ATTG Polymorphism Research Articles

Association Between the NFKB1-94ins/del ATTG Polymorphism and Cancer Risk: An Updated Meta-Analysis

To assess the effect of the NFKB1 -94ins/del polymorphism on cancer, we conducted a meta-analysis based on 25 studies including 8,750 cases and 9,170 controls. Overall, the -94ins/del polymorphism was associated with cancer risk in the pooled analysis and in Asian population, whereas no association was observed in Caucasian population. Stratified analysis by subtypes of cancer showed that the -94ins/del polymorphism was associated with oral squamous cell carcinoma and ovarian cancer risk, but had no association with colorectal cancer, bladder cancer, and renal cell cancer. Our meta-analysis suggests the NFKB1 -94ins/del polymorphism affects cancer susceptibility, and the association is ethnic-specific.

MP28-10 IGF1R IMMUNOEXPRESSION IN SUPERFICIAL NON-MUSCLE INVASIVE UROTHELIAL CARCINOMA OF URINARY BLADDER

higher risk of developing non-muscle invasive bladder cancer (OR 1⁄4 2.07, 95% CI 1⁄4 1.51€C2.85), grade 1 bladder cancer (OR 1⁄4 2.40, 95% CI 1⁄4 1.68€C3.43), single tumor bladder cancer (OR 1⁄4 2.04, 95% CI 1⁄4 1.48€C2.82) and smaller tumor size bladder cancer (OR 1⁄4 2.10, 95% CI 1⁄4 1.51€C2.92). The expression of NFKB1 mRNA in bladder cancer tissues with homozygous insertion genotype was higher than that with deletion allele. CONCLUSIONS: In conclusion, the -94 ins/del ATTG polymorphism in NFKB1 promoter may contribute to the etiology of bladder cancer in the Chinese population.

Polymorphism of the NFKB1 affects the serum inflammatory levels of IL-6 in Hashimoto thyroiditis in a Turkish population

Hashimoto thyroiditis (HT) is a chronic inflammatory autoimmune disease of thyroid gland affected by interaction of multiple genes and various cytokines. Variants in the genes coding for the NFKB and IKB proteins can be potentially involved in the development of the inflammatory diseases. NFKB, a key transcription factor of the regulation of immune responses, is interesting candidate for association studies about autoimmune disorder.The aim of the present study was to investigate the relationship between NFKB1 and NFKBIA (NFKB1 inhibitor gene) polymorphisms, and the risk of HT in a Turkish Population in the context of IL-6 serum levels which may contribute to susceptibility to the disease. We analyzed the distribution of NFKB1-94ins/del ATTG and NFKBIA 3′UTR A→G polymorphisms using PCR-RFLP method and IL-6 serum levels using ELISA method in 120 HT patients and 190 healthy controls in Turkish population.Although, there was no statistical significant difference in distribution of the genotypes and alleles of NFKB1-94ins/del ATTG or NFKBIA 3′UTR A→G polymorphisms in patients and control subjects as single, ins/ins/GG combined genotype had protective effect on the disease when compared to ins/ins/AG combined genotype as combined genotypes of both polymorphisms. In addition to this finding, IL-6 serum levels in HT patients with del/del genotype were significantly higher than in patients with del/ins genotype (p<0.001). According to the combined genotype analysis of NFKB1-94ins/del ATTG and NFKBIA 3′UTR A→G polymorphisms, IL-6 levels were also higher in patients with del/del genotype when at least one G allele existing (p=0.007).Therefore, our findings suggest that the functional promoter NFKB1-94ins/del ATTG polymorphism was significantly associated with population HT disease through acting by directly modulating IL-6 serum levels.

Association between NFKB1 -94ins/del ATTG Promoter Polymorphism and Cancer Susceptibility: An Updated Meta-Analysis.

