Evidence for genetic susceptibility towards development of posttransplant lymphoproliferative disorder in solid organ recipients

BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) is a life-threatening complication after organ transplantation. The identification of risk factors for PTLD development is important for disease management. It has been shown that cytokine gene polymorphisms are associated with lymphoma and Epstein-Barr virus (EBV)-associated diseases in nonimmunosuppressed patients. In the present case-control study, we analyzed the impact of -1082 interleukin (IL)-10, -308 tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1 (codon 10, 25), and +874 interferon (IFN)-gamma gene single-nucleotide polymorphisms on the late onset EBV-associated PTLD. METHODS: Out of 1,765 solid organ recipients, 38 patients with late-onset EBV-associated PTLD and 408 matched solid organ recipients were selected and enrolled in the study. Single nucleotide polymorphisms (SNPs) for -1082IL-10, -308TNF-alpha, TGF-beta1 (codon 10, 25), and +874IFN-gamma genes were analyzed by a sequence specific primer polymerase chain reaction and were related to the PTLD development, and the disease course and outcome. RESULTS: The TGF-beta1 (codon 25) GG genotype was detected more frequently in controls than in PTLD patients (odds ratio=0.34, 95% confidence interval: 0.17-0.69, P=0.0022). The frequency of -1082 IL-10 GG genotype was also significantly higher in controls than in PTLD patients (odds ratio=0.5, 95% confidence interval: 0.25-1.0, P=0.044). There were no associations between -308TNF-alpha, TGF-beta1 codon 10, and +874IFN-gamma SNPs and PTLD. Disease course and outcome were not associated with any cytokine SNPs. CONCLUSIONS: Polymorphisms in two key anti-inflammatory cytokines, IL-10 and TGF-beta, are associated with susceptibility to EBV-associated PTLD, suggesting that a shift in pro-/anti-inflammatory response is involved in the pathogenesis of PTLD.     

Impact of cytokine gene polymorphism on cardiovascular risk in renal transplant recipients

Cardiovascular events are the leading causes of morbidity and mortality in renal transplant recipients (RTR). Given the role of inflammation in atherosclerosis, the contribution of functional polymorphisms of cytokines to cardiovascular diseases (CVD) was assessed in RTR in this study. Polymorphisms of tumour necrosis factor alpha (TNF-alpha) gene [-308 (G-->A), -238 (G-->A)], interleukin-10 (IL-10) gene [-1082(A-->G), -819 (T-->C), -592 (A-->C)], transforming growth factor beta 1 (TGF-beta1) gene [codon 10 (T-->C), codon 25 (G-->C)], carotis intima media thickness (CIMT), left ventricular mass index (LVMI), 24-h ambulatory blood pressure and serum lipoprotein homocysteine level, erythrocyte sedimentation rate, serum C-reactive protein (CRP) and serum fibrinogen level of RTR were determined. Seventy-two RTR (26 cadaveric allograft, 46 living-related allograft, 43 male, 29 female) were included in this study. LVMI were similar in TNF-alpha, IL-10 and TGF-beta1 genotypes. Right and left CIMT were higher in TT genotype (n = 16) than CT (n = 46) and CC (n = 10) genotypes of TGF-beta1 codon 10 (T-->C) gene polymorphism (RCIMT, 7.7 +/- 2.2 mm vs. 7.0 +/- 1.4 mm vs. 5.9 +/- 1.4 mm, P = 0.025; LCIMT, 8.5 +/- 2.5 mm vs. 7.0 +/- 1.3 mm vs. 6.1 +/- 1.2 mm, P = 0.002). Lipoprotein (a) level of TT genotype (35.5 +/- 22.5 mg/dl) was higher than CC (4.1 +/- 2.8 mg/dl) and CT (20.4 +/- 11.2 mg/dl) genotypes of TGF-beta1 codon 10 (T-->C) gene polymorphism (P = 0.037). High producers of cytokine IL-10 -1082 [GG (n = 22) vs. AA + AG (n = 50)] and low producers of TGF-beta codon 25 [GC + CC (n = 17) vs. GG (n = 55)] had lower IMT of carotid artery but the difference did not reach statistical significance (P > 0.05). The CIMT of renal transplant patients was similar in IL-10 (-819, -592) and TNF-alpha (-308, -238) genotypes. No difference was observed in 24-h ambulatory blood pressure levels, serum lipoproteins, plasma homocysteine level, erythrocyte sedimentation rate, serum CRP, serum fibrinogen level in IL-10, TNF-alpha and TGF-beta1 genotypes. Besides the well-known factors, TGF-beta1 gene polymorphisms might play a role in CVD in RTR even at early stages of asymptomatic atherosclerosis.     

