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.     

Association of interleukin-1 receptor antagonist gene polymorphism with IgA nephropathy

It is evident that cytokines play an important role in the pathogenesis as well as disease progression of IgA nephropathy (IgAN). Several gene polymorphisms of the pertinent cytokines have an influence on the level of cytokine production. Interleukin-1 receptor antagonist (IL-1ra) gene polymorphism has been found to affect disease susceptibility and activity in several inflammatory diseases. In the present study, we analyzed polymorphism of the variable number tandem repeat (VNTR) of IL-1ra in patients diagnosed as having IgAN (n = 106) and normal controls (n = 74). The allele frequency of IL-1ra polymorphism in IgAN patients was not statistically different from that of the control group. There was no significant difference in the carriage rate of the two-repeat allele (IL1RN*2) between IgAN patients and the control group (8.5 vs. 6.8%). The carriage rate of IL1RN*2 was significantly higher in IgAN patients with severe proteinuria (>or=1.6 g/day) or increased serum creatinine level (>or=2.0 mg/dl; p < 0.05). Furthermore, the carriage rate of IL1RN*2 was significantly higher in patients with severe mesangial cell proliferation (p < 0.01). Our results suggest that IL-1ra polymorphisms are not associated with the development of IgAN in Japanese patients but the presence of IL1RN*2 may be associated with increased disease activity.     

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.     

白细胞介素1受体拮抗剂等位基因与紫癜性肾炎和IgA肾病的相关联系

目的 为了进一步阐明紫癜性肾炎(HSPN)及IgA肾病(IgAN)二者在发病机理上可能存在的联系。方法 用PCR方法对43例HSPN,97例IgAN患者和98名正常人IL-l受体拮抗剂(IL-lra)基因数目可变的串联重复(VNTR)多态性进行了分析。结果 HSPN患者白细胞介素l受体拮抗剂等位基因(IL IRN 2)的携带率明显高于正常人(P<0.02)和IgAN患者(P<0.05)。在IgAN患者中表现为反复发作性肉眼血尿者其IL IRN 2等位基因的携带率明显高于其它临床类型IgAN患者(P<0.o1),而与HSPN无显著性差异(P>0.05)。结论 HSPN患者IL-lra基因特定的遗传背景在其发病机理中可能起一定作用。IgAN患者中表现为反复发作性肉眼血尿者较其它临床类型IgAN患者与HSPN有更多的相似之处,而ILlRN 2等位基因高携带率可能是二者发病机理的共同点之一。     

Association of IL-1β, IL-1ra, and TNF-α gene polymorphisms in childhood nephrotic syndrome

We investigated the association between IL-1, IL-1ra, and TNF- gene polymorphisms and childhood nephrotic syndrome (NS). We analyzed the genetic polymorphism of IL-1, IL-1ra, and TNF- genes in 152 patients with childhood NS and 292 healthy adult controls. The C to T exchange at position –511 of IL-1 and the G to A at –308 of the TNF- gene were genotyped. Five alleles of the IL-1ra gene were identified and designated as IL1RN*1, IL1RN*2, IL1RN*3, IL1RN*4, and IL1RN*5, according to the variable number of tandem repeats in intron 2. The allele frequencies of IL-11 (-511C), IL-12 (-511T), TNF1 (-308G), and TNF2 (-308A) were 53.0, 47.0, 92.1, and 7.9%, respectively, in the childhood NS group. This was not significantly different from normal controls. In the childhood NS group, the allele frequencies of IL1RN*1, IL1RN*2, IL1RN*3, IL1RN*4, and IL1RN*5 were 90.8, 7.6, 1.6, 0, and 0% [IL1RN*1 odds ratio (OR)=0.296, P=0.0001, IL1RN*2 OR=3.902, P=0.0002]. A high allele frequency of IL1RN*2 and a lower allele frequency of IL1RN*1 were found in childhood NS, although there was no association with IL-1 and TNF-. A high allele frequency of the IL1RN*2 allele may affect disease susceptibility in childhood NS.     

Polymorphism in IgA nephropathy

Summary: IgA nephropathy (IgAN) is polyphormic in its clinical manifestation, course and prognosis. Patients with isolated IgA deposit in glomeruli tend to have a high incidence of macroscopic haematuria and carry a better prognosis. In contrast, patients with deposits of IgA and IgG and IgM have a higher incidence of nephrotic syndrome and hypertension. In parallel, patients with IgA and IgG and IgM tend to have more glomerulosclerosis and tubulointestitial lesions. Recently, the angiotensin converting enzyme (ACE) gene polymorphism and its association in disease risk provided interesting exploration leading us to speculate about a possible mechanism to explain the variation in the rate of progression of IgAN; although, the results are still controversial. The variability of plasma ACE concentration has been shown to be associated with an insertion/deletion polymorphism. The frequencies of ACE genotype in 177 Chinese patients with IgAN has been observed. We found that patients with IgAN showed a higher frequency of DD genotype than normal population. In contrast to the previous reports, we did not find any association between ACE genotype and the rate of progression of IgAN. As different genotypes of IL-1 receptor antagonist (IL-1 ra) are also responsible for the circulating levels of IL-1 ra, the polymorphism of IL-1 ra gene has been analyzed in 100 IgAN patients. There was no significant difference in the frequency of IL1RN*2 allele between normal subjects and IgAN. However, patients with recurrent macroscopic haematuria showed a higher carriage rate of IL1RN*2. Hereditable factors, in combination with a number of recognized environmental risk factors, are important determinants of the pathogenesis and natural history of IgAN. The notion that the gene polymorphism might be responsible for the clinical features and progression of IgAN is both intriguing and provocative. The lessons from previous multiple small size studies have produced conflicting results illustrating the need for observation of large numbers of cases in further studies to verify these observed associations.     