Nuclear factor-κB is associated with the pathogenesis of numerous malignancies, and the functional polymorphism −94ins/del ATTG (rs28362491) in the human NFKB1 gene is associated with cancer risk. Previous studies on the association between the −94ins/del ATTG polymorphism and cancer risk reported conflicting results. To clarify this relationship, we performed a meta-analysis of 21 case-control studies involving 6127 cases and 9238 controls. We used pooled odds ratios (ORs) with their 95% confidence intervals (95% CIs) to assess the association. We found that the NFKB1 promoter −94ins/del ATTG polymorphism was significantly associated with cancer risk in four genetic models (ins/ins versus del/del, OR = 1.47, 95% CI = 1.11–1.93; dominant model, OR = 1.26, 95% CI = 1.03–1.53; recessive model, OR = 1.26, 95% CI = 1.05–1.51; ins allele versus del allele, OR = 1.19, 95% CI = 1.05–1.35). Stratified analyses revealed a significant association between the polymorphism and ovarian, oral, and prostate cancers. Similar results were determined in an Asian population and not in a Caucasian population. Thus, our results suggested that the polymorphism can contribute to cancer risk. Moreover, the polymorphism can exert race- and cancer-specific effects on cancer risk. Further large-scale and functional studies are necessary to elucidate this possible effect.

Functional Promoter -94 ins/del ATTG Polymorphism in NFKB1 Gene Is Associated with Bladder Cancer Risk in a Chinese Population

BackgroundA functional -94 insertion/deletion polymorphism (rs28362491) in the promoter of the NFKB1 gene was reported to influence NFKB1 expression and confer susceptibility to different types of cancer. This study aims to determine whether the polymorphism is associated with risk of bladder cancer.Materials and methodsTaqMan assay was used to determine genotype among 609 cases and 640 controls in a Chinese population. Logistic regression was used to assess the association between the polymorphism and bladder cancer risk, and quantitative real-time polymerase chain reaction was used to determine NFKB1 mRNA expression.ResultsCompared with the ins/ins/ins/del genotypes, the del/del genotype was associated with a significantly increased risk of bladder cancer [adjusted odd ratio (OR) = 1.92, 95% confidence interval (CI) = 1.42–2.59]. The increased risk was more prominent among subjects over 65 years old (OR = 2.37, 95% CI = 1.52–3.70), male subjects (OR = 1.97, 95% CI = 1.40–2.79) and subjects with self-reported family history of cancer (OR = 3.59, 95% CI = 1.19–10.9). Furthermore, the polymorphism was associated with a higher risk of developing non-muscle invasive bladder cancer (OR = 2.07, 95% CI = 1.51–2.85), grade 1 bladder cancer (OR = 2.40, 95% CI = 1.68–3.43), single tumor bladder cancer (OR = 2.04, 95% CI = 1.48–2.82) and smaller tumor size bladder cancer (OR = 2.10, 95% CI = 1.51–2.92). The expression of NFKB1 mRNA in bladder cancer tissues with homozygous insertion genotype was higher than that with deletion allele.ConclusionsIn conclusion, the -94 ins/del ATTG polymorphism in NFKB1 promoter may contribute to the etiology of bladder cancer in the Chinese population.

The functional −94 insertion/deletion ATTG polymorphism in the promoter region of NFKB1 gene increases the risk of sporadic colorectal cancer

Objective: To investigate the allele and genotype frequencies of NFKB1 −94 ins/del ATTG (rs28720239) polymorphism and to evaluate the association between the polymorphism and colorectal cancer (CRC) risk in Malaysian population. Methods: Genomic DNA was extracted from the peripheral blood samples of 474 study subjects, which consisted of 237 histopathologically confirmed CRC patients and an equal number of cancer-free controls. The NFKB1 −94 ins/del ATTG (rs28720239) polymorphism was genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method and confirmed by DNA sequencing. The association between the polymorphic genotypes and CRC risk was evaluated by deriving odds ratios (ORs) and 95% confidence intervals (CIs) using unconditional logistic regression analysis. Results: The frequencies of wildtype (del/del), heterozygous (del/ins) and variant (ins/ins) genotypes in CRC patients were 31.7%, 53.6% and 14.8%, respectively, while those in cancer-free controls were 35.0%, 58.2% and 6.8%, respectively. The frequency of the variant genotype was significantly higher in cases compared to controls (P<0.01). Evaluation of the risk association of the polymorphic genotypes revealed that the variant genotype could contribute to a significantly increased risk of CRC (OR=2.42, 95% CI=1.24–4.73, P<0.01). Conclusions: The variant allele of NFKB1 −94 ins/del ATTG (rs28362491) polymorphism is associated with higher risk of sporadic CRC in Malaysian population.

