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.     

Promoter polymorphisms of the TNF-alpha (G-308A) and IL-6 (C-174G) genes predict the conversion from impaired glucose tolerance to type 2 diabetes: the Finnish Diabetes Prevention Study

High levels of cytokines are risk factors for type 2 diabetes. Therefore, we investigated whether the promoter polymorphisms of the tumor necrosis factor-alpha (TNF-alpha; G-308A) and interleukin 6 (IL-6; C-174G) genes predict the conversion from impaired glucose tolerance (IGT) to type 2 diabetes in the Finnish Diabetes Prevention Study. Altogether, 490 overweight subjects with IGT whose DNA was available were randomly divided into one of the two treatment assignments: the control group and the intensive, individualized diet and exercise intervention group. The -308A allele of the TNF-alpha gene was associated with an approximate twofold higher risk for type 2 diabetes compared with the G-308G genotype (odds ratio 1.80, 95% CI 1.05-3.09; P = 0.034). Subjects with both the A allele of the TNF-alpha gene and the C-174C genotype of the IL-6 gene had a 2.2-fold (CI 1.02-4.85, P = 0.045) higher risk of developing type 2 diabetes than subjects without the risk genotypes. We conclude that the -308A allele of the promoter polymorphism (G-308A) of the TNF-alpha gene is a predictor for the conversion from IGT to type 2 diabetes. Furthermore, this polymorphism seems to have a gene-gene interaction with the C-174C genotype of the IL-6 gene.     

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.     

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.     

Tumor necrosis factor gene polymorphisms and inflammatory response in coronary artery bypass grafting patients

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha), a key factor in the inflammatory cascade, has been implicated in coronary artery disease. Two biallelic polymorphisms in the TNF gene locus (TNFA at position -308 and TNFB at +252) may influence TNF-alpha production. Individuals with the rare TNFA2 allele or TNFB2 homozygosity have augmented TNF-alpha production. We investigated the genotypes associated with increased TNF-alpha production in coronary artery bypass grafting (CABG) patients and if these genotypes influence the magnitude of the postoperative inflammatory response. METHODS: TNF gene polymorphisms were analyzed by multiplex fluorescent solid-phase minisequencing in 86 CABG patients. Plasma concentrations of TNF-alpha, IL-6 and C3a and C-reactive protein (CRP) were analyzed before and after surgery in 45 of the patients and compared with genetically high and low TNF-alpha producers. RESULTS: Thirty percent of the patients carried the TNFA2 allele and 45% were TNFB2 homozygous. The allelic frequencies were TNFA1/TNFA2 = 0.84/0.16 and TNFB1/TNFB2 = 0.32/0.68. Pre- and postoperative levels of TNF-alpha, IL-6, C3a and CRP did not differ significantly between genetically high and low TNF-alpha producers. CONCLUSIONS: The frequency of high TNF-alpha producing genotypes in a CABG population was comparable to that previously reported from normal populations. Furthermore, we found no evidence that the investigated TNF-alpha gene polymorphisms influence postoperative inflammatory response after uncomplicated coronary surgery.     

Tumor necrosis factor gene polymorphisms and inflammatory response in coronary artery bypass grafting patients

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha), a key factor in the inflammatory cascade, has been implicated in coronary artery disease. Two biallelic polymorphisms in the TNF gene locus (TNFA at position -308 and TNFB at +252) may influence TNF-alpha production. Individuals with the rare TNFA2 allele or TNFB2 homozygosity have augmented TNF-alpha production. We investigated the genotypes associated with increased TNF-alpha production in coronary artery bypass grafting (CABG) patients and if these genotypes influence the magnitude of the postoperative inflammatory response. METHODS: TNF gene polymorphisms were analyzed by multiplex fluorescent solid-phase minisequencing in 86 CABG patients. Plasma concentrations of TNF-alpha, IL-6 and C3a and C-reactive protein (CRP) were analyzed before and after surgery in 45 of the patients and compared with genetically high and low TNF-alpha producers. RESULTS: Thirty percent of the patients carried the TNFA2 allele and 45% were TNFB2 homozygous. The allelic frequencies were TNFA1/TNFA2=0.84/0.16 and TNFB1/TNFB2=0.32/0.68. Pre- and postoperative levels of TNF-alpha, IL-6, C3a and CRP did not differ significantly between genetically high and low TNF-alpha producers. CONCLUSIONS: The frequency of high TNF-alpha producing genotypes in a CABG population was comparable to that previously reported from normal populations. Furthermore, we found no evidence that the investigated TNF-alpha gene polymorphisms influence postoperative inflammatory response after uncomplicated coronary surgery.     