Nonimmunologic complications and gene polymorphisms of immunoregulatory cytokines in long-term renal transplants

BACKGROUND: While the influence of cytokine gene polymorphisms on immunologic complications after organ transplantation is widely evaluated, little is known about predictive value of cytokine genotype for the development of nonimmunologic post-transplant complications: hypertension, dyslipoproteinemia, diabetes mellitus, hyperuricemia. METHODS: The -1082IL-10, -308TNF-alpha, transforming growth factor-beta1 (TGF-beta1) (codon 10, 25), -174IL-6, +874IFN-gamma gene single nucleotide polymorphisms (SNP) were studied in 278 long-term renal transplants by polymerase chain reaction-sequence specific primer (PCR-SSP) with respect to nonimmunologic post-transplant complications. RESULTS: Significant association of the TGF-beta (codon 25) GG genotype with hyperuricemia (P= 0.0013) and dyslipoproteinemia (P= 0.0171) was found. The TGF-beta1 (codon 25) CG genotype was detected more frequently in patients with normal uric acid levels. The +874IFN-gamma AA genotype was associated with type 2/steroid-induced diabetes (P= 0.0127). Frequency of the -1082IL-10 AG genotype was significantly higher in hyperuricemic patients versus controls (P= 0.0022). No associations of polymorphisms in the tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), TGF-beta codon 10 genes with hyperuricemia, dyslipoproteinemia, or diabetes were detected. We failed to observe significant differences in cytokine genotype distribution between hypertensive and normotensive patients. CONCLUSION: We established an association of particular cytokine genotypes with nonimmunologic post-transplant complications. This supports an idea that assessment of cytokine SNPs may allow more accurate prediction of nonimmunologic complications and appropriate adjustment of pre-emptive treatments in long-term transplant patients.     

Association of TGF-beta1 polymorphisms with chronic renal disease

BACKGROUND: Transforming growth factor beta1 (TGF-beta1) plays an important role in tissue fibrosis and has been found to participate in cardiovascular disease (CVD). This study aimed to evaluate the association of TGF-beta1 polymorphisms with chronic renal disease (CRD), and its progression to dialysis in a retrospective longitudinal study of an end-stage renal disease (ESRD) cohort. METHODS: The Arg/Pro (codon 25) and Leu/Pro (codon 10) polymorphisms were genotyped in 104 ESRD patients aged 64 +/- 14 yrs (mean +/- SD), 62 males, and in 104 matched controls. RESULTS: The genotype distribution of Leu10Pro and Arg25Pro polymorphisms was different between patients and controls: Leu/Leu, Leu/Pro, Pro/Pro: 0.35, 0.50, 0.15 vs. 0.30, 0.24, 0.46 (p=0.001) and Arg/Arg, Arg/Pro, Pro/Pro: 0.79, 0.21, 0 vs. 0.87, 0.10, 0.03 (p=0.019). Similarly, haplotypes constructed with the combination of both polymorphisms were different among groups. There were no differences in CRD progression rate among genotypes. Codon 10 Leu allele was associated with the presence of clinical CVD in the ESRD patients (Leu/Leu, Leu/Pro, Pro/Pro: with CVD 0.49, 0.49, 0.02 vs. without CVD 0.27, 0.51, 0.22 (p=0.01). Combined polymorphism haplotypes were also significantly different between ESRD patients with and without CVD. This association was independent from other risk factors. CONCLUSIONS: TGF-beta1 polymorphisms are associated with ESRD, particularly in patients with associated clinical CVD, and could be useful as genetic markers of CRD and higher cardiovascular risk.     