Association Between NFKB1 −94 Insertion/Deletion ATTG Polymorphism and Risk of Intracranial Aneurysm

Growing evidence indicates that vascular inflammation is a common phenomenon in the pathogenesis of intracranial aneurysms (IAs). Nuclear factor kappa B is a key molecule that is involved in the vascular inflammation of IA. We hypothesized that an insertion/deletion (ins/del) ATTG polymorphism located between two putative key promoter regulatory elements in the NFKB1 gene may be related to the risk of IA. We performed a case-control study, including 164 patients with IA and 525 healthy controls in a Chinese population using a polymerase chain reaction-polyacrylamide gel electrophoresis assay. A significantly decreased risk of IA was observed in the ATTG1/ATTG2 and ATTG2/ATTG2 genotypes compared with the ATTG1/ATTG1 genotype (ATTG1/ATTG2 vs. ATTG1/ATTG1: odds ratio [OR]=0.58, 95% confidence interval [95% CI]=0.39-0.87, p=0.007; ATTG2/ATTG2 vs. ATTG1/ATTG1: OR=0.12, 95% CI=0.06-0.23, p<0.001), and also the ATTG2 allele (ATTG2 vs. ATTG1: OR=0.41, 95% CI=0.32-0.54, p<0.001). These findings suggest that the NFKB1 -94ins/del ATTG polymorphism may contribute to the risk of IA.

Relationship between NF-κB1 −94 ins/del ATTG polymorphism and susceptibility of multiple sclerosis in Iranian MS patients

Multiple sclerosis (MS) is one of the most common neurological diseases of the central nervous system (CNS) which is mediated by the autoimmune reactions against myelin sheath. Both genetic and environmental factors are thought to be involved in the pathogenesis of MS. NF-κB1 is one of the most important molecules which regulates the immune functions. NF-κB1 −94 ins/del ATTG promoter polymorphism is a well-studied region in NF-κB1 gene associated with several common autoimmune diseases such as systemic lupus erythematosus (SLE). Our hypothesis was aimed to address the potential association of NF-κB polymorphism and MS. Therefore, we analyzed 200 sex and age matched MS patients along with 200 healthy individuals using PCR–RFLP. The data revealed no significant differences in the frequency of the −94 ins/del ATTG polymorphism in multiple sclerosis patients compared with the control group. To conclude, our study showed no association between −94 ins/del ATTG polymorphism and risk of multiple sclerosis in Iranian patients.

The NFKB1 -94 ATTG insertion/deletion polymorphism (rs28362491) contributes to the susceptibility of congenital heart disease in a Chinese population

Congenital heart disease (CHD) is the most frequently occurring congenital disorder in newborns and is the most frequent cause of infant death from birth defects. Human genetic studies have identified that numerous genes encoding transcription factors that regulate specific events in heart development are responsible for inherited and sporadic CHD. Nuclear factor-kappa B (NF-κB) is a major transcription regulator of immune response, apoptosis and cell-growth control genes. The aim of this study was to investigate whether the functional -94 insertion/deletion ATTG polymorphism (rs28362491) in the promoter of nuclear factor κB gene (NFKB1) is associated with susceptibility to CHD. Polymerase chain reaction (PCR)-polyacrylamide gel electrophoresis (PAGE) method was used to genotype rs28362491 in 122 atrial septal defect (ASD) patients, 114 ventricular septal defect (VSD) patients, and 412 controls. The frequencies of II (Insertion/Insertion) genotype in the ASD and VSD patients were significantly higher than that of controls (p=0.004 for ASD Vs. controls, and p=0.009 for VSD Vs. controls, respectively), and the frequencies for I allele in CHD patients were also significantly higher than that in controls (p=0.01 for ASD Vs. controls, and p=0.009 for VSD Vs. controls, respectively). This study suggests that the functional -94 insertion/deletion ATTG polymorphism in the promoter of NFKB1 is associated with CHD.

Roles of functional NFKB1 and βTrCP insertion/deletion polymorphisms in mRNA expression and epithelial ovarian cancer susceptibility

