Association of the TNF-α, IL-2, and IL-2RB gene variants with susceptibility to psoriasis in a Turkish cohort.

AIM OF THE STUDY: The aim of this study was to investigate the role TNF-α, IL-2, and IL-2RB variants in psoriasis (Ps) and to evaluate the association between these variants and clinical features. MATERIAL AND METHODS: A total of 74 psoriatic patients and 74 healthy individuals were genotyped for these variants by PCR and/or RFLP. RESULTS: The AA genotype of TNF-α (-308) was significantly more common in the patients (p = 0.013). TNF-α (-238) AA genotype was significantly increased in the patients (p = 0.028), while the GG genotype was decreased in the patient group, compared to the controls (p = 0.016). IL-2 (-330) variant GG and TT genotype was more common in the patients (p = 0.037, p = 0.009, respectively), while IL-2 (-330) GT genotype was increased in the control subjects (p = 0.001). IL-2 (-330) GG genotype frequency was significantly decreased (p = 0.021) and the TT genotype frequency was significantly increased among patients with psoriatic arthritis in comparison with Ps patients (p = 0.014). IL-2RB TC genotype frequency was significantly decreased and TT genotype frequency was significantly increased in the patients with positive family history of Ps compared to those who had a negative family history (p = 0.017, p = 0.014, respectively). Also, IL-2RB CC genotype was significantly increased among the patients with late-onset Ps in comparison with the early onset Ps group (p = 0.009). The frequency of IL-2 (-330) TT genotype was significantly higher in mild Ps patients than moderate-severe patients (p = 0.043). CONCLUSIONS: Our data suggest a potential role of these genes as candidate genes for susceptibility to Ps in a Turkish cohort.

Identification QTLs Controlling Genes for Se Uptake in Lentil Seeds.

Lentil (Lens culinaris Medik.) is an excellent source of protein and carbohydrates and is also rich in essential trace elements for the human diet. Selenium (Se) is an essential micronutrient for human health and nutrition, providing protection against several diseases and regulating important biological systems. Dietary intake of 55 µg of Se per day is recommended for adults, with inadequate Se intake causing significant health problems. The objective of this study was to identify and map quantitative trait loci (QTL) of genes controlling Se accumulation in lentil seeds using a population of 96 recombinant inbred lines (RILs) developed from the cross "PI 320937" × "Eston" grown in three different environments for two years (2012 and 2013). Se concentration in seed varied between 119 and 883 µg/kg. A linkage map consisting of 1,784 markers (4 SSRs, and 1,780 SNPs) was developed. The map spanned a total length of 4,060.6 cM, consisting of 7 linkage groups (LGs) with an average distance of 2.3 cM between adjacent markers. Four QTL regions and 36 putative QTL markers, with LOD scores ranging from 3.00 to 4.97, distributed across two linkage groups (LG2 and LG5) were associated with seed Se concentration, explaining 6.3-16.9% of the phenotypic variation.

Might there be a link between intron 3 VNTR polymorphism in the XRCC4 DNA repair gene and the etiopathogenesis of rheumatoid arthritis?

DNA repair genes are involved in several diseases such as cancers and autoimmune diseases. Previous studies indicated that a DNA repair system was involved in the development of rheumatoid arthritis (RA). In this study, we aimed to examine whether four polymorphisms in the DNA repair genes (xeroderma pigmentosum complementation group D [XPD], X-ray repair cross-complementing group 1 [XRCC1], and X-ray repair cross-complementing group 4 [XRCC4]) were associated with RA. Sixty-five patients with RA and 70 healthy controls (HCs) were examined for XPD (A-751G), XRCC1 (A399G), and XRCC4 (intron 3 VNTR and G-1394T) polymorphisms. All polymorphisms were genotyped by PCR and/or PCR-RFLP. The association between the polymorphisms and RA was analyzed using the chi-square test and de Finetti program. The intron 3 VNTR polymorphism in the XRCC4 gene showed an association with RA patients. The DI genotype was found lower in RA patients (χ(2)=8.227; p=0.0021), while the II genotype was higher in RA patients (χ(2)=5.285; p=0.010). There were deviations from the Hardy-Weinberg Equilibrium (HWE) in both intron 3 VNTR and G-1394T polymorphisms in the XRCC4 gene and in the polymorphism in the XRCC1 gene, and the observed genotype counts deviated from those expected according to the HWE (p=0.027, 0.004, and 0.002, respectively); however, there was no deviation in the other gene polymorphisms. There is no statistical difference between the RA patients and HCs for XPD (A-751G), XRCC1 (A399G), and XRCC4 (G-1394T) gene polymorphisms (p>0.05). Although XPD (A-751G), XRCC1 (A399G), and XRCC4 (G-1394T) gene polymorphisms have been extensively investigated in different clinical pictures, this is the first study to evaluate the role of these polymorphisms in the genetic etiopathogenesis of RA in Turkish patients. In conclusion, we suggested that the intron 3 VNTR polymorphism in the XRCC4 gene may be associated with the etiopathogenesis of RA as a marker of immune aging.

