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.     

Predictive value of cytokine gene polymorphisms for the development of end-stage renal disease

BACKGROUND: Cytokines play a crucial role in different immunopathological conditions. Cytokine secretion is reported to be determined by polymorphisms in the cytokine genes. Since TNF-alfa and IL-10 are involved in regulation of inflammation, and TGF-beta 1 can induce fibrosis and renal insufficiency - dominant features of end-stage renal disease (ESRD), we explored the hypothesis that polymorphisms of these cytokine genes may be possible genetic susceptibility factors for the progression of renal failure. METHODS: We studied the IL-10 (-1082), TNF-alfa (-308), TGF-beta 1 (codon 10;25) gene single nucleotide polymorphisms in 118 healthy donors and 103 patients with ESRD (44 hemodialysis patients with diabetic nephropathy and 59 hemodialysis patients with glomerulonephritis) using PCR-SSP. RESULTS: Significant associations of ESRD with the TGF-beta 1 (codon 10) TT (odds ratio [OR] = 5.31; 95% confidence interval [95% CI], 3.77-7.02; p<0.001) and IL-10 (-1082) GG (OR=2.35; 95% CI, 1.67-3.15; p<0.01) genotypes were found. Statistical analysis of genotype frequencies made separately for the underlying renal disease (diabetes or glomerulo-nephritis) revealed the same linkage trend: TGF-beta 1 (codon 10) TT and IL-10 (-1082) GG were associated with type 2 diabetic nephropathy (p<0.001 and p<0.05, respectively) and chronic glomerulonephritis (p<0.001 and p<0.01, respectively). No significant differences in the TNF-alfa , TGF-beta 1 (codon 25) genotype distribution between healthy controls and patients with diabetic nephropathy- or glomerulonephritis-associated ESRD were detected. CONCLUSIONS: Carriage of the TGF-beta 1 (codon 10) TT and IL-10 (-1082) GG genotypes may increase susceptibility to ESRD in German patients with type 2 diabetes or glomerulonephritis.     

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.     

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.     

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.     

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.     

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.     

The interleukin-6 -174promoter polymorphism is associated with long-term kidney allograft survival

BACKGROUND: Th1-dependent effector mechanisms may be responsible for allograft rejection. Recently, interleukin-6 (IL-6) has been shown to antagonize CD4+ T cells to effector Th2 cells and, in the process, differentiate them into Th1 cells. METHODS: To assess the role of IL-6 in long-term allograft survival, 158 patients after first cadaveric kidney transplantation were analyzed for the biallelic -174G-->C promoter polymorphism of the IL-6 gene. RESULTS: Carriers of the -174C-allele (genotype GC/CC) had an inferior three-year graft survival (71/104 = 68.3%; P = 0.0059) with a 3.7-fold increased relative risk of graft loss compared to carriers of the -174GG-genotype (48/54 = 88.9%). The -174GC/CC-genotype retained its negative impact on graft survival when other established prognostic factors and further cytokine polymorphisms (-308TNF-alpha, TGF-beta1 codon 10 & 25, -592/-819/-1082IL-10 and +874IFN-gamma) were considered simultaneously. CONCLUSIONS: Since the clinical impact on transplant outcome seems as important as matching for histocompatibility antigens, genotyping of the IL-6 -174polymorphism may offer a new method for identifying patients at increased risk of allograft loss.     

Interleukin-6 and interferon-gamma gene polymorphisms in the development of bronchiolitis obliterans syndrome after lung transplantation