Epithelial ovarian cancer (EOC) is the leading cause of death among all gynecological cancers. Nuclear factor-kappa B (NF-κB) is involved in carcinogenesis and in the development of EOC. The β-transducin repeat-containing protein (β-TrCP) is a positive regulator of the NF-κB signaling pathway. Recent studies have indicated that the -94 ins/del ATTG polymorphism in the promoter region of the NFKB1 gene, and the 9N ins/del polymorphism in the 3'-untranslated region of the β-TrCP gene are associated with increased susceptibility to a variety of cancers. We examined a potential association between these two polymorphisms and EOC. Genotypes were determined for 187 patients with EOC and 221 healthy control subjects, using the MassARRAY system. We found a significant association between the -94 ins/del ATTG genotype distribution and EOC. The frequency of the -94 del ATTG allele was significantly lower in EOC patients compared to healthy controls. The NF-κB mRNA level in cancer tissue was significantly correlated with -94 ins/del ATTG genotypes. Compared to the ATTG1/ATTG1 phenotype, the NF-κB mRNA level was 2.089 and 1.257 times higher in the ATTG2 (insertion)/ATTG2 homozygote and the ATTG1 (deletion)/ATTG2 heterozygote, respectively. However, we found no evidence of association between the 9N ins/del polymorphism of the β-TrCP gene and EOC in this Chinese population. Based on these results, we suggest that the NF-κB -94 ins/del ATTG polymorphism is a risk factor for EOC susceptibility.

The nuclear factor-kB functional promoter polymorphism is associated with endometriosis and infertility

An aberrant immunologic mechanism has been suggested to be involved in the pathogenesis of endometriosis. Nuclear factor-kB (NF-kB) plays a key role in the immune and inflammatory response and modulates cell proliferation, apoptosis, adhesion, invasion, and angiogenesis in many cell types involved in the development of endometriosis. We hypothesized a possible relationship between the NFKB1 promoter regulatory polymorphism and endometriosis and/or infertility. A genetic association study comprising 172 infertile women with endometriosis, 77 women with idiopathic infertility and 189 controls was performed. Detection of the -94 insertion/deletion ATTG (rs28362491) polymorphism in the NFKB1 gene was done using the RFLP-PCR (Restriction Fragment Length Polymorphism-Polymerase Chain Reaction) technique. The results were statistically analyzed, and a p-value <0.05 was considered significant. Single-marker analysis revealed a significant association between the -94 insertion/deletion ATTG polymorphism and endometriosis-related infertility (p=0.014, OR=1.47, 95% CI=1.09-1.97), especially in moderate/severe disease cases. Considering the idiopathic infertility group, a significant association was also found (p=<0.001, OR=2.01, 95% CI=1.35-2.98), suggesting that the -94 insertion/deletion ATTG polymorphism is associated with endometriosis and/or infertility. In the population sample studied, the -94 insertion/deletion ATTG polymorphism in the NFKB1 gene was positively associated both with moderate/severe endometriosis and idiopathic infertility.

NFKB1 polymorphism is associated with age-related gene methylation in Helicobacter pylori-infected subjects

CpG island aberrant methylation is shown to be an important mechanism in gene silencing. The important role of NF-κB in the inflammatory response to H. pylori colonization has been indicated. We investigated the influence of NFKB1 polymorphisms, -94 ins/del (rs28362491) and -449 C>G (rs72696119), on the aberrant gene methylation under H. pylori infection. Gastric mucosal samples were obtained from sub-subjects without malignancies. Methylation status of genes (p14ARF, p16INK4a, DAPK and CDH1) was determined by methylation-specific PCR (MSP). The genotyping of NFKB1 was performed by PCR-SSCP. There was a strong allelic association between rs28362491 and rs72696119, and all H. pylori-infected -94 del/del homozygotes had a -449 GG genotype. The -94 del/del homozygosity was significantly associated with risk for development of CpG island high methylation (CIHM) (two or more gene methylations), especially DAPK and CDH1 methylations, and the number of methylated genes was significantly higher in -94 del/del homozygotes than in ins/del and ins/ins (ins carrier) H. pylori-infected elder subjects. In addition, this methylated gene number was significantly increased with age in H. pylori-infected del/del homozygotes, but not in infected ins carriers. Furthermore, the inflammation score was significantly higher in H. pylori-infected del/del homozygotes compared to ins carriers. NFKB1 -94 ins/del ATTG polymorphism (rs28362491) was significantly associated with the increased risk for the development of age-related gene methylation in non-cancerous gastric mucosa under H. pylori-induced inflammation.