Prognostic importance of single-nucleotide polymorphisms in IL-6, IL-10, TGF-ß1, IFN-γ, and TNF-α genes in chronic phase chronic myeloid leukemia.

The aim of this study was to explore the association between polymorphisms of five cytokine genes and clinical parameters in patients with Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) treated with imatinib. We analyzed five cytokine genes (interleukin [IL]-6, IL-10, gamma interferon [IFN-γ], transforming growth factor beta-1 [TGF-ß1], and tumor necrosis factor-alpha [TNF-α]) in 60 cases with Ph+ CML and 74 healthy controls. Cytokine genotyping was performed by the polymerase chain reaction-sequence-specific primer. All data were analyzed using the de Finetti program and SPSS version 14.0 for Windows. No significant differences were detected between the CML group and healthy controls with respect to the distributions and numbers of genotypes and alleles in TNF-α, TGF-ß1, IL-10, and IFN-γ. However, the GG genotype associated with high expression in IL-6 was found to be significantly more frequent in CML as compared to controls (p=0.010). The median follow-up time was 49.3 months (range 6.1-168.4) and the median duration of imatinib treatment was 39.5 months (range 5.2-103.4) for these patients. On multivariateanalysis, only IL-10 GCC/GCC highly produced haplotypes were significantly associated with a shorter event-free survival. The relationship between cytokine genotypes/haplotypes and clinical parameters in CML has not been investigated before. Our results suggest that IL-10 may be a useful marker for CML prognosis and theGG genotype of the IL-6 gene may be associated with susceptibility.

Can mycoplasma contribute to formation of prostate cancer?

PURPOSE: To reveal the possible role of mycoplasmas in the etiopathogenesis of prostate cancer. METHODS: In the study, prostate biopsy was performed on 62 patients with an abnormal digital rectal examination and/or elevated PSA. The patients' age was between 62 and 77 (mean 65.4 years) years. Thirty-one patients had adenocarcinoma of the prostate histopathologically (group 1). From these patients, the specimens were divided into two subgroups as specimens with malignant findings (group 1A) and specimens with benign findings (group 1B). The control group consisted of 31 patients with benign prostatic hyperplasia (group 2). In the specimens, the presence of mycoplasma DNA was investigated by the polymerase chain reaction method. RESULTS: The mycoplasma DNA was found to be positive in 11 (35.4 %) patients in group 1A and in 4 (12.9 %) patients in group 1B. There was no mycoplasma DNA in the patients in group 2. The differences between group 1A and group 1B, and between group 1A and group 2 were statistically significant (p values, respectively, 0.006 and 0.0001). CONCLUSIONS: Our data supported the thesis that mycoplasma infections play a role in the etiopathogenesis of the prostate cancer.

Association of macrophage migration inhibitory factor and mannose-binding lectin-2 gene polymorphisms in acute rheumatic fever.

BACKGROUND: Macrophage migration inhibitory factor and mannose-binding lectin-2 play important roles in the pathogenesis of several acute and chronic inflammatory/autoimmune disorders. The aim of the study was to investigate any possible association between migration inhibitory factor and mannose-binding lectin-2 gene polymorphisms and acute rheumatic fever in children. Material and methods A total of 38 unrelated children with acute rheumatic fever and 40 age- and sex-matched healthy controls were analysed for codon 54 A/B polymorphism in mannose-binding lectin-2 gene and -173 G/C polymorphism in migration inhibitory factor gene by using the polymerase chain reaction method. RESULTS: Frequency of BB genotype of mannose-binding lectin-2 gene was higher in the patient group. Interestingly, children with acute rheumatic fever with AA genotype tended to have chorea compared with children with BB genotype. There was a statistically significant increase in frequency of the migration inhibitory factor -173 CC genotype in patients compared with the control subjects. CONCLUSION: The present study is the first to investigate the mannose-binding lectin-2 gene polymorphism in children with acute rheumatic fever. BB genotype of mannose-binding lectin-2 (codon 54) and CC genotype of migration inhibitory factor (-173) may have a role in the immunoinflammatory process of acute rheumatic fever.

