significant differences in genotype and allele frequencies were observed between groups. The patient group had higher frequency of P1 allele than controls, with odds ratio for P1 allele 1.6 (95% CI 1.1-2.3) and P1P1 genotype 2.73 (95% CI 1.06-7.5). There were no differences in polymorphism distribution between ESRD patients without CP and controls. Periodontal disease was more severe in older patients (≥50 years). Similarly, patients with T2DM had more severe manifestation of CP than patients without diabetes (p = 0.01 for plaque index, p = 0.004 for bleeding index and p = 0.03 for gingival index). CONCLUSION: Our findings suggest that VNTR polymorphism in IL4 gene might be a risk factor for chronic periodontitis in patients with ESRD.

Interleukin-4 Gene Intron 3 VNTR Polymorphism in Type 2 Diabetes Patients with Peripheral Neuropathy.

OBJECTIVE: Diabetic peripheral neuropathy (DPN) is one of late complications of diabetes mellitus. The aim of this study was to evaluate the association between variable number tandem repeat (VNTR) polymorphism in intron 3 of interleukin-4 gene and risk of DPN. METHODS: We examined 926 T2DM patients and 420 healthy controls. In the patient group, 44% had DPN. Genomic DNA was isolated from all subjects and genotyped for the IL-4 VNTR polymorphism by polymerase chain reaction (PCR). RESULTS: No significant difference was observed in the frequency of minor P1 allele between T2DM patients and controls (OR 1.00, 95% CI 0.81-1.23, p = 0.988). The distribution of IL-4 VNTR polymorphism was compared between patients with DPN and those without it. The polymorphism was not significantly associated with DPN in studied subjects. In comparison of 406 T2DM patients with DPN and 520 patients without it, the OR (95% CI) for P1 allele was 0.82 (0.65-1.04), p = 0.10 and for P1P1 genotype 1.00 (0.53-1.89), p = 0.991. When two subgroups of patients with DPN, those with cardiovascular disease (CVD) and without CVD, were compared, subgroup with coexisting CVD had significantly higher frequency of P1 allele than patients without CVD, with odds ratio for the P1 allele 3.27 (95% CI 1.83-5.83), p = 0.0001. CONCLUSION: Our results demonstrated that VNTR polymorphism in the IL-4 gene is associated with DPN in type 2 diabetes patients with coexisting CVD.

Cholesteryl Ester Transfer Protein Gene Polymorphism (I405V) and Risk of Ischemic Stroke.

BACKGROUND: Cholesteryl ester transfer protein (CETP) plays a major role in the metabolism of high-density lipoprotein. Polymorphisms in the CEPT gene can affect susceptibility to atherosclerosis and cardiovascular disease. The aim of this study was to evaluate the association of the CETP I405V polymorphism with ischemic stroke. METHODS: Five hundred eighty stroke patients and 505 healthy controls were involved in a study. Genomic DNA from all subjects was genotyped for the I405V polymorphism by polymerase chain reaction and restriction analysis. RESULTS: The comparison of stroke and control groups showed a significant increase of V allele and VV genotype in stroke patients (OR 1.61, 95% CI 1.34-1.93 and 2.83, 95% CI 1.78-4.51, respectively). The distribution of alleles and genotypes was also compared between stroke patients with type 2 diabetes mellitus (T2DM) and patients without it. No statistically significant differences were observed between two subgroups. The OR for V allele was 1.15, 95% CI .91-1.46 and for VV genotype 1.25, 95% CI .73-2.15. In comparison of these subgroups separately with controls, the results were similar to obtained for entire STR group. When the distribution of I405V polymorphism in relation to T2DM was analyzed in subgroups of men (n = 296) and women (n = 284) no statistically significant differences were observed. CONCLUSION: Our results demonstrate that the I405V polymorphism in the CETP gene is strongly associated with ischemic stroke. The presence of T2DM did not affect this association. To our knowledge this is the first such association documented in Caucasian population.

Effect of G(-174)C polymorphism in interleukin-6 gene on cardiovascular disease in type 2 diabetes patients.

