Impact of donor and recipient cytokine genotypes on renal allograft outcome

Allelic differences in gene promoter or codifying regions have been described to affect regulation of gene expression, consequently increasing or decreasing cytokine production and signal transduction responses to a given stimulus. This observation has been reported for interleukin (IL)-10 (-1082 A/G; -819/-592 CT/CA), transforming growth factor (TGF)-beta (codon 10 C/T, codon 25 G/C), tumor necrosis factor (TNF)-alpha (-308 G/A), TNF-beta (+252 A/G), interferon (IFN)-gamma (+874 T/A), IL-6 (-174 G/C), and IL-4R alpha (+1902 G/A). To evaluate the influence of these cytokine genotypes on the development of acute or chronic rejection, we correlated the genotypes of both kidney graft recipients and cadaver donors with the clinical outcome. Kidney recipients had 5 years follow-up, at least 2 HLA-DRB compatibilities, and a maximum of 25% anti-HLA pretransplantation sensitization. The clinical outcomes were grouped as follows: stable functioning graft (NR, n = 35); acute rejection episodes (AR, n = 31); and chronic rejection (CR, n = 31). The cytokine genotype polymorphisms were defined using PCR-SSP typing. A statistical analysis showed a significant prevalence of recipient IL-10 -819/-592 genotype among CR individuals; whereas among donors, the TGF-beta codon 10 CT genotype was significantly associated with the AR cohort and the IL-6 -174 CC genotype with CR. Other albeit not significant observations included a strong predisposition of recipient TGF-beta codon 10 CT genotype with CR, and TNF-beta 252 AA with AR. A low frequency of TNF-alpha -308 AA genotype also was observed among recipients and donors who showed poor allograft outcomes.     

IL-10 polymorphisms and prostate cancer risk: a meta-analysis

Evidence is accumulating that chronic inflammation may have an important role in prostate cancer (PCa). Three common polymorphisms in the promoter of interleukin-10 (IL-10) gene, -1082 A>G, -819 C>T and -592 C>A, have been implicated to alter the risk of PCa, but the results of relative studies are inconclusive or controversial. To derive a more precise estimation of the relationship, we performed an updated meta-analysis on the basis of 10 studies. A comprehensive search was conducted to examine all the eligible studies of IL-10 polymorphism and PCa risk. We used odds ratios (ORs) to assess the strength of the association, and 95% confidence intervals (CIs) give a sense of the precision of the estimate. Overall, there were no significant associations between increased risk of PCa and IL-10 -1082 A>G, -819 C>T and -592 C>A polymorphisms. However, meta-analysis suggested that IL-10 -819 C>T and -592 C>A polymorphisms might be modestly associated with PCa aggressiveness (T versus C, OR=1.162, 95% CI: 1.035-1.305, P=0.011; A versus C, OR=1.131, 95% CI: 1.012-1.264, P=0.030; respectively). IL-10 -819 C>T and -592 C>A polymorphisms might impact PCa progression. Variant alleles at both -819 and -592 were modestly associated with advanced stages of PCa. Additional well-designed studies are warranted to validate these findings.     

Genetic polymorphisms impact the risk of acute rejection in pediatric heart transplantation: a multi-institutional study

OBJECTIVE: The objective of this study was to determine the association between the genetic polymorphisms of proinflammatory and regulatory cytokines and long-term rates of repeat and late acute rejection episodes in pediatric heart transplant (PHTx) recipients. METHODS: Three hundred twenty-three PHTx recipients: 205 White non-Hispanic, 43 Black non-Hispanic, and 75 Hispanic were analyzed for time to first repeat and late acute rejection episodes by race, age at transplantation, and gene polymorphism (interleukin [IL]-6, -174 G/C, IL-10, -1082 G/A, -819 C/T, 592 C/A; vascular endothelial growth factor (VEGF) -2578 C/A, -460 C/T, +405 C/G; tumor necrosis factor alpha (TNF-alpha)-308 G/A). RESULTS: Recipient black race and older age at transplant were risk factors for both repeat and late rejections, though black race was more significantly related to late rejection (P=0.006). Individually, TNF-alpha high, IL-6 high, VEGF high, and IL-10 low phenotypes did not impact the risk of repeat or late rejection. However, the combination VEGF high/IL-6 high and IL-10 low was associated with increased estimated risk of late rejection (P=0.0004) and only marginally with repeat rejection (P=0.051). In a multivariate analysis, adjusting for age and race, VEGF high/IL-6 high and IL-10 low still remained an independent risk factor for late acute rejection (RR=1.91, P<0.001). CONCLUSION: This is the largest multicenter study to document the impact of genetic polymorphism combinations on PHTx recipients' outcome. The high proinflammatory (VEGF high/IL-6 high) and lower regulatory (IL-10 low) cytokine gene polymorphism profile exhibited increased risk for late rejection, irrespective of age and race/ethnicity.     

