Ö. Ates

Interleukin-10 and Tumor Necrosis Factor-α Gene Polymorphisms in Tuberculosis

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is an infectious disease in humans killing nearly three million people and eight million cases annually. The cytokines TNF-α and IL-10 have been implicated in the pathogenesis of TB. Certain single nucleotide polymorphisms within the promoter region of the IL10 and TNF genes have been associated with altered levels of circulating IL10 and TNF- α. We analyzed TNF-α (−308 G/A, −238 G/A, −376 G/A) and IL10 (−1,082 G/A, −819 C/T, −592 C/A) polymorphisms in 128 patients with TB and 80 healthy subjects using by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). A significant association was found between TB and −1,082 G allele (Pc: 0.000, O.R 2.22, 95% CI 1.45–3.41). Significant difference was observed in IL10 GCC and ACC haplotypes distribution between TB and control subjects (Pc: 0.000, O.R 2.22, 95% CI 1.45–3.41; Pc: 0.004, O.R 0.53, 95% CI 0.35–0.81). No statistically significant association was found between IL-10 −819 C/T, TNF-α 308 G/A, −238 G/A, −376 G/A polymorphisms, functional TNFα/IL-10 genotypes and TB. Our findings suggest that IL-10 108 2G/A alleles or haplotypes containing these alleles may influence the Th1/Th2 balance and hence may play a role in TB susceptibility and increase risk of developing disease. This polymorphism may be one of the many genetic factors affecting disease outcome.

Tumor necrosis factor-alpha and Interleukin-10 gene promoter polymorphisms in Turkish rheumatoid arthritis patients

Tumor necrosis factor and interleukin 10 have been implicated in the pathogenesis of rheumatoid arthritis (RA). Certain single-nucleotide polymorphisms (SNPs) within the promoter region of the IL-10 and TNF genes have been associated with altered levels of circulating IL10 and TNF. We aimed to explore the association of IL-10 and TNF-α polymorphisms in Turkish RA patients. We analyzed the association of TNF-α (−308G/A, −238G/A, −376G/A) and IL10 (−1082G/A, −819C/T, −592C/A) polymorphisms in 98 Turkish patients with rheumatoid arthritis and 122 healthy subjects using ARMS-PCR. The correlation of these findings with RF positivity and erosive disease in RA patients was also sought. A significant association was found between having RA and −1082 G allele (p = 0.008; OR = 1.44, 95% CI 1.11–1.86). There was no association between RA and −819C/T polymorphism. Significant differences were observed in IL10 GCC and ACC haplotypes distribution between RA and control subjects (p = 0.006; OR = 1.46, 95% CI 1.13–1.89 and p = 0.011; OR = 1.43, 95% CI 1.09–1.88, respectively). No statistically significant association was found between TNF-α 308G/A, −238G/A, −376G/A polymorphisms and RA. No significant association was found between RF positivity and erosive disease and TNF-α, IL10 gene polymorphisms. In addition, when combined genotypes were analyzed, no significant difference was found between RA patients and healthy controls. Our findings suggest that IL-10 1082 G/A polymorphism or GCC, ACC haplotypes may be associated with RA in Turkish patients.

The association between BsmI variant of vitamin D receptor gene and susceptibility to tuberculosis

Vitamin D receptor (VDR) gene variants may play a key role in the susceptibility to tuberculosis (TB). We have investigated the association BsmI, TaqI, FokI polymorphisms in the VDR gene with susceptibility to tuberculosis. This study included 128 patients with TB (pulmonary and extrapulmonary TB) and 80 healthy subjects living in Istanbul, Turkey. Genetic polymorphisms were studied by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) techniques at genomic DNA isolated from whole blood-EDTA. The present study results indicate that the genotype and allele frequencies for patient group (BB:22, Bb:53, bb:25; B allele:48%, b allele:52%) was significantly different from the control group (BB:6, Bb:48, bb: 46; B allele:30 b allele:70) due to an overrepresentation of B allele (P: 0.000 OR: 1.61 95% 1.23–2.11). However there were no significant differences in distribution of allele/genotype frequencies of FokI, TaqI variants between TB and healthy controls. This study results suggest that BsmI variant of VDR gene may play an important role in susceptibility to tuberculosis.

Factor V Leiden, Prothrombin G20210A, and Protein C Mutation Frequency in Turkish Venous Thrombosis Patients

Several inherited polymorphisms are associated with risk of venous thrombosis, including mutation at codon 506 of the factor V gene, mutation at position 20210 of the prothrombin gene, and mutations in the protein C gene. In this study, genotyping for factor V, prothrombin, and protein C mutations was performed in 50 patients and 25 control subjects by polymerase chain reaction—based analysis. The prevalence of factor V and prothrombin mutations was not significantly different from that in the general population. Nine of the patients had heterozygous protein C mutation. There was a high prevalence of the mutated protein C allele in the pulmonary emboli group (42.8%). Protein C mutation incidence was higher in the pulmonary emboli group than in the deep vein thrombosis (8.33%) and cerebral vein thrombosis (16.1%) groups. These results indicate that patients with protein C deficiency have a greater risk of thrombosis than patients with factor V or prothrombin G20210A mutation.