Interleukin-6 (IL-6) is an important pro-inflammatory cytokine of relevance to cardiovascular diseases. The aim of this case-control study was to evaluate the association between the G(-174)C functional polymorphism in the IL-6 gene and risk of cardiovascular disease (CVD) in type 2 diabetes patients. We examined 1090 patients with T2DM and 612 controls. All subjects were genotyped for the G(-174)C polymorphism by polymerase chain reaction (PCR) and restriction analysis. There were no significant differences in the distribution of genotypes and alleles between T2DM patients and healthy controls. Significantly higher C allele frequency was observed in CVD+ patients compared to CVD- subgroup (53% vs. 32%, p<0.0001). The odds ratio for C allele was 2.4 (95% CI 1.99-2.9, p<0.0001) and for CC genotype 4.55 (95% CI 3.12-6.63, p<0.000). When the distribution of G(-174)C polymorphism was compared in subgroups with different clinical phenotypes of CVD, a significant association of CC genotype with myocardial infarction was observed. Forty eight percent of patients with MI had the CC genotype compared to 22% of patients without MI (p<0.0001). In conclusion, type 2 diabetes patients carrying the C allele of the IL-6 G(-174)C polymorphism have a significantly increased risk of CVD.

Transcription factor 7-like 2 (TCF7L2) gene polymorphism and clinical phenotype in end-stage renal disease patients.

Variants of the transcription factor 7-like 2 gene (TCF7L2) have been associated with type 2 diabetes and cardiovascular disease in different populations. Here we investigated the potential association of the rs7903146 polymorphism in the TCF7L2 gene with clinical profile of end-stage renal disease (ESRD) patients. We examined a cohort of 1065 ESRD patients with diabetic and non-diabetic renal disease. The control group consisted of 924 healthy individuals. All subjects were genotyped for the rs7903146 single nucleotide polymorphism by polymerase chain reaction. The genotype distribution and allele frequencies were significantly different between ESRD patients and controls (p < 0.01). The OR for the TT genotype was 2.81 (95% CI 2.08-3.79). Genotype and allele frequencies were compared between subgroups of patients with different clinical phenotypes. The frequency of the T allele was significantly higher in patients with diabetic nephropathy versus non-diabetic renal disease (p = 0.007, OR 1.70, 95% CI 1.36-2.11). The statistically significant differences were demonstrated between patients with and without cardiovascular disease, with the OR for T allele 1.57 (95% CI 1.31-1.90). The odds ratio for TT genotype was 2.38 (95% CI 1.62-3.51). In our study the T allele of the rs7903146 SNP in the TCF7L2 gene confers the risk of developing diabetic nephropathy. We described for the first time a strong relationship between the TCF7L2 gene variant rs7903146 and cardiovascular disease in end-stage renal disease patients.

Prevalence of genetic risk factors related with thrombophilia and hypofibrinolysis in patients with osteonecrosis of the femoral head in Poland.

BACKGROUND: The etiology of osteonecrosis of femoral head (ONFH) has not been fully elucidated. Increased intravascular coagulation and/or hypofibrinolysis have been proposed as pathogenic mechanisms. Previous reports demonstrated significant association between incidence of ONFH and polymorphisms of genes related with thrombophilia especially in Caucasian subjects. The aim of our study was to evaluate the relationship between genetic mutations leading to coagulation disorders and ONFH in Polish patients. METHODS: We have investigated the frequencies of four markers among 68 unrelated individuals with clinically and radiographically documented ONFH and among 100 healthy unrelated blood donors in Eastern part of Poland. The three genes were involved in thrombophilia: factor V Leiden (G1691A), prothrombin (G20210A), Methylenetetrahydrofolate Reductase (MTHFR C677T) and one in hypofibrinolysis: Tissue Plasminogen Activator (PLAT TPA25 I/D). The samples were genotyped with polymerase chain reaction followed by restriction enzyme analysis for the restriction fragment length polymorphisms. The allele and genotype frequencies were analyzed in the relation to ONFH etiology (idiopathic and secondary), gender, age (patients younger or older than 50 years) and the number of affected joints (unilateral or bilateral ONFH). RESULTS: No significant difference in allele frequencies between patients and control groups were observed in genes involved in thrombophilia. We have found a statistically significant increased frequency of D allele of PLAT TPA 25 I/D polymorphism between the entire group of patients with ONFH and controls (p=0,026, OR=1,54, CI 0,99-2,4). D allele frequency was also significantly increased in patients with primary ONFH (p=0,009, OR=1,81 CI 1,1-3,01), in males (p= 0,013; OR 1,74; 95% CIs 1,08-2,78), patients older than 50 years (p= 0,018, OR= 2,04; 95% CIs 1,09-3,82) and in cases with bilateral ONFH (p= 0,01; OR= 1,92; 95% CIs 1,13-3,27) (Table 9). The differences in DD homozygous genotype frequency were statistically significant for patients with idiopathic ONFH compared with control group (p=0,023, OR=2,75, CI 0,99-7,9) and in cases of bilateral ONFH (p=0,034; OR 3,12; 95% CIs 1,06-9,18) (Table 10). The frequencies of ID heterozygous genotype were statistically significantly higher in entire group of patients with ONFH (p=0,004 OR 2,71; 95% CIs 1,32-5,57), idiopathic ONFH (p= 0,01; OR 2,91; 95% CIs 1,24-6,87), males (p=0,0007; OR 3,75; 95% CIs 1,67-8,42), patients older than 50 years (p=0,001; OR 6,89; 95% CIs 1,87-25,84) and in cases with bilateral ONFH (p=0,009; OR 3,19; 95% CIs 1,26-8,03). CONCLUSION: The results suggest that inherited hypofibrinolysis is a risk factor of idiopathic ONFH in Polish population.