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.     

IgA肾病和紫癜性肾炎患者白细胞介素-1受体拮抗剂基因多态性的功能研究

目的阐明白细胞介素１受体拮抗剂（ＩＬ１ｒａ）基因多态性对其功能的影响，论证ＩＬ１ｒａ基因型与ＩｇＡ肾病（ＩｇＡＮ）及紫癜性肾炎（ＨＳＰＮ）临床表型之间联系的机理。方法用ＰＣＲ方法对ＩｇＡＮ和ＨＳＰＮ患者ＩＬ１ｒａ基因型进行分析，从ＩＬ１ｒａ不同基因型患者获取外周血单核细胞，观察单核细胞经单核巨噬细胞集落刺激因子（ＧＭＣＳＦ）刺激后，ＩＬ１ｒａ、ＩＬ１α和ＩＬ１β的产生能力。结果无论是ＩｇＡＮ，还是ＨＳＰＮ患者，携带ＩＬ１ｒａ基因ＩＬ１ＲＮ＊２等位基因者其单核细胞ＩＬ１ｒａ的产生能力明显低于不携带该等位基因的个体，而ＩＬ１α和ＩＬ１β的产生能力与是否携带ＩＬ１ＲＮ＊２等位基因无关。结论ＩＬ１ｒａ基因多态性能对其功能产生影响。携带ＩＬ１ＲＮ＊２等位基因者其体内ＩＬ１ｒａ的产生能力存在缺陷。该结果为临床上根据ＩＬ１ｒａ基因型有针对地采取干预治疗奠定了基础。     

Polymorphisms in interleukin-1 beta and Interleukin-1 receptor antagonist genes are associated with kidney failure in Korean patients with type 2 diabetes mellitus

BACKGROUND/AIM: Cytokines play an important role in the pathogenesis of kidney diseases. The aim of the study was to investigate the impact of interleukin (IL)-1 cluster genes on diabetic nephropathy in Korean patients with type 2 diabetes mellitus (DM). METHODS: We investigated -511 C/T polymorphism of IL-1 beta and tandem repeat polymorphism in intron 2 of IL-1 receptor antagonist in type 2 DM patients with end-stage kidney failure as compared with patients without nephropathy. RESULTS: The IL1B2 allele was found more frequently in patients with kidney failure than in controls (57.4 vs. 46.1%, p < 0.05). An excessive homozygous carriage of IL1B2 was found in patients with kidney failure when compared with controls (30.5 vs. 18.3%, p < 0.05). The allelic frequency of IL1RN*2 was also higher in cases than in controls without nephropathy (8.4 vs. 2.8 %, p < 0.05). The carriage rate of IL1RN*2 was significantly associated with an increased risk of kidney failure (15.8 vs. 5.6%; OR 3.19, 95% CI 1.24-8.17). The risk of kidney failure was highest in those carrying both IL1RN*2 and IL1B2 (OR 3.90, 95% CI 1.34-11.40). CONCLUSION: IL1B2 and IL1RN*2 genotypes of the IL-1 cluster genes are associated with diabetic nephropathy in Korean patients with type 2 DM.     

Interleukin-1 receptor antagonist genotype is associated with coronary atherosclerosis in patients with type 2 diabetes

Recently, inflammation has received considerable attention in the pathogenesis of both type 2 diabetes and atherosclerosis. The interleukin-1 receptor antagonist (IL-1ra) is a major modulator of the interleukin-1 pro-inflammatory pathway. We studied the relationship between a variable number tandem repeat (VNTR) polymorphism in intron 2 of the IL-1ra gene (IL1RN) and coronary artery disease (CAD) in patients with and without type 2 diabetes, following 787 consecutive patients admitted for suspected CAD. According to the current criteria of the American Diabetes Association, 250 patients had type 2 diabetes. In this group of patients, allele 2 carriers (n = 108) had an increased prevalence of CAD compared with noncarriers (85.2 vs. 73.2%), a difference that remained significant in a multivariate logistic regression model (odds ratio 2.2, 95% CI 1.1-4.3, P = 0.02). No association of CAD with allele 2 carrier status was present among nondiabetic patients (n = 537). Enzyme-linked immunosorbent assays showed decreased baseline plasma levels of IL-1ra in patients with type 2 diabetes, which may in part explain the role of the IL1RN VNTR in these patients.     