Association of TNF‐α, TGF‐β1, IL‐10, IL‐6, and IFN‐γ gene polymorphism with acute rejection and infection in lung transplant recipients

Infection and rejection are common complications faced by lung transplant recipients (LTRs) and have become major impediments to long‐term survival. Cytokines may play an important role in the development of these complications. In this study, we explored the correlation between TNF‐α (?308 A/G), TGF‐β1 (+869 T/C, +915 G/C), IL‐10 (?592 C/A, ?819 T/C, ?1082 G/A), IL‐6 (?174 G/C), and IFN‐γ (+874 T/A) gene polymorphisms and the incidence of acute rejection and infection. Transplant outcomes were reviewed in a retrospective cohort of 113 LTRs from a single center between December 2004 and November 2012. Cytokine polymorphisms were measured using sequence‐specific primer‐based PCR. HLA typing was performed for the donors and recipients. We found that the LTRs with the IL‐10 ?819 CC and ?592 CC genotypes had a significantly decreased risk of infection (p = 0.017, OR = 0.177, 95% CI = 0.04–0.85). However, we found no significant association between cytokine polymorphisms and acute rejection. Furthermore, the data revealed that the occurrence of acute rejection was strongly associated with infection episodes (χ² = 8.5256, p < 0.01). These results suggest that LTRs possessing the IL‐10 ?819 CC and ?592 CC genotype may be protected from the occurrence of infection. Our results demonstrated that infection is an important cause of acute rejection for LTRs.     

A study of cytokine gene polymorphisms and protein secretion in renal transplantation

Although there is evidence that cytokine gene polymorphisms are associated with varying quantities of cytokine protein production, the exact role of these polymorphisms in allograft rejection remains unclear. In a previous study, we demonstrated a significant association between high IL-10 secretion in mixed lymphocyte culture (MLC), together with HLA mismatching for at least 4-6 antigens, with the occurrence of acute rejection following renal transplantation. We, therefore, wished to ascertain whether cytokine gene polymorphisms are associated with varying levels of protein secretion and/or allograft rejection in the same group of patients. Cytokine protein secretion in MLC for IL-4, IL-6, IL-10 and IFN-gamma was measured by ELISA in 49 patient-donor pairs. Protein secretion for the above cytokines was also measured in phytohaemagglutinin (PHA) stimulated cultures in 30 normal controls. In both patient and control groups, single nucleotide polymorphism analysis for IL-4 G(-590)T, IL-6 G(-174)C, IL-10 G(-1082)A, IL-10 C(-819)T, IL-10 C(-592)A, TNF-alpha G(-308)A and microsatellite analysis for IFNG (CA repeat) was performed. No correlation was found between cytokine gene polymorphisms and cytokine protein secretion in either mitogen stimulated cultures (control group) or MLC (patient group). In addition, no correlation was demonstrated between cytokine gene polymorphisms and renal allograft rejection.     

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.     

Association of four DNA polymorphisms with acute rejection after kidney transplantation

Renal transplant outcomes exhibit large inter-individual variability, possibly on account of genetic variation in immune-response mediators and genes influencing the pharmacodynamics/pharmacokinetics of immunosuppressants. We examined 21 polymorphisms from 10 genes in 237 de novo renal transplant recipients participating in an open-label, multicenter study [Cyclosporine Avoidance Eliminates Serious Adverse Renal-toxicity (CAESAR)] investigating renal function and biopsy-proven acute rejection (BPAR) with different cyclosporine A regimens and mycophenolate mofetil. Genes were selected for their immune response and pharmacodynamic/pharmacokinetic relevance and were tested for association with BPAR. Four polymorphisms were significantly associated with BPAR. The ABCB1 2677T allele tripled the odds of developing BPAR (OR: 3.16, 95% CI [1.50–6.67]; P  =   0.003), as did the presence of at least one IMPDH2 3757C allele (OR: 3.39, 95% CI [1.42–8.09]; P  =   0.006). BPAR was almost fivefold more likely in patients homozygous for IL-10 -592A (OR: 4.71, 95% CI [1.52–14.55]; P  =   0.007) and twice as likely in patients with at least one A allele of TNF-α G-308A (OR: 2.18, 95% CI [1.08–4.41]; P  =   0.029). There were no statistically significant interactions between polymorphisms, or the different treatment regimens. Variation in genes of immune response and pharmacodynamic/pharmacokinetic relevance may be important in understanding acute rejection after renal transplant.     