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.     

Innate immunity genes influence the severity of acute appendicitis

OBJECTIVE: Using acute appendicitis as a model, we tested the hypothesis that polymorphisms in genes involved in host defense can be associated with the severity of local infection-inflammation in humans. SUMMARY BACKGROUND DATA: Innate immunity is the body's front-line system for antimicrobial host defense. Local inflammation is a major innate immune mechanism for containing and destroying microbes, but it may also contribute to tissue injury. METHODS: We studied 134 patients with acute appendicitis treated at an urban hospital. We looked for associations between the severity of appendicitis (uncomplicated vs. perforated or gangrenous), plasma and peritoneal cytokine concentrations, and single nucleotide polymorphisms in genes involved in recognizing bacterial molecules [CD14 (-159 C-->T); TLR4 (896 A-->G)] and in mounting an inflammatory response [IL-6 (-174 G-->C), TNF-alpha (-308 G-->A), IL-1beta (-31 C -->T)]. RESULTS: Ninety-one patients (68%) had uncomplicated appendicitis and 43 (32%) had complicated disease. The SNPs in the CD14, TLR4, IL-1beta, and TNF-alpha genes were not associated with the severity of appendicitis. A strong association was found between C-allele carriage at -174 in the IL-6 gene and decreased risk of complicated disease (adjusted odds ratio = 0.24, 95% CI = 0.07-0.76). Lower plasma and peritoneal fluid IL-6 concentrations in the IL-6 -174 C-carriers than in the GG homozygotes suggest that this polymorphism contributes to decreased IL-6 production in vivo. CONCLUSIONS: Polymorphism in the IL-6 gene was associated with the severity of appendicitis, even after adjustment for duration of symptoms. The risk for developing appendiceal perforation or gangrene may be determined, in part, by variation in the IL-6 gene.     

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.     

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.     

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.     

TNF Alpha−308 Genotype and Renin–Angiotensin System in Hemodialysis Patients: An Effect on Inflammatory Cytokine Levels?

BACKGROUND: Renin-angiotensin system (RAS) was suggested to modulate inflammatory cytokine production. Angiotensin II was consistently shown to increase production of tumor necrosis factor alpha (TNF-alpha). However, inflammatory cytokines and RAS were modulated by genetic polymorphisms such as TNF-alpha-308 G > A and angiotensin-converting enzyme (ACE) I/D gene polymorphisms. The aim of this study was to investigate the effects of ACE and TNF-alpha genotypes on inflammatory cytokines in hemodialysis (HD) patients. METHODS: ACE I/D and TNF-alpha-308 G > A genotypes, pre- and postdialysis plasma renin activity (PRA), serum ACE, interleukin-1 beta (IL-1beta), and TNF-alpha levels were determined in 22 HD patients. RESULTS: Predialysis serum ACE activity is correlated with TNF-alpha (r = 0.63; P = 0.01), and PRA was correlated with IL-1beta levels (r = 0.49; P = 0.02). Pre/postdialysis IL-1beta and TNF-alpha were similar in DD and II/ID ACE genotypes. Predialysis TNF-alpha and IL-1beta (32.4 +/- 5; 35.1 +/- 4.2 vs. 28.1 +/- 3.7; 26.5 +/- 6.2 pg/mL; P < 0.05) and postdialysis TNF-alpha levels (30.4 +/- 1.4 vs. 28.4 +/- 0.82 pg/mL; P < 0.05) were significantly higher in TNF1/2 than TNF1/1 patients. CONCLUSION: ACE and TNF-alpha-308 G > A (1/2) gene polymorphisms may contribute to modulation of proinflammatory cytokine production and hence chronic inflammation in HD patients.     