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.     

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.     

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.     

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.     

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-1beta and IL-1 receptor antagonist haplotypes with rate of decline in lung function in smokers

BACKGROUND: There is increasing evidence that the cytokine network is central to the immunopathology of inflammatory airway diseases. The interleukin 1 (IL-1) receptor antagonist (IL-1RN) is a naturally occurring anti-inflammatory agent that binds to the IL-1 receptor but does not possess agonist activity. Each of the genes of the IL-1 locus on chromosome 2q14 is polymorphic. The IL1RN gene contains an 86 bp tandem repeat and allele 2 of this polymorphism has been associated with various inflammatory diseases. The IL-1beta (IL1B) gene contains a promoter polymorphism (C-511T) that has been associated with inflammatory diseases and is in linkage disequilibrium with the IL1RN polymorphism. METHODS: We investigated whether polymorphisms in the IL1B and IL1RN genes were associated with rate of decline of lung function. Genotypes were determined in 284 smokers with a rapid decline in lung function and 306 smokers with no decline in lung function. RESULTS: None of the genotypes was associated with the rate of decline of lung function. However, the distribution of IL1B/IL1RN haplotypes was different between smokers with a rapid decline in lung function and those with no decline in lung function (p=0.0005). CONCLUSION: These results suggest that IL1B/IL1RN haplotypes play a role in the rate of decline in lung function in smokers.     

Possible correlation between polymorphism in the tumor necrosis factor-beta gene and the clinicopathological features of bladder cancer in Japanese patients

OBJECTIVES: In a variety of cancers, several polymorphisms of the tumor necrosis factor (TNF) genes have been reported to result in different clinical outcomes. We investigated whether a polymorphism of the TNF gene is associated with a susceptibility to bladder cancer and its disease status. METHODS: Polymorphisms in the TNF-alpha gene promoter (-308 bp) and the NcoI site in the first intron of the TNF-beta gene were analyzed in 141 Japanese patients with bladder cancer and 173 Japanese controls by polymerase chain reaction-restriction fragment length polymorphism. The correlations between the polymorphisms of the TNF genes and the clinicopathological features were analyzed. RESULTS: The number of cases and controls with TNF-alpha2 was too small to be assessable. In contrast, the TNF-beta1/2 genotype at the NcoI site in the first intron conferred a 1.71-fold increased risk of bladder cancer compared to the TNF-beta2/2 genotype. In the bladder cancer group, patients with the TNF-beta1 allele had a significantly higher risk for a high-grade tumor (grade 3) or carcinoma in situ (CIS) than those without the TNF-beta1 allele. Moreover, in the superficial bladder cancers, patients with the TNF-beta1 allele showed a significantly higher intravesical recurrence rate than those without the TNF-beta1 allele. CONCLUSION: This polymorphism in the TNF-beta gene appears to be associated with tumor occurrence and disease status, such as the tumor grade and the presence of CIS. Further study with an increased sample size is warranted.     

Possible association of CTLA-4 gene polymorphism with cyclosporine-induced gingival overgrowth in kidney transplant recipients

T-lymphocytes may play a role in the pathogenesis of inflammatory periodontal diseases and cyclosporine (CsA)-induced gingival overgrowth (GO). The gene encoding CTLA-4 (Cytotoxic T-lymphocyte antigen 4, a molecule influencing T-cell activation), is known to have a single nucleotide polymorphism (SNP) in promoter C>T -318; an exon 1 A>G 49, and a microsatellite dinucleotide repeat polymorphism (AT)(n) in exon 4. The purpose of this study was to analyze the possible influence of polymorphisms of CTLA-4, interleukin (IL)-2, and tumor necrosis factor (TNF)-alpha on GO incidence in eighty two renal transplant recipients. 34 CsA-treated with significant GO (CsAGO+); 22, CsA-treated with no GO (CsAGO-), and 26 tacrolimus (Tac)-treated without GO (TacGO-). The SNPs of CTLA-4 (-318 C>T and +49 A>G), IL-2 (-330T>G), and TNF-alpha (-308 G>A) were determined by SSP-PCR methods. The CTLA-4 (AT)(n) genotype was determined using polymerase chain reaction and fluorescence-based analysis with capillary electrophoresis. Allele frequencies in all patient groups were similar for CTLA-4 -318C>T, IL-2, and TNF-alpha. However, patients with CsAGO+ showed differences from CsAGO- for allele and genotype frequencies in position +49A>G of the CTLA-4 gene. The +49G allele was two times less frequent among CsAGO+ than CsAGO- (P = .0052; P corrected = .008). Slight differences between CsAGO+ and CsAGO- were noticed for the genotype distribution of CTLA-4 (AT)(n) (P = .056). The results suggested that appearance of an adenosine allele(A) in position +49 of the CTLA-4 gene may be a permissive element for CsA-induced GO.