Interleukin-10-1082 G/a polymorphism and acute renal graft rejection: a meta-analysis

Objective: The aim of this study was to investigate the association between interleukin (IL)-10-1082 (G/A) promoter polymorphism and acute rejection (AR) in renal transplant recipients. Methods: We searched MEDLINE, EMBASE, Web of Science, and Cochrane Central Register from the inception to March 2015 for relevant studies. Data concerning publication information, population characteristics, and transplant information were extracted. Odds ratios (ORs) was calculated for the association between IL-10-1082 GG genotype (or IL-10-1082 G allele) and AR risk. Results: This meta-analysis included 22 case–control studies including 2779 cases of renal transplant recipients. The pooled estimate showed that the IL-10-1082 GG genotype was not significantly associated with AR risk (OR_random=1.07, 95% CI 0.80–1.43, p?=?0.64). Similarly, the pooled estimate showed that the IL-10-1082 G allele was not significantly associated with AR risk (OR_fixed=1.02, 95% CI 0.90–1.16, p?=?0.74). None of subgroup analyses yielded significant results in the association between IL-10-1082 GG genotype (or IL-10-1082 G allele) and AR risk. Meta-regression confirmed that there was no significant correlation between the pre-selected trial characteristics and our study results. Conclusions: This meta-analysis suggests that IL-10-1082 G/A polymorphism is not significantly associated with AR risk in renal transplant recipients.     

Cytokine gene polymorphisms in heart transplantation: association of low IL-10 production genotype with Quilty effect.

BACKGROUND: Cytokines are important modulators of post-transplant, allogeneic immune responses. In heart transplantation, endomyocardial biopsies allow monitoring of histologic and immunologic events that occur inside the graft; their correlation with risk factors condition graft outcome. Recent reports indicate that various cytokine gene allelic polymorphisms control the number of cytokines produced and may be associated with graft outcome. METHODS: We studied 71 heart transplant recipients between December 1985 and December 2000. We used sequence-specific primers (SSP) polymerase chain reaction to study interleukin-10 (IL-10) polymorphisms at -1082 (G/A), -819 (C/T), and -592 (C/A); tumor necrosis factor alpha (TNF-alpha) at -308 (G/A) and -238 (G/A); transforming growth factor beta (TGF-beta) variants at codon 10 (C/T) and codon 25 (G/C); and interferon-gamma (IFN-gamma) polymorphisms at +874 (T/A). We determined the association of allele, genotype, and haplotype frequencies with the presence of histologically proven rejection episodes (according to International Society for Heart and Lung Transplantation criteria) and the presence of Quilty lesions in endomyocardial biopsy specimens. RESULTS: We found no association between the polymorphisms studied and the frequency and severity of acute and chronic rejection episodes. However, the gene frequency of allele A at IL-10 -1082, associated with decreased IL-10 production, was increased in patients with Quilty lesions (p = 0.0027, odds ratio = 2.98). Similarly, we found more AA homozygous individuals, compared with AG heterozygous and GG homozygous individuals (p = 0.0017), among patients with Quilty effect. The ATA and ACC IL-10 haplotypes also were associated with Quilty effect (p = 0.0051). CONCLUSIONS: These results suggest that genetically controlled decreased IL-10 production predisposes to the development of Quilty lesions. The decreased negative regulatory effect of IL-10 on T cells and macrophages may result in enhanced graft infiltration.     

Cytokine gene polymorphisms and risks of acute rejection and delayed graft function after kidney transplantation

BACKGROUND: Pretransplantation identification of patients at an increased risk for adverse events would allow more individualized treatment strategies possibly improving long-term outcome. We studied cytokine gene polymorphisms of kidney allograft recipients and their donors to identify factors predisposing for acute rejection (AR) and delayed graft function (DGF). METHODS: A total of 291 adult cadaver kidney recipients transplanted at a single transplantation centre between 1999 and 2002 were investigated. Recipients and donors were typed for TNF-alpha(-308G/A), TGF-beta1(codon 10T/C, codon 25C/G), IL-10(-1082G/A, -819C/T, -592C/A), IL-6(-174C/G), and IFN-gamma(+874T/A) polymorphisms using a SSP-PCR kit. An AR episode was defined based on clinical and histological findings (Banff criteria). RESULTS.: The incidence of AR was 17%. In univariate statistical analyses recipients with TNF-alpha -308AA-genotype were found to be at a significantly increased risk for rejection (odds ratio [OR] 5.0, 95% CI 3.0-8.3, P = 0.003). The association was independent from the patient-donor HLA-mismatch status. In addition, patients with IL-10 ACCACC, ATAATA, GCCATA (-1082A/G, -819C/T, -592C/A, respectively) haplotypes were predisposed to rejection (OR 1.9, 95% CI 1.1-3.1, P = 0.016). Further, the combination of recipient TGF-beta1 25GG-genotype and donor IL-10 -819T-allele was associated with rejection (OR 1.8, 95% CI 1.1-3.0, P = 0.027). These variables remained significant risk factors also in a multivariate logistic regression analysis. The incidence of DGF was 22%. The risk was increased by a donor TNF-alpha -308GA-genotype (OR 1.6, 95% CI 1.1-2.6, P = 0.040). CONCLUSIONS: Our results confirm that cytokine gene polymorphisms influence the outcome of kidney transplantation. Our data especially identify the TNF-alpha -308AA-genotype as a factor predisposing for AR episodes.     