Endothelial nitric oxide synthase gene intron 4 polymorphism in non-traumatic osteonecrosis of the femoral head.

PURPOSE: Nitric oxide (NO) synthesised by endothelial NO synthase (eNOS) is a potent regulator of internal haemodynamics. A polymorphism in intron 4 of the eNOS is associated with different vascular disorders. We investigated the potential involvement of this polymorphism in idiopathic and secondary osteonecrosis of the femoral head (ONFH) in Polish patients. METHODS: We performed a study involving 68 patients with ONFH (45 idiopathic and 23 secondary) and 100 healthy controls. All subjects were genotyped for the eNOS4 polymorphism by the polymerase chain reaction followed by agarose gel electrophoresis. RESULTS: The analysis revealed that the frequencies of eNOS4 genotypes were significantly different in ONFH patients (both idiopathic and secondary) than in controls. The frequencies of the 4a allele were significantly higher in the total group of patients versus controls [22.79 vs 9%, p = 0.00039, odds ratio (OR) 2.98]. In subgroup analysis the 4a allele increased significantly in both idiopathic (20 vs 9%, p = 0.0074, OR = 2.52) and secondary (28.26 vs 9%, p = 0.00047, OR = 3.98) ONFH patients compared to control subjects. The frequency of the 4a/b genotype in the total group of patients (36.76 vs 16%, p = 0.0011, OR = 3.24) as well as patients with idiopathic (35.56 vs 16%, p = 0.0069, OR = 2.96) and secondary (39.13 vs 16 %, p = 0.0073, OR = 3.89) ONFH was higher than in the control group. CONCLUSIONS: There was a significantly higher frequency of eNOS 4a allele carriers among the total group of patients as well as in idiopathic and secondary ONFH. This suggests that the eNOS gene polymorphism may be associated with increased risk of ONFH.

MMP9 Gene Polymorphism (rs3918242) Increases the Risk of Cardiovascular Disease in Type 2 Diabetes Patients.

Matrix metalloproteinase 9 (MMP-9) C(-1562)T gene polymorphism has been considered a risk factor for cardiovascular disease (CVD). Our study aimed to evaluate the association between this polymorphism and CVD in diabetes patients. The genotyping was performed in 740 patients with T2DM and 400 healthy subjects. A significant difference in the polymorphism distribution was revealed between patients and controls. The T allele and TT homozygote were associated with increased risk of diabetes (OR 1.88, p < 0.0001 and OR 3.77, p = 0.0002, respectively). The comparison between CVD+ and CVD- subgroups showed a much higher frequency of the T allele in patients with CVD (OR 2.87, 95% CI 2.14-3.85, p < 0.0001). Patients with the TT genotype had a higher prevalence of CVD (OR 3.19, 95% CI 1.55-6.56, p = 0.0015). The carrier genotypes (CT/TT) were correlated with HDL levels in both CVD+ and CVD- subgroups (p < 0.001 for both). In the logistic regression analysis, only C(-1562)T SNP was a significant predictor of CVD in diabetic patients (p < 0.001). In conclusion, our study suggests an association between MMP-9 C(-1562)T polymorphism and an increased risk of CVD in T2DM. If replicated in other studies, it could be considered a genetic marker for predicting risk of T2DM and its cardiovascular comorbidity.