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.     

Cytokine gene polymorphism in kidney transplantation--impact of TGF-beta 1, TNF-alpha and IL-6 on graft outcome

Chronic allograft nephropathy (CAN) is one of the main causes of graft loss in renal transplantation. Polymorphisms with functional significance in the promoter and coding regions of cytokine genes have been suggested as a possible factor for graft rejection. The aim of this study was to investigate the impact of cytokine gene polymorphism of pro and anti-inflammatory cytokines on development of CAN in a group of renal transplant patients and donors. Eight single nucleotide polymorphisms (SNPs) including TNFA (-308), TGFB1 (cdns10, 25), IL-10 (-1082, -819, -592), IL-6 (-174) and IFNG (+874) were analyzed in 56 patients with stable graft function (SGF), 10 with CAN and 28 kidney donors by PCR-SSP method. CAN was significantly associated with the recipient TGFB1 cod10 T/T and combination of cods10, 25 T/T G/G genotypes (high producer), (p<0.05). Influence of patient's TNFA genotype correlated with high level of gene expression on the development of CAN was further demonstrated when the patients were stratified according to the HLA mismatches (HLA-DRB MMs). Additionally donor TNFA-308 G/A (high) and IL-6-174 CC (low) genotypes were increased in cases with CAN. No statistically significant differences in distribution of IL-10, IL-6 and IFNG genotypes between recipients with SGF and CAN were found. In conclusion our data suggest that the high producer genotype of profibrogenetic TGF-beta1, pro-inflammatory TNF-alpha and genetically determined low production of immunoregulatory IL-6 cytokine might be risk factors for CAN development.     

Cytokine polymorphisms do not influence acute rejection in renal transplantation under tacrolimus-based immunosuppression

INTRODUCTION: Acute rejection remains an important cause of graft loss after renal transplantation. It has been suggested that cytokine genotyping may play a predictive role in identifying individuals who are at higher risk of acute rejection with a view to individualizing their immunosuppression. The aim of this study was to investigate any possible associations between acute rejection and certain cytokine polymorphisms. METHODS: We genotyped 91 cadaveric renal transplant recipients on tacrolimus-based immunosuppression and 84 of their donors. The cytokine polymorphisms studied were the following: tumor necrosis factor (TNF)-alpha-1032 T/C, TNF-alpha-865 C/A, TNF-alpha-859 G/A, interleukin (IL)1-R1-970 C/T, IL-10 haplotype [-1082, -819, -592], and IL-6-174 C/G. RESULTS: We found no association between any polymorphism and the incidence of acute rejection. This was true for both the recipient and donor population. CONCLUSION: Cytokine polymorphisms did not influence acute rejection in our study. We conclude that in the modern era of immunosuppression cytokine genotyping is not a significant predictor of acute rejection in renal transplantation.     

Vascular endothelial growth factor gene polymorphisms are associated with acute renal allograft rejection.

Acute rejection is a major cause of reduced survival of renal allografts. Vascular endothelial growth factor (VEGF) is a mitogen for endothelial cells and is expressed widely by renal tissue and T cells. VEGF influences adhesion and migration of leukocytes across the endothelium. This study investigates whether genetically determined variation in VEGF expression influences the development of renal allograft rejection. VEGF promoter polymorphisms were examined by using sequence-specific primer-PCR in 173 renal transplant recipients. Acute rejection occurred in 38.7%; median time to first rejection episode was 14 d. VEGF in vitro expression was investigated in stimulated leukocytes from 30 controls. The -1154*G and -2578*C alleles were associated with higher VEGF production. VEGF -1154 GG and GA genotypes were significantly associated with acute rejection risk at 3 mo (P = 0.004, odds ration [OR] = 6.8, 95% CI = 1.8 to 25 and P = 0.035, OR = 4.1, 95% CI = 1.1 to 15, respectively). Furthermore, VEGF -2578 CC and CA genotypes were associated with increased rejection risk (P = 0.005, OR = 4.1, 95% CI = 1.5 to 11.3 and P = 0.035, OR = 2.7, 95% CI = 1.1 to 7, respectively). These polymorphisms demonstrate linkage disequilibrium (P = 0.001). These data indicate that the -1154*G and -2578*C containing genotypes, encoding higher VEGF production, are strongly associated with acute rejection and may be useful markers of rejection risk.     