IL-10 genotype predicts serum levels of adhesion molecules, inflammation and atherosclerosis in hemodialysis patients

BACKGROUND: Hemodialysis (HD) patients suffer from inflammation and accelerated atherosclerosis that accounts for a large number of premature deaths. The anti-inflammatory interleukin (IL)-10 gene is polymorphic and potential direct effects of IL-10 gene polymorphisms on the circulating serum levels of adhesion molecules, inflammation and atherosclerosis in HD patients still have to be elucidated. METHODS: In a cross-sectional study, circulating serum levels of vascular cell adhesion molecule-1 (VCAM-1), E-selectin (E-selectin), and intracellular adhesion molecule-1 (ICAM-1), serum albumin and C-reactive protein (CRP) were measured in 121 HD patients (70 male and 51 female, with mean age 49 +/- 18 yrs). Carotid artery intima media thickness (IMT) was evaluated by Doppler ultrasonography. Patients were genotyped for the polymorphic base at position -1082 of the IL-10 promoter sequence by polymerase chain reaction (PCR). RESULTS: Circulating serum levels of all three adhesion molecules were higher in patients with -1082/AA genotype (p = 0.001). Higher serum albumin levels together with lower CRP levels were observed in patients with -1082/GG genotype (p < 0.05). Prevalence of atherosclerosis was higher in patients with -1082/AA genotype compared to heterozygous and -1082/GG genotype (41, 34 and 26%, respectively, p = 0.018). CONCLUSIONS: These results suggest that IL-10 gene polymorphism has an effect on inflammatory process and atherosclerosis in HD patients. Endothelial protective functions of IL-10 can modulate the circulating serum levels of adhesion molecules. Therefore, IL-10 gene polymorphism could lead to high or low inflammatory process and consequently, to atherosclerosis. IL-10 genotyping can define a high-risk group for atherosclerosis among HD patients.     

A meta-analysis on correlation between interleukin-6 -174G/C polymorphism and end-stage renal disease

Background: The level of interleukin-6 (IL-6) and its gene polymorphism are associated with the end-stage renal disease (ESRD) and the related complications. This study aimed to investigate the correction between IL-6 -174G/C polymorphism and ESRD by meta-analysis.

Methods: Using the databases including PubMed, Embase, Cochrane library, CNKI, and CBM, the data of case-control studies on correlation between IL-6 -174G/C polymorphism and ESRD from database establishment to January 2016 were collected. According to inclusion and exclusion criteria, the quality of literatures was evaluated. The relevant research data were extracted, followed by meta-analysis using Revman 5.3 software (London, UK). The combined odds ratio (OR) and 95% confidence interval (95%CI) of each genetic model were calculated, and the publication bias data was assessed using the Stata 12.0 software (College Station, TX).

Results: A total of five literatures were included, with 1199 cases in case group and 1089 cases in control group. Meta-analysis showed that, there was no significant correlation between each genetic model of IL-6 -174G/C polymorphism and ESRD [(C versus G): OR?=?1.36, 95%CI (0.69, 2.66), p?=?.38; (CC?+?GC versus GG): OR?=?1.28, 95%CI (0.58, 2.82), p?=?.54; (CC versus GG?+?GC): OR?=?1.71, 95%CI (0.82, 3.54), p?=?.15; (CC versus GG): OR?=?1.74, 95%CI (0.76, 3.99), p?=?.19; (GC versus GG): OR?=?1.18, 95%CI (0.55, 2.54), p?=?.67]. The race subgroup analysis showed that, there was no significant correlation between each genetic model of IL-6 -174G/C polymorphism and ESRD in the Caucasians (p?>?.05).