BACKGROUND: A number of genetic polymorphisms have been shown to regulate the production and secretion of tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1, interferon (IFN)-gamma, interleukin (IL)-6, and IL-10. Several of these genetic polymorphisms have been shown to be associated with either acute or chronic rejection of kidney, liver, and heart allografts and with development of allograft fibrosis after lung transplantation. The aim of this study was to assess the effect of these genetic polymorphisms on the development of bronchiolitis obliterans syndrome (BOS) after lung transplantation. METHODS: Genetic polymorphisms were detected by means of polymerase chain reaction in 93 lung allograft recipients for functional polymorphisms in the TNF-alpha (-308), TGF-beta1 (+869 and +915), IL-6 (-174), IFN-gamma (+874), and IL-10 (-1082, -819, and -592) genes. Then, a correlation between BOS development and the presence of these cytokine genotypes was determined using Kaplan-Meier actuarial analysis. RESULTS: A significant correlation was detected between the presence of high-expression polymorphisms of the IL-6 and IFN-gamma genes and BOS development after lung transplantation (P =0.045 and 0.039, respectively). Also, patients with high-expression polymorphisms in both genes developed BOS significantly earlier than patients with low-expression polymorphisms in one or both genes, suggesting a synergistic effect of the alleles during BOS pathogenesis (P =0.016). No correlation was detected between polymorphisms of the TNF-alpha, TGF-beta1, and IL-10 genes and development of BOS after lung transplantation. CONCLUSIONS: The presence of high-expression polymorphisms at position -174 of the IL-6 gene and position +874 of the IFN-gamma gene significantly increases the risk for BOS development after lung transplantation.     

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.     

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.     

Cytokines, their genetic polymorphisms, and outcome after abdominal aortic aneurysm repair.

BACKGROUND: Excessive cytokine production has been implicated in the development of organ failure. Polymorphic sites in cytokine genes have been shown to affect levels of production in vitro and may influence cytokine production in vivo. The aims of this study were to determine if cytokines or their genetic polymorphisms were related to outcome after abdominal aortic aneurysm (AAA) repair. METHODS: A prospective study of 135 patients undergoing open AAA repair. Plasma levels of TNF-alpha, IL-1beta, IL-6 and IL-10 were measured 24 h post-operatively and genotypes for the TNF-alpha -308, IL-1beta+3953, IL-6 -174, IL-10 -1082 and IL-10 -592 polymorphisms were determined for each patient. RESULTS: After elective AAA high levels of IL-10 were associated with both prolonged critical care (P<0.001) and hospital stay (P=0.001). The presence of a G allele at the IL-6 -174 locus was associated with a higher incidence of organ failure (P=0.04) and an A allele at TNF-alpha -308 with prolonged critical care stay (P=0.03). After ruptured AAA the development of multi-organ failure was associated with high levels of IL-6 (P=0.01) and TNF-alpha (P=0.04). High TNF-alpha levels were also associated with mortality (P=0.01). CONCLUSION: Post-operative cytokine levels are related to outcome after AAA repair. Cytokine gene polymorphisms may provide a method for determining which patients are at high risk of complications.     

Genetic polymorphisms and the risk of infection following esophagectomy. positive association with TNF-alpha gene -308 genotype

OBJECTIVE: To examine the association of single nucleotide polymorphisms (SNPs) in inflammation-related genes in the development of infections following esophagectomy. SUMMARY BACKGROUND DATA: Genetic polymorphisms for immunoregulatory cytokines may explain individual variation in response to trauma. Esophagectomy is associated with a high risk of postoperative infection and sepsis, and this study explored a number of SNPs in cytokine genes and their relationship to postoperative infection. METHODS:: In a prospective analysis of 197 patients with esophageal cancer undergoing resection, 55 developed postoperative infections. DNA was extracted and genotyping was performed for polymorphisms in genes encoding TNF-alpha, IL-1beta, IL-1 receptor antagonist, IL-10, and Toll-like receptor 4 (TLR-4) using Taqman chemistry and PCR/RFLP. In a blinded analysis, the cohort with infections was compared with the no complication cohort (n = 114) and a cohort that had noninfective complications (n = 28). RESULTS: No differences in polymorphisms for IL-1beta, IL-1 RN, IL-10, and TLR-4 genes were observed across groups. The frequency of TNF-alpha -308 GG homozygotes was significantly (P = 0.021) higher in the postoperative infection group. The G allele was significantly higher in the postoperative infection group compared with the no complication group (P = 0.017) and other complication group (P = 0.013). By multivariate analysis, this polymorphism as well as age and body mass index were predictors of infection. CONCLUSION: The TNF-alpha -308A allele has been shown to be associated with higher circulating levels of TNF-alpha and the -308 G allele is a comparative low secretor allele. We propose that the polymorphism in the promotor region of TNF-alpha gene may lead to altered expression and a possible suboptimal activity of TNF-alpha in persons with GG genotypes, and these data suggest a link with infection following major surgery.     