NFKB1−94 Insertion/Deletion ATTG Polymorphism Contributes to Risk of Systemic Lupus Erythematosus

Growing evidence has shown that nuclear factor-κB (NF-κB) plays a key role in the initiation and progression of systemic lupus erythematosus (SLE) pathogenesis. A common polymorphism (-94 insertion/deletion ATTG, rs28362491) in the promoter region of NFKB1 gene was identified as functional. The -94del ATTG allele exhibited loss of binding to nuclear proteins and resulted in reduced promoter activity. We investigated the association between NFKB1 -94 insertion/deletion ATTG polymorphism and risk of SLE. A total of 224 SLE patients and 256 control subjects were genotyped using a polymerase chain reaction-polyacrylamide gel electrophoresis strategy and DNA sequencing. We found that the ATTG(1)/ATTG(2) genotype was associated with a significantly decreased risk of SLE (odds ratio=0.52, 95% confidence interval: 0.32-0.87, p=0.012). This finding indicates that the -94 insertion/deletion ATTG polymorphism may play pivotal roles in the development of SLE in the Chinese population. Further studies with larger sample size are warranted to confirm this finding, especially in different populations.

Nuclear Factor (NF) κB polymorphism is associated with heart function in patients with heart failure

BackgroundCardiac remodeling is generally an adverse sign and is associated with heart failure (HF) progression. NFkB, an important transcription factor involved in many cell survival pathways, has been implicated in the remodeling process, but its role in the heart is still controversial. Recently, a promoter polymorphism associated with a lesser activation of the NFKB1 gene was also associated with Dilated Cardiomyopathy. The purpose of this study was to evaluate the association of this polymorphism with clinical and functional characteristics of heart failure patients of different etiologies.MethodsA total of 493 patients with HF and 916 individuals from a cohort of individuals from the general population were investigated. The NFKB1 -94 insertion/deletion ATTG polymorphism was genotyped by High Resolution Melt discrimination. Allele and genotype frequencies were compared between groups. In addition, frequencies or mean values of different phenotypes associated with cardiovascular disease were compared between genotype groups. Finally, patients were prospectively followed-up for death incidence and genotypes for the polymorphism were compared regarding disease onset and mortality incidence in HF patients.ResultsWe did not find differences in genotype and allelic frequencies between cases and controls. Interestingly, we found an association between the ATTG1/ATTG1 genotype with right ventricle diameter (P = 0.001), left ventricle diastolic diameter (P = 0.04), and ejection fraction (EF) (P = 0.016), being the genotype ATTG1/ATTG1 more frequent in patients with EF lower than 50% (P = 0.01). Finally, we observed a significantly earlier disease onset in ATTG1/ATTG1 carriers.ConclusionThere is no genotype or allelic association between the studied polymorphism and the occurrence of HF in the tested population. However, our data suggest that a diminished activation of NFKB1, previously associated with the ATTG1/ATTG1 genotype, may act modulating on the onset of disease and, once the individual has HF, the genotype may modulate disease severity by increasing cardiac remodeling and function deterioration.

A Functional Promoter Polymorphism inNFKB1Increases Susceptibility to Endometriosis

Numerous proinflammatory cytokines, such as TNFalpha and IL-6, which are nuclear factor kappaB (NF-kappaB) target genes, have been shown to promote proliferation in endometriotic cells, and several other genes involved in promoting growth are also NF-kappaB target genes. The aim of this study was to investigate whether the functional insertion/deletion polymorphism (-94 insertion/deletion ATTG) in the promoter of nuclear factor kappaB gene (NFKB1) is associated with susceptibility to endometriosis. Polymerase chain reaction-polyacrylamide gel electrophoresis method was used to genotype the NFKB1 -94 insertion/deletion ATTG polymorphism in 206 women with endometriosis and 365 ethnicity-matched healthy control women. The genotyping method was confirmed by the DNA sequencing analysis. Genotype at the -94 insertion/deletion ATTG polymorphism in the NFKB1 promoter was in Hardy-Weinberg equilibrium in either case or control subjects. The frequency of the ATTG(2)/ATTG(2) genotype and ATTG(2) allele in the endometriosis was significantly higher than that of control subjects (59.7% vs. 37%, odds ratio = 3.069, p < 0.001 for ATTG(2)/ATTG(2) genotype; 75.2% vs. 59.7%, odds ratio = 2.049, p < 0.001 for ATTG(2) allele), indicating that the -94 insertion/deletion ATTG polymorphism in the NFKB1 promoter was associated with endometriosis. This study suggests that the functional -94 insertion/deletion ATTG polymorphism in the promoter of NFKB1 is associated with an increased risk for endometriosis.