Conclusion: IL-6 -174G/C polymorphism has no significant correlation with the susceptibility risk of ESRD, and may not be a risk factor for ESRD.     

Impact of Nitric Oxide Synthase Glu298Asp Polymorphism on the Development of End-Stage Renal Disease in Type 2 Diabetic Egyptian Patients

Abstract

Background: Nitric oxide is an important regulator of renal hemodynamics. This study aimed to investigate the role of endothelial nitric oxide synthase (eNOS) gene polymorphism in type 2 diabetic patients with end-stage renal disease (ESRD) and to elucidate any alteration of nitric oxide synthase (NOS) activity caused by this polymorphism. Methods: The study included 80 patients with type 2 diabetes of >10 years duration (40 with diabetes-derived ESRD, 40 without nephropathy) and 20 healthy controls. Plasma nitrate/nitrite level, and serum NOS activity were measured and eNOS Glu298Asp genotypes were determined. Results: The frequency of Glu/Glu (GG) genotype in diabetics with ESRD was lower than controls. However, the frequency of Asp/Asp (TT) genotype was increased in diabetics with ESRD as compared to those without nephropathy and controls. Diabetics with ESRD had significantly lower nitrate/nitrite level and NOS activity than those without nephropathy. Diabetic patients with TT genotype are at a significant risk for ESRD. Moreover, subjects carrying TT genotype had lower nitrate/nitrite level and NOS activity than those carrying GG genotype. In diabetics with ESRD, creatinine clearance was positively correlated with both nitrate/nitrite level and NOS activity. Conclusions: These results imply that TT genotype of eNOS may be associated with an increased risk of ESRD in Egyptian type 2 diabetics. It could represent a useful genetic marker to identify diabetics at high risk for the development of ESRD. However, larger future prospective studies are required to confirm the role of eNOS gene polymorphism in the progression of diabetic nephropathy to ESRD.     

Role of TGF-beta1 in renal parenchymal scarring following childhood urinary tract infection.

BACKGROUND: Significant variability exists in the outcome of renal parenchymal inflammation following urinary tract infection (UTI) in childhood as some children experience renal parenchymal scarring (RPS) while others do not scar. Since TGF-beta1 is pro-fibrotic, we examined the role of this cytokine in RPS following UTI. METHODS: Five polymorphisms of the TGF-beta1 gene were investigated as well as the relationship between these polymorphisms and TGF-beta1 production by peripheral blood mononuclear cells (PBMC) in vitro. DNA was isolated from 91 children shown to have developed RPS, 43 children with no evidence of scarring (NS) following UTI, and 171 healthy controls. Genotyping was performed by restriction fragment length polymorphism (RFLP). PBMC were isolated from a subgroup of 24 patients from the total population. Cells were stimulated with LPS + PMA + PHA and then TGF-beta1 production was determined by ELISA. RESULTS: Comparing the NS with the RPS group, there was an increase in the -800 GA genotypes (18.6 vs. 7.4%, P=0.05; chi2) and the Leu10-->Pro CT (62.8 vs. 41.5%, P=0.021), and a decrease in the -509 TT genotype (0.0 vs. 8.5%, P=0.049). PBMC TGF-beta1 production was higher in those patients with the -800 GG compared to those with a GA genotype stimulation index [stimulated/unstimulated TGF-beta1 levels were 1.54 interquartile range (IQR) 1.42 to 1.75 vs. 1.19, IQR 0.94 to 1.51, P=0.031]. CONCLUSIONS: There is an association between the TGF-beta1 -800 GA, -509 TT and Leu10-->Pro CT genotypes and the presence or absence of RPS. The low TGF-beta1 producer status of the -800 GA genotype may protect against the development of a pro-fibrotic pathology.     

