IL-8 Gene Variants and Expression in Childhood Asthma.

PURPOSE: To examine the IL-8 expression levels and association of genetic variants with the risk of childhood persistent asthma prognosis. METHODS: Overall, 170 asthmatic children and 170 healthy controls were included in this case-control study. The human IL-8 serum levels were measured using ELISA. The IL-8 mRNA expression levels were assessed by a real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. RESULTS: The IL-8 expression at both protein and mRNA levels was found to be significantly elevated in asthmatic children compared to healthy subjects (P < 0.0001, P = 0.004; respectively). Higher levels of IL-8 mRNA are detected in subjects with moderate to severe asthma. The presence of IL8-251 A/T (rs4073) and + 781C/T (rs2227306) polymorphisms was significantly associated with an increased risk of asthma (P = 0.002, P = 0.036, respectively). In addition, we noted a significant association between these polymorphisms and an elevated risk of atopic asthma (P < 0.05). For rs2227306 SNP, the highest median level of IgE was detected for the presence of TT genotype (865 ± 99.74 IU/mL). Although, the rs4073 polymorphism conferred a higher risk to develop asthma at an advanced stage of severity (P = 0.008). The rs4073 T and rs2227306 C alleles are considered as risk factors for asthma development. The rs4073 T allele is represented also as a risk factor for asthma severity in Tunisian children. CONCLUSIONS: Both IL-8 gene and protein expression may play a key role in asthma pathogenesis.

Interleukin-17A and -17F genes polymorphisms in lung cancer.

Interleukin-17 (IL-17) is a proinflammatory cytokines produced by T helper 17 (Th17) cells, which plays an important role in both innate and adaptive immune systems. Genetic variants in the IL-17 genes may influence the immunopathogenesis of many cancers. In our study, we investigated the association of three single-nucleotide polymorphisms (SNPs: -152 G/A, 7488 A/G and 7383 A/G) in the IL-17A and IL-17F genes with lung cancer risk, in the Tunisian population. The genotypic and allelic distributions of IL-17A and IL-17F genes polymorphisms were analyzed by Polymerase Chain-Reaction (PCR) and Restriction Fragment Length Polymorphism (RFLP) for 239 patients and 258 healthy controls. Our results revealed a statistically significant association between IL-17F 7488G allele and increased lung cancer risk (P=0.028). Stratification analysis indicated that IL-17F 7488G allele enhances the risk of lung cancer development among men and oldest age subject groups (P<0.05). Patients with IL-17F 7488G allele were also more likely to be diagnosed at advanced stage (P=0.04), or with metastatic lung cancer (P=0.035). Furthermore, no significant association between IL-17F 7383 A/G, IL-17 -152G/A polymorphisms and lung cancer risk was observed (P>0.05). However, we reported contradictory findings on the association of IL-17 -152 G/A polymorphisms with lung cancer risk. In addition, we suggested the existence of a biological interaction between IL-17A, but not IL-17F polymorphisms and smoking. Our findings suggest that IL-17F 7488G allele is associated with increased lung cancer risk in the Tunisian population.

Association of vitamin D receptor FokI and ApaI polymorphisms with lung cancer risk in Tunisian population.

Many studies reported that Vitamin D Receptor (VDR) gene polymorphisms might influence the cancer risk due to their antiproliferative, antiangiogenic, and apoptotic effects. The aim of this study was to explore the genetic association of VDR polymorphisms with lung cancer risk in Tunisian population. The genotype and haplotype frequencies of four VDR polymorphisms, FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232) and TaqI (rs731236) were studied using polymerase chain reaction and restriction fragment length polymorphism analysis in 240 patients with lung cancer and 280 healthy controls. The distribution of genotype frequencies differed significantly between lung cancer subjects and controls (FokI P adj = 0.002; ApaI P adj = 0.013). Haplotype analyses revealed a significant association between G-A-C and A-C-T haplotypes and lung cancer risk (P corr = 0.0128, P corr = 0.008). When patients were stratified according to gender, age, and smoking, significant associations were detected with FokI and TaqI polymorphisms. We found a lack of association between BsmI, TaqI polymorphisms and lung cancer risk (P > 0.05). Only, the attributable proportion due to interaction and the synergic index for interaction between ApaI polymorphism and smoking were statistically significant (P adj = 0.74, 95 % CI = 0.38-1.20) and (P adj = 0.63, 95 % CI = 0.05-1.21), respectively. Both the additive interaction measures suggested the existence of a biological interaction between SNP ApaI, but not FokI, and smoking. The multiplicative interaction measure was not statistically significant (P > 0.05). This is the first study in Tunisia, which suggested that VDR FokI and ApaI polymorphisms might be risk factors for lung cancer development.