The del/del genotype of the nuclear factor-κB -94ATTG polymorphism and its relation to aggressive periodontitis

Periodontitis is influenced by specific host-dependent immune responses. Periodontopathogens induce innate immune responses, amongst others, via toll-like receptor 2 (TLR2), resulting in activation of the nuclear transcription factor nuclear factor-kappaB (NF-kappaB). The aim of this case-control study was to evaluate links between genetic variants of these genes and chronic/aggressive periodontitis in a multivariate model. A total of 141 patients with periodontitis (63 with chronic periodontitis and 78 with aggressive periodontitis) and 81 controls without periodontitis were included in the study. Polymorphisms in TLR2 (Arg677Trp, Arg753Gln) and in NF-kappaB (-94ins/delATTG) were determined by restriction fragment length polymorphism and fragment length analyses, respectively. Subgingival bacterial colonization was evaluated using a PCR/DNA probe test (micro-Ident). Although there was no association of the TLR2 polymorphism Arg753Gln with periodontitis, heterozygous carriers (Arg/Gln) were at a higher risk for colonization with bacteria of the 'red complex' (corrected p-value = 0.042). The del/del genotype of the NF-kappaB polymorphism was associated with aggressive periodontitis considering age, gender, smoking and approximal plaque index as potential confounders (odds ratio = 2.81, p = 0.035, 95% confidence interval: 1.08-7.33). del/del carriers had a higher risk for subgingival colonization with Aggregatibacter actinomycetemcomitans (odds ratio = 2.36, p = 0.030, 95% confidence interval: 1.09-5.1; adjusted for age, gender, smoking and pocket depth(bacteria)). The del/del genotype of NF-kappaB was shown to be associated with the occurrence of aggressive periodontitis.

Relationship between NFKB1 -94 insertion/deletion ATTG polymorphism and susceptibility of cervical squamous cell carcinoma risk

BackgroundA very high expression of nuclear factor-kappa B protein (nuclear p50, encoded by NFKB1) in high-grade squamous intraepithelial lesion and invasive cancers has been observed. The aim of this study was to determine whether the functional NFKB1 -94 insertion/deletion ATTG polymorphism (rs28362491) is associated with cervical squamous cell carcinoma (CSCC). Materials and methodsPCR–polyacrylamide gel electrophoresis method was used to genotype the NFKB1 -94 insertion/deletion ATTG polymorphism in 233 women with CSCC and 365 ethnicity-matched healthy control women. The genotyping method was confirmed by the DNA sequencing analysis. ResultsThe frequency of ATTG2/ATTG2 genotype and ATTG2 allele in the CSCC patients was significantly higher than that of controls, indicating that the -94 insertion/deletion ATTG polymorphism in NFKB1 promoter was associated with CSCC [P=0.001, odds ratio (OR)=2.560, 95% confidence interval (CI) 1.459–4.492 and P=0.001, OR=1.493, 95% CI 1.168–1.908, respectively]. Results of stratified analyses revealed that this polymorphism is associated with younger age (≤35 years) and positive parametrial invasion but not with tumor differentiation, high clinical stage or lymph node status. ConclusionOur results indicate that the functional NFKB1 -94 insertion/deletion ATTG polymorphism is associated with CSCC, especially with younger age (≤35 years) and positive parametrial invasion of CSCC patients.

IL-8 −251 T > A Polymorphism Is Associated with Bladder Cancer Susceptibility and Outcome after BCG Immunotherapy in a Northern Indian Cohort

Chemokines and transcription factor NF-kappaB play a pivotal role in development of carcinoma of the bladder (CaB). The present study was conducted to analyze the association of chemokines IL-8 -251 T>A and +678 C>T and NF-kappaB -94 (ATTG) insertion/deletion polymorphisms with the risk of CaB and outcome after bacillus Calmette-Guerin (BCG) immunotherapy in a cohort of northern India. Histologically confirmed 205 CaB cases and 270 controls were included. Of these, 71 patients were treated with BCG immunotherapy. Genotyping was done using allele-specific PCR methodology. The variant genotype (AA) of IL-8 -251 polymorphism was associated with more than 2-fold risk of CaB (OR 2.12; p = 0.003; 95% CI 1.28-3.52). None of the other genotypes showed association with CaB risk. Subsequently, the diplotype -251A/+678T demonstrated a 1.8-fold increased risk for CaB (OR 1.84, 95% CI 1.37-2.47). Furthermore, -251 AA genotypes reduced the risk of recurrence after BCG immunotherapy (AA; HR 0.12; 95% CI 0.04-0.41). Subsequently, improved recurrence-free survival (mean recurrence-free survival for GG, GA and AA genotypes was 24, 39 and 53 months respectively). Similarly, NF-kappaB ATTG Ins/Ins genotype was at reduced risk of recurrence after BCG treatment compared to Del/Del genotype, which exhibited a 2.5-fold increased risk of recurrence in patients treated with BCG immunotherapy (HR, 2.53; 95% CI 1.00-6.36). Subsequently, mean recurrence-free survival (Ins/Ins, 41; Ins/Del, 44 and Del/Del, 10 months; log rank, 0.030). Our results suggested that the IL-8 -251 T>A polymorphism may be a relevant host susceptibility factor for bladder carcinoma development and may influence outcome after BCG immunotherapy. Similarly, NF-kappaB ATTG polymorphism may also modify risk-free survival of BCG-treated patients.