Cytokine-related genotypic differences in peak interleukin-6 blood levels of patients with SIRS and septic complications

BACKGROUND: The aim of the present study was to investigate whether tumor necrosis factor (TNF), interleukin (IL)-1, and IL-6-related genotypic differences affect IL-6 blood levels in patients with systemic inflammatory response syndrome (SIRS) in an intensive care unit (ICU). METHODS: Seven polymorphisms of TNF, IL-1, and IL-6-related polymorphisms were studied with an allele-specific polymerase chain reaction. One hundred and thirteen patients diagnosed with SIRS whose sequential organ failure assessment scores were > or =5 at the time when their daily measured IL-6 blood level peaked during the ICU stay (IL-6 max) were examined. IL-6 max, survival, and septic complications were compared between carriers and non-carriers of less frequent alleles, indicated as allele*2, in each polymorphism. RESULTS: In single nucleotide polymorphism (SNP) at position -238 site of TNF-alpha (TNF-alpha-238*G/A), IL-6-596*G/A, and IL-6-174*C/T, allele*2 frequencies were much lower in the Japanese than in the Caucasian population. IL-6 max was significantly higher in allele*2 carriers of IL-1beta-511*C/T. Associations were found between susceptibility to septic shock and allele*2 carriage for both IL-1beta-511*C/T and TNF-alpha-308*G/A, and also between poor prognosis and allele*2 carriage in both IL-1 receptor antagonist second intron various number of tandem repeats polymorphism (IL-1raRN*1-5) and TNF-alpha-308*G/A. IL-1beta-511*C/T and IL-1raRN*1-5 were in linkage disequilibrium in this study population. CONCLUSIONS: Carriers of less frequent alleles in IL-1-related polymorphisms appear to have significant vulnerability to production of excessive IL-6 blood levels and to deterioration in septic shock.     

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.     

Interleukin genetic variants and the risk of renal failure in infants with infection

Systemic infection is a major risk factor for the development of neonatal acute renal failure (ARF). We investigated whether genetic polymorphisms of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-10 genes leading to a more intense inflammatory response might predispose very low birth weight (VLBW) infants to the development of ARF in severe infection. The medical records of 92 VLBW newborns (birth weight under 1,500 g) with systemic infection were analyzed. ARF developed in 38 infants during the 1st postnatal week, while 54 neonates exhibited normal renal function. The variants of TNF-alpha, IL-1beta, IL-6, and IL-10 genes were determined from dried blood samples with polymerase chain reaction and restriction fragment length polymorphism methods. The allele frequencies did not differ in ARF and in non-ARF babies, while the (TNF-alpha /IL-6) AG/GC or AG/CC haplotypes were more often present in ARF (26% vs. 6%, P<0.01). The single presence of TNF-alpha, IL-1beta, IL-6, and IL-10 variants does not influence the development of ARF, but the constellation of TNF-alpha and IL-6 genetic variants is associated with ARF. We hypothesize that the simultaneous presence of these polymorphisms might lead to an enhanced inflammatory response in the kidneys in babies with infection.     

Tumor necrosis factor-alpha gene G-308A polymorphism is a risk factor for the development of membranous glomerulonephritis

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is a major pro-inflammatory cytokine. Recently, the G-308A polymorphism of the TNF-alpha gene has been associated with modified gene expression and increased TNF-alpha production in the -308A allele. We evaluated its influence on the incidence and clinical course of membranous glomerulonephritis. METHODS: We studied 53 patients with biopsy-proven primary membranous glomerulonephritis followed up for 5.7 +/- 4.9 years. 100 volunteers were analyzed as controls. According to the slope of the curve of reciprocal serum creatinine against time, group A (slow progressors, n = 35) and group B (fast progressors, n = 18) were defined. TNF-alpha G-308A polymorphism was determined by polymerase chain reaction amplification. RESULTS: The frequency of the A-allele (associated with higher TNF-alpha levels) was significantly higher in patients than control subjects (patients: G-allele: 0.66, A-allele: 0.34; controls: G-allele 0.85, A-allele 0.15, p < 0.001). Similarly, the genotype distribution differed significantly between our study and control populations (patients: GG-genotype: 41.5%, GA: 49.1%, AA 9.4%; controls: GG: 71%, GA: 27%, AA 2%, p = 0.001). Age, renal function, proteinuria and blood pressure were similar at the time of renal biopsy between patients with different genotypes (NS). There was also a tendency towards an overpresentation of the A-allele in group B indicating a possible impact on the progression of membranous nephropathy, but a significance was not reached. Furthermore, no impact on renal survival in the Kaplan- Meier analysis was detected (NS). CONCLUSION: Our results suggest that TNF-alpha gene G-308A polymorphism is a risk factor for the development of membranous glomerulonephritis.     