Polymorphisms in NADPH oxidase CYBA gene modify the risk of ESRD in patients with chronic glomerulonephritis

End-stage renal disease (ESRD) was defined as start of renal replacement therapy or death due to kidney disease. However, death due to acute kidney injury was not included. It typically occurs when chronic renal failure progresses to a point where the kidneys are permanently functioning at less than 10% of their capacity. Oxidative stress (OS) plays a crucial role in ESRD. Nicotinamide adenine dinucleotide phosphate (NADPH) is one of the most important enzymes during oxidative stress. Cytochrome b light chain (CYBA), encoded by a polymorphic gene, which is a critical component of the nicotinamide adenine dinucleotide (NADH)/NADPH oxidase system and plays an important role in electron transport and superoxide anion production, is located on chromosome band 16q24 and has six exons spanning almost 7.76 kb of genomic DNA. CYBA gene polymorphisms can influence the activity of NADPH oxidase. To evaluate the association between CYBA gene polymorphisms and ESRD, we genotyped five CYBA polymorphisms using TaqMan allelic discrimination assay on DNA samples from 306 healthy controls and 332 patients with ESRD. Our results suggested that rs1049255 polymorphism of CYBA modified the risk of ESRD (p = 0.019; OR = 0.625; 95%CI = 0.424–0.921). GG genotype and G allele might be a protective factor against the risk of ESRD, especially in patients with chronic glomerulonephritis.     

Association of interleukin-6 -174G/C promoter polymorphism with hypertension and left ventricular hypertrophy in dialysis patients

BACKGROUND: Gene polymorphisms of proinflammatory cytokines, such as interleukin-6 (IL-6) and the chemokine receptor CX3CR1, have been found in association with cardiovascular disease in the general population. In dialysis patients, in whom the prevalence of cardiovascular comorbidity is strikingly high, these polymorphisms have not been investigated. METHODS: The -174G/C polymorphism of the IL-6 gene and the chemokine receptor CX3CR1 polymorphisms 249V/I and 280T/M were examined for their association with cardiovascular abnormalities in a cohort of 161 patients with end-stage renal disease (ESRD) treated by hemodialysis. Arterial blood pressure, electrocardiogram (ECG) ischemic changes, and left ventricular mass index (LVMI) were the parameters examined for the association study. The control group was made up of 169 healthy subjects. RESULTS: We found that for both IL-6 and chemokine receptor, genotype frequency and allelic distribution in both ESRD patients and controls were comparable. The genetic association study showed that in the whole group of dialysis patients, individuals with GC + CC genotype for the -174G/C polymorphism had a higher diastolic blood pressure (P = 0.008) and LVMI (P = 0.026) than GG homozygotes. The prevalence of left ventricular hypertrophy (LVH) in the former group was 58.6% vs. 39.2% in the latter (P = 0.02). The same analysis limited to diabetic patients in dialysis, showed that the prevalence of LVH in those with CG + CC genotype was 87.5% vs. 36.3% in those with GG genotype (P = 0.02). In diabetic patients, lower levels of serum albumin was found in the GC + CC genotypic group than in GG subjects; 34.63 +/- 5.18 g/L vs. 41.75 +/- 4.79 g/L (P = 0.003). CONCLUSION: These data demonstrate an association between the IL-6 promoter polymorphism -174G/C and high blood pressure and LVH in hemodialysis patients, especially those with diabetes. The results strengthen the hypothesis that chronic inflammation is a mechanism of cardiovascular damage in dialysis patients and the role played by the IL-6 system in this mechanism.     

An interleukin-10 promoter polymorphism may influence tumor development in renal cell carcinoma

PURPOSE: Polymorphisms in the promoter of the interleukin-10 (IL-10) gene may influence tumor development by altering the levels of IL-10 present in the serum or tumor microenvironment. In this study we looked for evidence of specific polymorphisms of the IL-10 promoter and whether lymphocyte expression of IL-10 correlates with specific genotypes. MATERIALS AND METHODS: Archival, paraffin embedded renal cell carcinoma tissue from 166 patients and 161 controls were genotyped for the IL-10-1082 single nucleotide polymorphism using real-time polymerase chain reaction. IL-10 protein expression in peripheral blood lymphocytes was assessed by standard enzyme-linked immunoassay in 32 patients with renal cancer. RESULTS: Patient-to-control comparisons identified the AA genotype to be significantly greater in patients with renal cell carcinoma (44% vs 30%, p <0.05). However, study of IL-10 protein expression in peripheral blood lymphocytes from patients with renal cancer showed no statistical difference in IL-10 expression among the GG, AA or AG genotypes. CONCLUSIONS: We found that there was a significantly larger proportion of patients with renal cell carcinoma with the AA homozygous genotype than in a normal population cohort. This result is in accordance with those in previous studies of prostate cancer and cutaneous malignant melanoma. In contrast to previous studies of other tumor types, no correlation could be established between IL-10-1082 polymorphism and serum IL-10.     