6634 Evidence for angiogenesis-independent contribution of VEGFR1 (FLT1) in gastric cancer recurrence

Hashimoto thyroiditis (HT) is a chronic inflammatory autoimmune disease of thyroid gland affected by interaction of multiple genes and various cytokines. Variants in the genes coding for the NFKB and IKB proteins can be potentially involved in the development of the inflammatory diseases. NFKB, a key transcription factor of the regulation of immune responses, is interesting candidate for association studies about autoimmune disorder.The aim of the present study was to investigate the relationship between NFKB1 and NFKBIA (NFKB1 inhibitor gene) polymorphisms, and the risk of HT in a Turkish Population in the context of IL-6 serum levels which may contribute to susceptibility to the disease. We analyzed the distribution of NFKB1-94 ins/del ATTG and NFKBIA 3′UTR A → G polymorphisms using PCR-RFLP method and IL-6 serum levels using ELISA method in 120 HT patients and 190 healthy controls in Turkish population.Although, there was no statistical significant difference in distribution of the genotypes and alleles of NFKB1-94 ins/del ATTG or NFKBIA 3′UTR A → G polymorphisms in patients and control subjects as single, ins/ins/GG combined genotype had protective effect on the disease when compared to ins/ins/AG combined genotype as combined genotypes of both polymorphisms. In addition to this finding, IL-6 serum levels in HT patients with del/del genotype were significantly higher than in patients with del/ins genotype (p < 0.001). According to the combined genotype analysis of NFKB1-94 ins/del ATTG and NFKBIA 3′UTR A → G polymorphisms, IL-6 levels were also higher in patients with del/del genotype when at least one G allele existing (p = 0.007).Therefore, our findings suggest that the functional promoter NFKB1-94 ins/del ATTG polymorphism was significantly associated with population HT disease through acting by directly modulating IL-6 serum levels.

NFKB1 –94 Insertion/Deletion ATTG Polymorphism in Gastroenteropancreatic Neuroendocrine Tumors

Nuclear factor-κB (NF-κB) is a transcription factor responsible for modulating the expression of many genes involved in immune response, inflammatory process, cell growth and survival. A functional and common promoter polymorphism of the NF-κB1 (NFKB1) gene leads to alteration in the activation pattern and expression of NF-κB, and thus, is probably associated with carcinogenesis. The aim of this study was to detect the importance and the frequency of NFKB1 –94 insertion/deletion ATTG promoter polymorphism in patients with gastroenteropancreatic neuroendocrine tumor. A case-control cohort including 50 patients with gastroenteropancreatic neuroendocrine tumor and 100 healthy controls was genotyped with the polymerase chain reaction method. Polymerase chain reaction products were analyzed in agarose gel electrophoresis and processed with the Van91I restriction enzyme. There are 2 cleavage points on the amplified region. When ATTG insertion or deletion is present, the function of restriction enzyme changes. Thirty patients (60%) had ID (insertion/deletion), 18 (36%) had II (insertion/insertion) and 2 (4%) had DD (deletion/deletion) genotypes. Fifty-eight of the control group (58%) had ID, 30 (30%) had II and 12 (12%) had DD genotypes. The frequencies of D and I alleles were 34 and 66 in the study group, and 82 and 118 in the control group, respectively. Although the frequencies of I and D alleles and genotype distribution did not differ between the study and control groups, there seem to be important differences concerning the DD genotype analyses of the NFKB1 –94ins/delATTG promoter polymorphism between patients with pancreatic neuroendocrine tumor and those with carcinoid tumor. This may support the view that the genetics of carcinoid tumors and pancreatic neuroendocrine tumors are different and should be further studied.