Leu72Met Polymorphism in Ghrelin Gene: A Potential Risk Factor for Hypertension in Type 2 Diabetes Patients.

Objective: Ghrelin (GHRL) is known to be engaged in metabolic and cardiovascular processes. There is evidence suggesting its involvement in the regulation of blood pressure and hypertension. The purpose of this preliminary case-control study was to determine the involvement of the Leu72Met (rs696217) polymorphism in the GHRL gene in type 2 diabetes (T2DM). Methods: The Leu72Met polymorphism was genotyped in 820 individuals with T2DM and 400 healthy subjects by the PCR-RFLP technique. The polymorphism distribution was first compared in those withT2DM and controls, then in subgroups of participants representing different clinical phenotypes. Results: No significant association was identified between Leu72Met and T2DM. The distribution of polymorphism was analyzed in subgroups of individuals with different clinical phenotypes (hypertension, diabetic nephropathy, obesity). In this analysis, rs696217 was associated with hypertension. The presence of T allele was associated with higher risk of hypertension (OR = 2.50, 95% CI 1.68-3.73, p < 0.001). When adjusted for age, gender and BMI, the association was still significant (OR = 2.62, 95% CI 1.83-3.96, p < 0.001). A post hoc power calculations based on a minor allele frequency revealed the power of 97% for comparison between HY+ and HY- subgroups. Conclusion: This is the first study demonstrating that the ghrelin Leu72Met SNP is associated with hypertension in Caucasians with T2DM. If confirmed in larger studies in different populations, it may be a novel potential risk factor for hypertension in individuals withT2DM.

Chemotactic cytokine receptor 5 gene polymorphism: relevance to microvascular complications in type 2 diabetes.

We investigated the involvement of chemotactic cytokine receptor 5 (CCR5) gene polymorphism in microvascular complications of T2DM. All subjects were genotyped with the 59029 SNP in the CCR5 gene. The genotype/allele frequencies did not differ between T2DM patients and controls. Genotype distribution was compared in patients with and without complications (nephropathy, retinopathy and neuropathy). The frequency of A allele was significantly higher in patients with complications (OR for A allele 3.07, 95% CI 2.49-3.77). The A allele carriage was associated with diabetic nephropathy (OR 6.17, 95% CI 3.28-11.6). An association was observed between 59029 polymorphism and age at T2DM onset. The A allele was more frequent in early onset than in late onset patients. For AA homozygotes OR was 2.38 (1.19-4.76) and 2.26 (1.12-4.58) in complicated and uncomplicated subgroups, respectively. These results suggest that CCR5 gene polymorphism is associated with diabetic nephropathy in T2DM.

Polymorphism of the renalase gene in end-stage renal disease patients affected by hypertension.

BACKGROUND: Renalase is a novel flavin adenine dinucleotide-dependent amine oxidase that is secreted by the kidney. It circulates in the blood and modulates the cardiac function and systemic blood pressure. Insufficiency of renalase in patients with chronic kidney disease may explain the frequent occurrence of hypertension among patients with end-stage renal disease (ESRD) and an increased risk of cardiovascular events in this group. The aim of the study was to assess the relationship of two renalase gene polymorphisms with hypertension in dialysed patients. METHODS: Rs2576178 polymorphism was genotyped in 369 patients, rs10887800 polymorphism was genotyped in 421 dialysed patients, using polymerase chain reaction (PCR) and subsequent cleavage with Msp I and Pst I restriction endonucleases. RESULTS: Genotype distribution and allele frequencies of rs2576178 polymorphism were compared in the following subgroups of patients: dialysed patients with hypertension: ESRD HY + (n = 200) and dialysed patients without hypertension: ESRD HY - (n = 169). There was a significant difference in the frequency of the G allele carriers. G allele carriers were associated with a 1.55 times higher risk of hypertension [odds ratio (OR) = 1.55; 95% confidence interval (CI): 1.023-2.357, P = 0.039]. Distribution of genotypes and frequencies of alleles of rs10887800 polymorphism were compared in the following subgroups of patients: ESRD HY + (n = 278) and ESRD HY - (n = 143). The G allele carriers were recognized with a significantly higher frequency in ESRD HY + patients (0.46 in ESRD HY + versus 0.37 in ESRD HY - ) [OR = 1.76; 95% CI: (1.159-2.667, P = 0.008)]. CONCLUSIONS: Our results are the first to suggest an association between renalase gene polymorphisms analysed and hypertension in dialysed patients. It may be an important step towards gaining a deeper insight into cardiovascular pathophysiology. Furthermore, it might provide an optimal treatment and better prognosis for patients with chronic kidney disease.