VEGF -460 genotype plays an important role in progression to chronic kidney disease stage 5.

BACKGROUND: Changes in renal vasculature, with vascular and interstitial fibrosis, are hallmarks of progression to chronic kidney disease (CKD) stage 5. Vascular endothelial growth factor (VEGF) is a potent angiogenic and vascular permeability factor. Transforming growth factor-beta1 (TGF-beta1) plays a critical role in promoting extracellular matrix (ECM) deposition and fibrosis. This study investigates whether genetic polymorphisms of VEGF or TGF-beta1 are associated with (i) progressive decline in renal function in patients with glomerular disorders (cohort 1) and (ii) predisposition to CKD stage 5 in a separate group of renal transplant recipients with various primary diseases (cohort 2). METHODS: Two patient groups were studied. Cohort 1 comprised 91 patients with biopsy-proven glomerular disease who were followed-up for 5 years before categorization as either non-progressors (with stable serum creatinine or < or =30% increase over 5 years, n = 39) or progressors (requiring dialysis, transplantation or whose serum creatinine increased by >30% over 5 years, n = 52). Cohort 2 comprised 107 patients with various primary renal diseases, who had reached CKD stage 5 and undergone renal transplantation at the time of study. All patients were genotyped for the VEGF polymorphisms at positions -460 (C/T) and +405 (G/C). Linkage disequilibrium (LD) was established using EHplus. SNPHAP was used to estimate haplotype frequency and to infer haplotypes to all patients. Cohort 1 patients were genotyped for the TGF-beta1 polymorphisms at positions -800, -509, codons 10 and 25. Genotyping was performed by polymerase chain reaction-restriction length polymorphism (PCR-RFLP). RESULTS: In cohort 1, there was a significant increase in frequency of the -460 VEGF CC genotype 30.8 vs 5.1%, P = 0.008; odds ratio (OR), CC vs TT 10.67, 95% confidence interval (CI), 1.94-58.72 and C allele 56.7 vs 37.2%, P = 0.009; OR 2.22, 95% CI, 1.21-4.04, in the progressor patients when compared with the non-progressors. In cohort 2, there was a significant increase in the VEGF -460 CC genotype when compared with healthy volunteers 37 vs 20.8%, P = 0.011; OR CC vs TT 1.59, 95% CI, 0.72-3.51. The -460 and +405 polymorphisms were in LD P < 0.00007. There were significant differences in diplotype (haplotype pair) frequencies in cohort 1 and 2, P = 0.018, which confirmed the importance of the -460C allele. There were no associations between the VEGF +405 or TGF-beta1 polymorphisms and progressive renal disease. CONCLUSION: In this study, we have demonstrated an association between the VEGF -460 polymorphism and progression to CKD stage 5. The function of this polymorphism remains unclear although previous evidence suggests that promoter constructs containing this single nucleotide polymorphism (SNP) have been associated with increased activity. Clearly there is a role for TGF-beta1 in chronic kidney disease. However, this study found no associations with four TGF-beta1 polymorphisms in this cohort.     

Genetic polymorphisms of the renin-angiotensin-aldosterone system in end-stage renal disease.