Tumor necrosis factor gene polymorphisms in Tunisian patients with non-small cell lung cancer.

BACKGROUND: Lung cancer (LC) is one of the most lethal malignant disorders; it is generally divided into two groups: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). In our present study we have been interested to NSCLC. Several approaches were adopted to study the etiology or pathophysiology of this disease. As recent reports have focused on the genetic susceptibility to this disease, with many candidate genes studied, we chose TNF in view of the major role it plays in the immune pro inflammatory system and its association with increased risk of a variety of human cancers. We have investigated three polymorphisms in the promoter region of the TNFalpha gene (-308 G/A and -238 G/A) and TNFbeta + 252A > G for their susceptibility to non-small cell lung cancer (NSCLC) in Tunisian population. METHODS: We compared the distribution of these polymorphisms between 133 NSCLC patients and 174 healthy controls using a polymerase chain reaction restriction fragment length-polymorphism (PCR-RFLP) analysis. The frequencies of the two TNFalpha (-238 and -308) "A" alleles were significantly higher in NSCLC patients than in healthy controls respectively (p = 0.01; OR = 1.92; 95% CI 1.14 - 3.23 and p = 0.0000008; OR = 3.65; 95% CI 2.12 - 6.30), whereas the frequency of the TNFbeta + 252 G allele was approximately similar in the two compared groups. RESULTS: This study supports a relationship between TNFalpha -238G/A and TNFalpha -308G/A polymorphisms and the susceptibility to lung cancer. Contrary to other studies, the -308 A and -238A alleles have an inductive action on lung cancer development and progression in our Tunisian population. CONCLUSIONS: This study indicates that the TNFalpha -308G > A and TNFalpha -238G > A would be associated with increased susceptibility to lung cancer but no significant association was found in TNFbeta + 252A > G polymorphism.

CCR2-64I polymorphism is associated with Non-Small Cell Lung Cancer in Tunisian patients.

Single nucleotide polymorphism (SNPs) in genes coding for chemokines may be associated with some cancer. The purpose of this study was to investigate the impact of CCR2-64I and CXCL12-3'A SNPs on the susceptibility and the clinicopathological characteristics of NSCLC (Non-Small Cell Lung Cancer) in the Tunisian population. 170 NSCLC patients and 225 healthy controls screened by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis were enrolled. A significant association for the homozygous genotype CCR2 64I/64I with lung cancer risk was observed (P=0.004). An increased significant frequency of the -64I allele (P=0.0006) was noted in the patient's group. Clinical analysis indicated a positive association of the -64I allele among squamous cell lung carcinoma patients (P=0.003). The CCR2 mRNA extracted from peripheral blood mononuclear cells (PBMC) was found highly expressed in NSCLC patients compared to controls. The same higher levels were found in patients carrying the CCR2 64I/64I genotype. No significant association was retrieved with CXCL12-3'A polymorphism. In conclusion, our results revealed that the subjects with -64I allele of CCR2-64I gene polymorphism, expressed a significantly higher risk for NSCLC risk without influence on its pathological progression.

Association of IL-8 gene polymorphisms with non small cell lung cancer in Tunisia: A case control study.

Interleukin 8 (IL-8), is a proinflammatory chemokine, has been reported to have angiogenic activity and to be responsible for tumor-associated angiogenesis in several cancers. In this study, we aimed to study the (IL-8) gene polymorphism in relation with risk development of non small cell lung cancer in Tunisian patient. Two single nucleotide polymorphisms (-251T/A [rs4073], +781C/T [rs2227306]) of the IL-8 gene were screened in 170 patients with NSCLC and 225 healthy controls by PCR-RFLP. Significant association for the IL-8 -251T/T genotypes (P=0.004) and an increased significant frequency of IL-8 -251T allele were noted in the patient's group (P=0.0007). Clinical analysis indicated a borderline positive association of IL-8 -251T allele among adenocarcinoma patients (P=0.003). Our study indicated that IL-8 -251T allele was highly associated with large tumor size and high grade stage of NSCLC. Moreover, a significantly increased risk of NSCLC was associated with IL-8 +781C allele in patients with large tumor size (T3 and T4) (P=0.004). IL-8 mRNA expression was found highly expressed in NSCLC patients compared to healthy controls. The same higher level was even found in patients carrying IL-8 -251T/T genotype. Our results indicated that the IL-8 promoter polymorphism is associated with NSCLC risk.