Cytokine gene polymorphism and postreperfusion syndrome during orthotopic liver transplantation

The molecular basis underlying the clinical response to acute liver stress remains to be clarified. Postreperfusion syndrome (PRS) occurring after the meeting of grafted liver with the recipient blood is characterized by hemodynamic instability that develops immediately after reperfusion of an orthotopic liver transplantation (OLT). Cytokines have a role during PRS. The aim of this study was to evaluate the role of some cytokine gene polymorphisms on PRS in patients. MATERIALS AND METHODS: Forty-six patients who underwent OLT were divided into two groups: with versus without PRS. Cytokine genotyping using patient blood was determined by the PCR-SSP method. RESULTS: Liver transplant patients as a whole are usually characterized as low producers of tumor necrosis factor (TNF)-alpha and interleukin (IL)-10, high producers of transforming growth factor (TGF)-beta1 and IL-6 and intermediate producers of interferon (IFN)-gamma. However no significant relationship was shown between the development of PRS and cytokine gene polymorphisms of TNF-alpha (-308 G/A), TGF-beta1 (C/T codon 10, C/G codon 25), IL-10 (-1082 G/A, -819 T/C, -592 A/C), IL-6 (-174 G/C), or IFN-gamma (+874 A/T). CONCLUSION: It seemed that our limited data did not substantiate a role of certain cytokine gene polymorphisms on PRS occurence during OLT. A larger study population may be required to examine this relationship.     

肝移植受者IL-10基因启动子多态性与急性排斥反应的关系

目的探讨肝移植受者白细胞介素10(IL-10)基因多态性与急性排斥反应的关系.方法应用PCR限制性片段长度多态性分析法,检测122例肝移植受者IL-10基因启动子的2个多态位点-1082和-592的各种基因型的分布,并分析它们与急性排斥反应的关系.结果IL-10-592位点,A/A,C/A,C/C等基因型间的急性排斥反应发生率分别为16.7%,19%,29%,相互比较,差异不显著(P>0.05);IL-10-1082位点,尽管G/G基因型的急性排斥反应发生率(33%)高于A/A型(18%),但差异仍不显著(P>0.05).结论IL-10基因多态性与肝移植受者术后急性排斥反应无确切关系.     

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.     

Cytokine gene polymorphisms and acute liver graft rejection: a meta-analysis.

In the field of liver transplantation, 7 reports have been published investigating the association between polymorphisms in cytokine genes and the occurrence of acute rejection in liver graft recipients. However, most of the individual studies lack the statistical power to detect a small-to-moderate effect of cytokine gene polymorphisms on the acute rejection rate. To overcome this problem, we performed a quantitative meta-analysis of 7 gene-association studies that were comparable with regard to definition of acute rejection and the type of immunosuppression used. In the overall analysis, the interleukin (IL)-10 polymorphism at position -1082 was identified as a genetic risk factor for acute liver graft rejection; liver transplant recipients carrying the IL-10 -1082.A allele displayed a lower rejection rate (common odds ratio [OR], .6; 95% confidence interval [CI], .4-.9). For the tumor necrosis factor (TNF)-A -308 polymorphism, a common OR could not be calculated due to significant heterogeneity of ORs between the studies (mean OR, 1.4; 95% CI, .8-2.6). No associations were found between acute liver graft rejection and single nucleotide polymorphisms in the IL-6 (position -174) and transforming growth factor (TGF)-beta1 (positions +869 and +915) genes. In conclusion, results from this meta-analysis suggest a role for the IL-10 -1082 polymorphism in human liver graft rejection.     

Frequencies at three polymorphic sites of interleukin-10 gene promoter in Brazilian renal recipients

We genotyped by PCR-RFLP 141 renal patients (77 men and 64 women with ages between 12 and 58, predominantly Caucasians) for allelic variants of three polymorphic sites of the interleukin-10 gene promoter, previously showed to be associated with different production of IL-10 cytokine: -1082 (G/A), -819 (C/T), and -592 (C/A). These polymorphisms may confer flexibility in the common immune responses and influence the outcome of allo-responses after transplantation. Our aim was to determine the frequencies of three functional polymorphic sites -1082, -819, and -592 of the interleukin-10 gene promoter in renal recipients of Curitiba, Paraná. Paraná State is located in southern Brazil, and its capital is Curitiba with approximately 1.5 million inhabitants. Genotypes were classified as follows: "low" IL-10 producer genotypes (ATA/ATA, ACC/ATA, ACC/ACC), "intermediate" genotypes (GCC/ACC, GCC/ATA), and "high" IL-10 producer genotype (GCC/GCC). In our population we observed linkage disequilibrium between alleles -819C and -592C and this haplotypic combination was more frequent (65%) than -819T and -592A. We found significantly reduced frequency of the genotype and haplotype responsible for high production of interleukin-10, maybe because we have a selected group (only renal patients) or maybe because Brazilian people are very heterogeneous (miscegenational), which may differ from other groups.     