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.     

Polymorphism of the cytokine genes and IgA nephropathy

BACKGROUND: IgA nephropathy (IgAN) is a form of chronic glomerulonephritis of unknown etiology and pathogenesis. Cytokine gene polymorphisms regulate cytokine production and play a role in immune and inflammatory responses; these immunological responses thus are possibly involved in the etiology and pathogenesis of IgAN. METHODS: We studied by polymerase chain reaction (PCR) polymorphisms of important cytokine genes of inflammation interleukin-1 (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-1 receptor antagonist (IL-1Ra) in 167 patients with IgAN and 400 healthy blood donor controls. IgAN patients had been followed up for 6 to 17 (median 11) years from renal biopsy. RESULTS: Carriage of the IL-1beta allele 2 (IL1beta2) or IL-1Ra allele 2 (IL1RN*2) was associated with an increased risk of IgAN. These alleles were highly linked and the odds ratio (OR) of IgAN for carriage of both alleles was 1.8 (95% confidence interval 1.2 to 2.6; P = 0.002). Carriage of the TNF-alpha allele 2 (TNF2) was associated with a decreased risk of IgAN (OR 0.5, range 0.3 to 0.7; P = 0.001). The risk of IgAN was found to be highest in those carrying IL1beta2 and IL1RN*2 but not TNF2 as compared to those who did not carry both of these IL-1 cluster genes and were carriers of TNF2 (OR 5.0 (2.4-10.3); P < 0.001). None of the polymorphisms studied was associated with poor prognosis. CONCLUSION: Carriage of IL1beta2 and IL1RN*2 together with non-carriage of TNF2 is associated with increased susceptibility, but not with a prognosis of IgAN.     

Interleukin 1 receptor antagonist and tumor necrosis factor-alpha gene polymorphism in patients with end-stage renal failure

End-stage-renal disease (ESRD) is a final result of various etiologies. Prognostic indicators leading to ESRD in chronic kidney diseases have been studied extensively, of which, genetic factors remain a subject of great concern. Interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) are potent proinflammatory cytokines that are involved in several chronic kidney diseases. Studies on cytokine gene polymorphism have revealed important information about the role of genetic factors in disease susceptibility and severity. Gene polymorphism of interleukin-1 receptor antagonist (IL-1ra) and TNF-alpha were determined in 297 ESRD patients and in 145 normal healthy controls. IL-1ra gene polymorphism was characterized as a variable number of tandem repeats of a 86 bp sequence within intron 2. Five alleles were identified and were designated as IL1RN*1, IL1RN*2, IL1RN*3, IL1RN*4, and IL1RN*5, corresponding to 4,2,5,3, and 6 repeats, respectively. A polymorphism in the promoter region of the TNF-alpha gene was also studied. This polymorphism involved a guanidine to adenosine transition at position -308 and was designated as TNF1 (- 308 G) and TNF2 (-308 A). The genotypes and allele frequencies were compared between patients and control group. The distributions of genotypes of IL-1ra and TNF-alpha did not differ significantly between ESRD patients and normal controls. Analysis of allele frequencies revealed a trend toward an increase in IL1RN*2 frequency (7.5% versus 3.8 %, p=0.064) and noncarriage of TNF2 in the patient group (7.2% versus 11.0%, p=0.076) when compared with the control group. When both alleles were considered together, the patient group had a significantly higher frequency of carriage of IL1RN*2 in combination with noncarriage of TNF2 (p=0.0468). We conclude that carriage of IL-1RN*2 and noncarriage of TNF2 allele appear to be poor prognostic factors in patients suffering from various chronic renal diseases that eventually enter end-stage renal failure.