The effect of polymorphisms in tumor necrosis factor-alpha, interleukin-10, and transforming growth factor-beta1 genes in acute hepatic allograft rejection

BACKGROUND: The occurrence of acute rejection in orthotopic liver transplantation is unpredictable. The role of cytokines in the process of rejection is not entirely clear. We investigated polymorphisms in the genes encoding tumor necrosis factor (TNF)-alpha, interleukin (IL)-10, and transforming growth factor (TGF)-beta1, which affect the amount of cytokine produced in vitro, in a liver transplant population to determine any association with acute rejection. METHOD: DNA was extracted from whole blood of liver transplant patients. After amplification with polymerase chain reactions, the polymorphisms at TNF-alpha -308, IL-10 -1082, and TGF-beta1 +869 and +915 were determined using sequence-specific oligonucleotide probes. Acute cellular rejection was a clinical and histological diagnosis. RESULTS: Acute cellular rejection requiring treatment occurred in 68 (48%) of 144 patients. Acute cellular rejection was significantly associated with the TNF-alpha -308 A/A genotype (P<0.02). There was no significant association with either IL-10 or TGF-beta1 polymorphisms in acute rejection. CONCLUSION: Patients with a homozygous TNF-alpha -308 genotype A/A are more likely to suffer from acute cellular rejection after liver transplantation.     

Cytokine gene polymorphisms and the inflammatory response to abdominal aortic aneurysm repair

BACKGROUND: Cytokines are key mediators of the inflammatory response to surgery and polymorphic sites in their genes have been shown to affect cytokine production in vitro. The aim of this study was to determine whether cytokine gene polymorphisms affect cytokine production in vivo in patients undergoing abdominal aortic aneurysm (AAA) repair. METHODS: One hundred patients admitted for elective AAA repair had plasma levels of interleukin (IL) 1beta, IL-6, IL-10 and tumour necrosis factor (TNF) alpha measured at induction of anaesthesia and 24 h after operation. Genotypes for each patient were determined using induced heteroduplex genotyping for the following loci: IL-1beta + 3953, IL-6 - 174, IL-10 - 1082/-592 and TNF-alpha - 308. RESULTS: Patients with an IL-10 - 1082 A allele had a significantly higher IL-10 response to surgery than those without an A allele (P = 0.030) and there was also a significant difference in IL-10 response between patients with IL-10 - 1082 AA genotypes and those with GG genotypes (P = 0.030). CONCLUSION: Elective AAA repair results in a measurable cytokine response. In this study the magnitude of this response was not affected by the individual patient's cytokine gene polymorphisms.     

Association of IL-10 polymorphism with severity of illness in community acquired pneumonia

BACKGROUND: The influence of genetic polymorphisms of interleukin (IL)-10, tumour necrosis factor (TNF)-alpha, and IL-6 gene promoters on severity of systemic inflammatory response syndrome (SIRS) associated with community acquired pneumonia (CAP) was studied. METHODS: Using PCR-RFLP analysis we analysed a -1082G/A single nucleotide polymorphism (SNP) of the anti-inflammatory IL-10 gene, a -308G/A SNP of the pro-inflammatory TNF-alpha gene and a -174G/C SNP of the IL-6 gene. Illness severity was stratified according to SIRS score, calculated by presence of up to four physiological indices: temperature, white blood cell count, heart rate and respiratory rate (non-SIRS, SIRS 2, SIRS 3, and SIRS 4). RESULTS: A statistically significant stepwise increase in frequency of the IL-10 G allele, associated with higher expression of the gene, was observed in patients with increasing severity of illness from non-SIRS (n=19) to SIRS 2 (n=17), SIRS 3 (n=33) and SIRS 4 (n=24). This was primarily due to a higher frequency of the GG genotype with increasing severity from non-SIRS through to SIRS 4. IL-10 G allele frequency was also increased in patients who died as a result of CAP (n=11) compared with CAP survivors (n=82) (p=0.01). No association was seen between the TNF-alpha -308G/A and IL-6 -174G/C SNPs and disease. Additionally, no interaction between all three SNP genotypes and disease severity was observed. CONCLUSIONS: A polymorphism affecting IL-10 expression may influence the severity of illness in patients with CAP.     