Association of cytokine polymorphisms with subclinical progressive chronic allograft nephropathy in Japanese renal transplant recipients: Preliminary study

BACKGROUND: The present study calculated the risk of developing subclinical progressive chronic/sclerosing allograft nephropathy (CAN) under tacrolimus-based immunosuppression according to genetic polymorphisms of cytokines and growth factors, and clinical events including delayed graft function (DGF), acute rejection (AR) and cytomegalovirus (CMV) infection. METHODS: The subjects were 50 recipients with stable graft function more than one year after renal transplantation. The criteria for subclinical progressive CAN were CAN grade 2 or 3 changes on Banff classification and stable serum creatinine (SCr) levels. Ten genetic polymorphisms were assessed. RESULTS: Eleven patients (22.0%) developed progressive CAN. The mean ages and SCr levels of recipients with and without progressive CAN were 41.2 and 47.1 years, and 1.46 and 1.22 mg/dL, respectively. There were no significant differences in donor age, number of HLA mismatches, DGF or CMV infection. Although the rate of AR episode seemed to be greater in patients with subclinical progressive CAN, the difference did not reach significance (P = 0.093). The frequencies of the interleukin (IL)-2 T-330G TT genotype (P = 0.046) and IL-4 C-590T C allele (P = 0.092) were higher in patients with progressive CAN. In univariate analysis, the presence of IL-2 T-330G TT (OR 4.57, P = 0.044) was associated with CAN development. CONCLUSION: The presence of IL-2 T-330G TT genotype may be a risk factor for CAN. Further studies with a large number of subjects and analyses of many cytokine polymorphisms would contribute to the ability to make prognostic determinations or tailor immunomodulatory regimens after renal transplantation.     

IL-2 and TNF-alpha promoter polymorphisms in patients with acute kidney graft rejection

INTRODUCTION: Proinflammatory cytokines have been implicated in the pathogenesis of acute kidney allograft rejection. The aim of the study was to examine the association between interleukin (IL)-2 -330 and tumor necrosis factor (TNF)-alpha -308 promoter polymorphisms and acute kidney allograft rejection. METHODS: The study included 72 patients with long-term stable graft function, and 57 diagnosed with acute kidney allograft rejection. RESULTS: Patients with acute kidney allograft rejection showed a prevalence of subjects with TNF-alpha T2 allele (P < .05). The risk of acute kidney allograft rejection diagnosis was 2.5-fold greater among carriers of the T2 allele than those homozygous for T1T1 (OR 2.53, 95% CI 1.19 to 5.37, P < .05) There was no statistically significant difference in the distribution of IL-2 genotypes between patients with stable graft function and acute kidney allograft rejection. CONCLUSION: The results suggest that TNF-alpha-308 promoter polymorphism is a risk factor for acute kidney allograft rejection.     

RANTES/CCL5 polymorphisms as a risk factor for recurrent acute rejection

BACKGROUND: The chemokine system plays an important role in the pathogenesis of acute rejection or atherosclerosis. Three polymorphisms in the promoter region of the chemokine RANTES (-403G/A, -28G/C, In1.1T/C) are associated with a different expression of this chemokine as well as the occurrence of cardiovascular disease. Therefore, we investigated the impact of these three polymorphisms on the outcome after renal transplantation. METHODS: In 261 patients receiving their first kidney transplant, we genotyped the RANTES promoter polymorphisms (-403G/A, -28G/C, In1.1T/C) by real-time PCR. RESULTS: For the RANTES -403G/A and for the intronic polymorphism In1.1T/C, we found a significantly higher rate of recurrent acute rejection episodes (-403G/A: 11.1 vs. 31.0%, In1.1T/C: 11.8 vs. 33.0%). For the overall rate of acute rejection, we observed no significant differences according to the RANTES promoter polymorphisms. The other tested variables (DGF, graft survival, renal function) were not associated with one of the three polymorphisms. CONCLUSION: Our data indicate a relevant role of RANTES in kidney transplantation, particularly for the occurrence of recurrent acute rejection. To clarify the role of the analysed polymorphisms for long-term survival, especially for the occurrence of cardiovascular events, larger studies in the future are needed.