BACKGROUND: Hypertension contributes to the progression to renal failure. A genetic susceptibility to hypertension may predispose to the development of end-stage renal disease (ESRD) and promote a more rapid progression to ESRD in patients with renal diseases. Genes encoding for angiotensinogen (AGT), angiotensin-converting enzyme (ACE), and aldosterone synthase (CYP11B2) are candidates for abnormal blood pressure regulation. METHODS: Genotyping was performed in 327 control subjects and 260 ESRD patients for the M235T-AGT, the insertion/deletion (I/D)-ACE, and the -344T/C-CYP11B2 gene polymorphisms using polymerase chain reaction, gel analysis, and appropriate restriction digest when required. RESULTS: Genotype frequencies did not differ significantly between ESRD patients and controls. When ESRD diabetic subjects were compared with diabetic patients without nephropathy, the prevalence of the AGT-MM genotype was lower (28.1 vs. 52.8%, P < 0.01), while the AGT-TT genotype was higher (15.6 vs. 2.7%, P < 0.05). The AGT-TT genotype was associated with a faster progression to ESRD in patients with glomerulonephritis (P < 0.05). In the total ESRD population, progression of renal disease was faster with the ACE-DD than with the DI and II alleles (P < 0.05). This association was particularly strong when the interaction with the AGT genotype was analyzed, with a rapid progression in ACE-DD as compared with ACE-DI and II in patients with the AGT-MM genotype (P < 0.01). CONCLUSIONS: Susceptibility for ESRD and faster progression to ESRD are linked with the AGT genotype in diabetic patients. Faster progression to ESRD is associated with the ACE genotype when the total population with ESRD and with the AGT genotype when patients with glomerulonephritis are considered. Thus, genes of the renin-angiotensin-aldosterone system are candidate genes for further understanding of the interindividual differences in the development and course of ESRD.     

Genetic association of interleukin-4, interleukin-10, and transforming growth factor-beta gene polymorphism with allograft function in renal transplant patients

Despite advances in immunosuppressive therapy in the past decade, allograft rejection remains the primary cause for kidney graft failure. Cytokines are known to be important mediators in renal allograft outcome. The aim of the present study was to ascertain whether interleukin (IL)-4, IL-10, and transforming growth factor (TGF)-beta cytokine gene polymorphisms contributed to kidney graft outcome. We evaluated single nucleotide polymorphism in IL-4 (-1098G/T, -590C/T, -33C/T), IL-10 (-1082A/G, -819C/T, -592A/C), and TGF-beta (codon 10 and 25) in 100 renal transplant recipients and 139 normal healthy control using polymerase chain reactions based on sequence-specific primers. Recipients were clinically characterized as rejection episode (RE) versus stable graft function (SGF). The results showed the frequencies of IL-4 -33 T allele in the RE, SGF, and control group to be 7%, 73%, and 28%, respectively. IL-10 -592 A allele frequency was 39% in RE, 26% in SGF, and 28% in the control group. TGF-beta codon 10 T allele was 39% in RE, 35% in SGF, and 53% in control group. In conclusion, this study suggested that some cytokine gene alleles reflected SGF among kidney transplant recipients.     

The effect of cytokine gene polymorphisms on pediatric heart allograft outcome.

BACKGROUND: Cytokines play a major role in the inflammatory and immune responses that mediate allograft outcome. Several studies have shown that the production of cytokines varies among individuals and these variations are determined by genetic polymorphisms, most commonly within the regulatory region of the cytokine gene. The aim of this study was to assess the effect of these allelic variations on acute rejection after pediatric heart transplantation. METHODS: We performed cytokine genotyping using polymerase chain reaction-sequence specific primers in 93 pediatric heart transplant recipients and 29 heart donors for the following functional polymorphisms: tumor necrosis factor-alpha (TNF-alpha) (-308), interleukin (IL)-10 (-1082, -819, and -592), TGF-beta1 (codon 10 and 25), IL-6 (-174), and interferon-gamma (INF-gamma) (+874). The distribution of polymorphisms in this population did not differ from published controls. The patients were classified as either non-rejecters (0 or 1 episode) or rejecters (> 1 episode) based on the number of biopsy proven rejection episodes in the first year after transplantation. RESULTS: Forty-two of the 69 TNF-alpha patients (61%) in the low producer group were non-rejecters, while 9 of the 24 (37.5%) with high TNF-alpha were non-rejecters (p = 0.047). In contrast, IL-10 genotype showed the opposite finding. Forty-two of the 66 patients (64%) in the high and intermediate IL-10 group were non-rejecters, while 9 of the 26 (35%) in the low IL-10 group were non-rejecters (p = 0.011). The combination of low TNF-alpha with a high or intermediate IL-10 genotype was associated with the lowest risk of rejection (34/49 or 69% non-rejecters). Neither the distribution of the IL-6, INF-gamma, and TGF-beta1 genotype in recipients nor the donor genotype showed any association with acute rejection. CONCLUSION: Genetic polymorphisms that have been associated with low TNF-alpha and high IL-10 production are associated with a lower number of acute rejection episodes after pediatric heart transplantation.