Arginase Gene Polymorphism Increases Risk of Diabetic Retinopathy in Type 2 Diabetes Mellitus Patients.

Studies have demonstrated that polymorphic variants of arginase 1 gene (ARG1) are involved in human diseases, such as coronary heart disease, hypertension, and diabetes. Our study aimed to investigate the association between ARG1 rs2781666 single nucleotide polymorphism (SNP) and diabetic retinopathy (DR) in type 2 diabetes (T2DM) patients. Polymorphism was genotyped in 740 T2DM patients and 400 healthy individuals. A significant difference in the genotype distribution was observed between the patients and the controls. The T allele and TT genotype were associated with an increased risk of T2DM (OR 1.4, 95% CI 1.14-1.72, p = 0.001 and OR 2.16, 95% CI 1.23-3.80, p = 0.007, respectively). When the T2DM subjects were stratified into DR+ and DR- subgroups, the T allele and TT genotype frequencies were significantly higher in the DR+ group compared to the DR- group, demonstrating OR 1.68 (1.33-2.12), p < 0.0001 and OR 2.39 (1.36-4.18), p = 0.002, respectively. Logistic regression analysis was applied to determine the interaction between the ARG1 genotypes and other risk factors. Only ARG1 rs2781666 SNP was a significant risk predictor of DR (p = 0.003). In conclusion, this is the first report discussing the effect of ARG1 polymorphism on the microvascular complications that are associated with diabetes. Our findings demonstrate that ARG1 rs2781666 SNP is significantly associated with an increased susceptibility to DR in T2DM patients.

Association between p22PHOX gene C242T polymorphism and hypertension in end-stage kidney disease patients.

Oxidative stress plays an important role in hypertension associated vascular damage. It is mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation. The C242T polymorphism in the p22PHOX gene encoding essential subunit of NADPH oxidase was associated with CVD, hypertension, and endothelial function. The aim of this study was to assess a potential association of C242T polymorphism with hypertension in end-stage kidney disease (ESKD) patients. DNA samples from 495 patients were genotyped by polymerase chain reaction (PCR) with subsequent cleavage with Rsa I restriction endonuclease. There were no significant differences in genotype and allele distribution between ESKD patients and healthy controls. When patients were stratified into male and female subgroups, there were no differences in the frequency of the T allele (0.35 and 0.34, respectively). Genotype and allele frequencies were also comparable between HY+ and HY- subgroups. We analyzed whether there were any differences between genders in the effect of C242T polymorphism on the presence of hypertension by comparing HY+ males with normotensive males and HY+ females with normotensive females. No difference in polymorphism distribution was found in female subgroup. The significant differences were observed in males. In HY+ subgroup, the frequencies of T allele and TT genotype were higher than in HY- males, with OR 1.91 (1.31-2.8), p = 0.0008 and OR 4.2 (1.67-10.6), p = 0.002, respectively. In conclusion, this is the first study to demonstrate significant association of the p22PHOX gene polymorphism with hypertension in male ESKD patients, with T allele as a risk factor for hypertension.

Renalase gene Glu37Asp polymorphism affects susceptibility to diabetic retinopathy in type 2 diabetes mellitus.