Analyses of functional IL10 and TNF-α genotypes in Behçet’s syndrome

We aim to ascertain the possible involvement of functional IL10 and TNF-α promoter polymorphisms on the susceptibility to Behçet’s syndrome (BS), to examine whether IL10 and TNF-α genotypes might work synergistically influencing susceptibility to BS. IL10 −1082G/A, −819C/T and −592C/A and TNF −308G/A polymorphisms were analyzed in 102 Turkish patients with BS and 102 healthy subjects by using amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). We have found no significant associations between IL10 −1082G/A, −819C/T, −592C/A, TNF-α −308G/A polymorphisms and BS. Also, no significant correlation was found between IL10 GCC, ACC, ATA haplotypes, GCC+/GCC+, GCC+/GCC−, GCC−/GCC− genotypes. There was no significant association between combined TNF-α/IL10 genotypes and BS. Our study indicates that functional TNF-α, IL10 genotypes or combined TNF-α, IL10 genotypes do not play a role in BS susceptibility in Turkish BS patients.

Association between 'interleukin' 10 gene (IL10) polymorphisms and systemic sclerosis with interstitial lung involvement.

Systemic sclerosis (SSc), also termed as “scleroderma”, is a progressive, systemic disease of unknown origin characterized by excessive fibrosis, vascular abnormalities and immune dysfunction. Extracellular matrix (ECM) production by fibroblasts in SSc is modulated and regulated by cytokines. Since IL10 has antiinflamatory properties and, contributes to the fibrotic processes in SSc, we analyzed IL-10 gene polymorphisms including −1082 G/A, −819 C/T and −592C/A in 45 systemic sclerosis patients with lung involvement and 150 healthy control using ARMS-PCR. While no association was found between SSc and −819C/T, −592C/A polymorphism, −1082 G/A allele frequency in SSc patients was higher than that in control and significant association was found between SSc and −1082 G/A (Pc: <0.000, OR: 2.85 95% CI: 1.74–4.63). In addition significant difference was found between the frequencies of the IL-10 GCC, ACC haplotypes (Pc: <0.000, OR: 2.85, 95% CI: 1.74–4.63; Pc: 0.012, O.R: 1.56, 95% CI: 1.09–2.23, respectively), GCC+/GCC+, GCC−/GCC− genotypes (Pc: 0.002, OR: 5.07, 95% CI: 1.82–14.21; Pc: <0.000, O.R: 4.00, 95% CI: 1.87–8.98, respectively) and SSc. Our findings suggest that IL-10 1082 G/A alleles or haplotypes containing these alleles may play role in SSc susceptibility.

NRAMP1 (SLC11A1): A Plausible Candidate Gene for Systemic Sclerosis (SSc) with Interstitial Lung Involvement

Systemic sclerosis (SSc), also termed “scleroderma,” is a progressive, systemic disease of unknown origin characterized by excessive fibrosis, vascular abnormalities and immune dysfunction. Nramp 1 gene has multiple pleiotropic effects on macrophage activation pathways, including up-regulation of the chemokine/cytokine genes KC, tumor necrosis factor α, interleukin-1 b, inducible nitric oxide syntase, and major histocompatibility complex class II expression, as well as tumoricial activity and antimicrobial activity. All of these pleiotropic effects are important for resistance to infection, but they may also be involved in the induction and maintenance of autoimmune diseases. We analyzed four natural resistance associated macrophage protein 1 (NRAMP1) gene polymorphisms including 5′ promoter (GT)n microsatellite, INT4 (469 + 14G/C), 3′UTR (1729 + 55del4), and D543N (codon 543, Asp to Asn) in 52 systemic sclerosis patients with interstitial lung involvement and 136 healthy controls. We found a significant association between INT4, (GT)n polymorphisms (p = 0.006 and 0.027, respectively), and SSc. Our findings suggest that NRAMP1 is a plausible candidate gene for SSc.

Analysis of transforming growth factor beta 1 (TGF-β1) gene polymorphisms in Turkish patients with scleroderma

Systemic sclerosis (SSc) is an autoimmune disease characterized by inflammation and fibrosis of the skin and visceral organs. Fibrosis associated with SSc is characterized by an increased synthesis of a wide range of extracellular matrix (ECM). TGF‐β is a pluripotent cytokine in a wide range of cell types. In particular it has been found to be a potent inducer of ECM protein synthesis and fibroblast migration. The TGF‐β1 gene is highly polymorphic and two signal sequence polymorphisms at codon 10 and codon 25 are linked to disease outcomes. In this study, we analysed two polymorphic sites of the TGF‐β1 gene, codon 10 and codon 25, in 43 Turkish SSc female patients with interstitial lung involvement and in 75 healty individuals by ARMS‐PCR. In our study no significant difference was found in codon 10, codon 25 genotype frequencies between patient with SSc and the control group (p = 0.676, 0.375, respectively). Our findings suggest that codon 10 and 25 polymorphism cannot be related with SSc for Turkish population. Copyright

Analysis of TNF polymorphisms in Turkish systemic sclerosis patients with interstitial lung involvement.

Systemic sclerosis (SSc), also termed scleroderma, is a progressive, systemic disease of unknown origin characterized by excessive fibrosis, vascular abnormalities, and immune dysfunction (LeRoy et al. 1988). Clinical findings of scleroderma are sclerotic changes in the skin, joints, and internal organ systems, for instance, lungs, heart, and gastrointestinal tract (Haustein 2002; Medsger 1997). The major pathological process of scleroderma comprises inflammation (Brinckmann et al. 2005). Tumor necrosis factor (TNF), one of the cytokines involved in inflammation, is produced by monocytes (secrete TNF-a) and lymphocytes (secrete TNF-b and LTb) (Beutler and Cerami 1989). The TNF-a gene has a highly polymorphic transcriptional region (Li Kam Wa et al. 1999; Witte et al. 2002). The -308G/A