Cytokine polymorphisms in men with chronic prostatitis/chronic pelvic pain syndrome: association with diagnosis and treatment response

PURPOSE: The chronic pelvic pain syndrome is a common disorder of unknown etiology. Elevated cytokines in prostate fluid and semen are frequent findings. We studied genetic polymorphisms that can alter cytokine gene expression in men with the chronic pelvic pain syndrome. MATERIALS AND METHODS: Genomic DNA was extracted from blood from 36 men with the chronic pelvic pain syndrome. Reversed sequence specific oligonucleotide probing was used to genotype the polymorphisms for cytokine promoter sites, namely tumor necrosis factor (TNF)-alpha 308, transforming growth factor (TGF)-beta 25, TGF-beta 10, interleukin (IL)-10 1082 and IL-6 174. Genotype frequencies were compared with 252 controls as well as among groups of patients with the chronic pelvic pain syndrome according to diagnostic category and treatment response. RESULTS: There were no differences in men with the chronic pelvic pain syndrome and control patients in the frequency of TNF-alpha, TGF-beta or IL-6 alleles, although those with the chronic pelvic pain syndrome were more likely to express the genotype associated with low IL-10 production (30.6% versus 12.1%, p = 0.007). When comparing National Institutes of Health diagnoses, category IIIa patients were more likely to have the low TNF-alpha genotype (categories II, IIIa and IIIb 33%, 100% and 18%, respectively, p = 0.04). All 11 of the 28 patients treated with the anti-inflammatory quercetin in whom treatment failed had the low TNF-alpha genotype versus 29.4% of those in whom treatment succeeded (p = 0.0003). Similarly men with quercetin treatment failure were much less likely to have the low IL-10 genotype than those with treatment success (9.1% versus 47.1%, p = 0.04). CONCLUSIONS: Patients with the chronic pelvic pain syndrome are more likely to have a low IL-10 producing genotype, suggesting autoimmunity as a potential etiology. Anti-inflammatory phytotherapy failure was associated with low TNF-alpha and high IL-10 phenotypes, which may help define a subset of patients with the chronic pelvic pain syndrome without an inflammatory etiology.     

The association between cytokine gene polymorphisms and graft rejection in liver transplantation: A systematic review and meta-analysis

We investigated the contribution of polymorphisms in cytokine genes (TNFa-308, IL10-1082 and -592, TGFb1-c10 and c25, and IFNg + 874) on the risk of graft rejection in liver transplantation. We performed a systematic review by identifying relevant studies and applied meta-analysis to pool gene effects. In total, 12 studies were eligible and included in the study. Data extraction and assessments for risk of bias were independently performed by two reviewers. Data for allele frequencies, allelic, and genotypic effects were pooled. Heterogeneity and publication bias were assessed. Pooled minor allele frequencies for TNFa-308, IL10-1082, TGFb1-c10, TGFb1-c25, IFNg + 874, and IL10-592 were 0.140 (95% CI: 0.083, 0.198), 0.432 (95% CI: 0.392, 0.472), 0.387 (95% CI: 0.307, 0.467), 0.090 (95% CI: 0.056, 0.123), 0.460 (95% CI: 0.392, 0.528), and 0.224 (95% CI: 0.178, 0.269), respectively. OnlyTNFa-308 and IL10-1082 polymorphisms were significantly associated with graft rejection. Patients who carried minor homozygous genotypes for these two polymorphisms were at 3.5 and 1.69 times higher risk of graft rejections than patients who carried major homozygous genotypes. The estimated lambdas were 0.41 and 0.47, suggesting an additive mode of effect was most likely. However, we could not detect the associations of TGFb1at c10 and c25, INFg + 874, and IL10-592 polymorphisms and graft rejection. In summary, our systematic review has demonstrated that TNFa-308 and IL10-1082 are potential risk factors of poor outcomes in liver transplantation. Future updated meta-analysis studies to confirm the power of these genotypes in association with allograft rejection are needed.