AIMS: Renalase (RNLS) is an enzyme with monoamine oxidase activity that metabolizes circulating catecholamines. The RNLS gene Asp37Glu missense polymorphism (rs2296545) has been associated with hypertension, cardiac hypertrophy and dysfunction, and stroke. The purpose of our study was to investigate the potential involvement of this polymorphism in the microvascular complications of type 2 diabetes (T2DM). METHODS: In this case-control study, the polymorphism was genotyped in 860 patients with T2DM and 400 healthy controls. The genotype and allele distribution was compared in subgroups of patients: with diabetic nephropathy (DN+) (n = 405) versus DN- (independently of the presence of DR) and, similarly, patients with diabetic retinopathy (DR+) (n = 328) versus DR- (independently of the presence of DN). RESULTS: No significant association was detected between analyzed polymorphism and DN. In contrast, the retinopathy subgroup showed a significantly higher frequency of G allele (OR 1.4, 95% CI 1.16-1.72, p = 0.0005) and GG genotype (OR 1.86, 95% CI 1.26-2.75, p = 0.001) than DR- patients. The effect of RNLS Glu37Asp polymorphism on DR remained significant after adjustments for age, gender, BMI, and duration of T2DM (p = 0.005). CONCLUSIONS: This is the first study to investigate RNLS gene polymorphism in microvascular complications of T2DM. The results suggest that RNLS rs2296545 SNP might be considered a risk factor for diabetic retinopathy in T2DM patients. This can provide new insight into the role of renalase gene in the pathophysiology of microvascular complications of diabetes.

Complement factor H gene polymorphism and risk of cardiovascular disease in end-stage renal disease patients.

The main cause of increased mortality in end-stage renal disease (ESRD) is cardiovascular disease (CVD). Complement factor H (CFH) may affect risk of CVD. Our study investigates a role of CFH Y402H polymorphism as a potential risk factor of CVD in a large group of patients. A group of 1200 patients with ESRD and 818 healthy controls were genotyped for the Y402H (T1277C) polymorphism. There was a significant difference in genotype frequencies between patients with CVD and those without CVD and healthy controls (p<0.001). Homozygosity for the C allele in CVD patients was associated with an odds ratio of 7.28 (95 % CI 5.32-9.95). No significant difference was found between patients without CVD and controls. Multivariate logistic regression analysis showed that Y402H genotype was independently associated with cardiovascular comorbidity in ESRD patients. This is the first study suggesting an association between CFH gene polymorphism and susceptibility to CVD in dialyzed patients.

Heat-shock protein gene polymorphisms and the risk of nephropathy in patients with Type 2 diabetes.

HSPs (heat-shock proteins) are molecular chaperones synthesized under stress conditions, and are involved in renal cell survival and matrix remodelling in acute and chronic renal diseases. In the present study, we investigated whether the HSP70 gene polymorphisms affect susceptibility to DN (diabetic nephropathy) in patients with T2DM (Type 2 diabetes mellitus). The study group consisted of 452 patients with nephropathy. Two control subgroups involved 340 healthy individuals and 132 patients with T2DM lasting > or =10 years who were free of nephropathy. Subjects were genotyped for the HSP70-1 +190 G/C and -110 A/C, HSP70-2 +1267 A/G and HSP70-hom +2437 T/C polymorphisms by PCR, followed by digestion with restriction endonucleases. There were no statistically significant differences in genotype distribution between patients with T2DM with DN and controls for the HSP70-hom polymorphism. Significant differences were observed for HSP70-1 and HSP70-2 polymorphisms. CC homozygotes of the -110 and +190 HSP70-1 polymorphisms were more frequent in patients with T2DM with DN compared with healthy controls (22 compared with 6% and 15 compared with 6.5% respectively; P<0.01). The OR (odds ratio) for the risk allele was 2.17 [95% CI (confidence interval), 1.73-2.72] for the -110 A/C and 1.74 (95% CI, 1.40-2.15) for +190 G/C polymorphisms. A strong association with DN was found for the +1267 HSP70-2 polymorphism. The GG genotype and the G allele were associated with DN, with the OR for the G allele being 4.77 (95% CI, 3.81-5.96). All GG homozygotes in the patient group had higher LDL (low-density lipoprotein)-cholesterol levels than AA homozygotes (P<0.01), suggesting that the observed effect might be associated with this cardiovascular risk factor. These patients progressed faster to end-stage renal failure than those with other genotypes. In conclusion, our results indicate that the HSP70-1 and HSP70-2 polymorphisms are associated with renal complications in T2DM and may be useful in identifying patients with increased risk of DN.