Mannose binding lectin and macrophage migration inhibitory factor gene polymorphisms in Turkish children with cardiomyopathy: no association with MBL2 codon 54 A/B genotype, but an association between MIF -173 CC genotype.

Myocardial inflammation is one of the commonest mechanisms in cardiomyopathy (CMP). Mannose binding lectin (MBL) is a key molecule in innate immunity, while macrophage migration inhibitory factor (MIF) is a constitutive element of the host defenses. We investigated the possible association between polymorphisms of MBL2 and MIF genes and CMP in Turkish children. Twenty-children with CMP and 30 healthy controls were analyzed for codon 54 A/B polymorphism in MBL, and -173 G/C polymorphism in MIF genes by using PCR-RFLP methods. No significant difference was found between genotypes and alleles of MBL2 gene codon 54 A/B polymorphism in patients and controls (p>0.05). However, serum uric acid levels was found higher in dilated CMP patients with AA genotype. Frequency of MIF -173 CC genotype was significantly higher in patients (p<0.05), and sodium levels were higher in patients with MIF -173 CC genotype. This study is the first to investigate the MBL and MIF gene polymorphisms in Turkish children with CMP. We conclude that CC genotype of MIF (-173) polymorphism may be a risk factor for CMP patients. However, further studies with larger samples are needed to address the exact role of this polymorphism in CMP.

Role of cytokine gene (IFN-γ, TNF-α, TGF-ß1, IL-6, and IL-10) polymorphisms in pathogenesis of acute rheumatic fever in Turkish children.

UNLABELLED: Acute rheumatic fever (ARF) is a delayed immunologically mediated sequela of throat infection by group A ß-hemolytic streptococci. Inflammatory cytokines may play a pathogenic role in ARF. The objective of this study was to investigate the potential associations between interferon (IFN)-γ, interleukin (IL)-6, tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-ß1, and IL-10 gene polymorphisms and childhood ARF. Thirty-eight ARF patients and 40 age- and sex-matched healthy controls were analyzed for eight polymorphisms in five different cytokine genes [IFN-γ (+874), IL-6 (-174), TNF-α (-308), TGF-ß1 (+10, +25), and IL-10 (-1082, -819, -592)]. Cytokine genotyping was performed by polymerase chain reaction sequence-specific primer methods. Patients with ARF had significantly higher frequencies of IFN-γ (+874) polymorphism in both TT genotype (p=0.0002) and T allele (p=0.0004). No statistically significant differences were observed in genotypes, haplotypes, and allele frequencies of IL-6, TNF-α, TGF-ß1, and IL-10 genes between ARF and control groups (p>0.05). GG genotype frequency of TNF-α gene (low expression) was higher in patients who had previous ARF history (p=0.006). High expression of TGF-ß1 (TT/GG, TC/GG) was more frequent in patients with CRP positivity (p=0.034). IL-6 CC genotype (low expression) frequency was higher in patients with tricuspid valve insufficiency (p=0.002), while IFN-γ TT genotype (high expression) frequency was higher in patients with mitral valve prolapse (p=0.049). CONCLUSION: High expression of the IFN-γ gene may carry a higher risk for ARF in Turkish children, while IL-6, TNF-α, and TGF-ß1 may have an impact in mediating some clinical and laboratory manifestations of the disease.

Genetic variation of myeloperoxidase gene contributes to preeclampsia: a preliminary association study in Turkish population.

OBJECTIVE: To examine MPO gene polymorphisms of women with preeclampsia in Turkish population. METHODS: Sixty-one preeclamptic and 61 normotensive women without history of preeclampsia in earlier pregnancies were enrolled in this prospective controlled study. MPO mutations were characterized by PCR-RFLP method. RESULTS: We demonstrated a significant difference in patients with preeclampsia in terms of genotype frequency. Heterozygous carriers of -463A among preeclamptic pregnancies were significantly frequent, whereas rare A/A homozygotes failed to differ from controls. CONCLUSION: The -463G/A polymorphism of leukocyte MPO could be an intriguing susceptibility factor that modulates an individual's risk of preeclampsia in Turkish population.

Endothelial nitric oxide synthase gene polymorphisms in preeclampsia with or without eclampsia in a Turkish population.

AIM: To evaluate endothelial nitric oxide synthase (eNOS) gene polymorphisms in preeclampsia with or without eclampsia in a Turkish population. MATERIAL AND METHODS: Fifty-seven preeclamptic and 60 normotensive women were enrolled in the present study. The study focused on two functional variants: a variant in exon 7-G to T conversion at nucleotide position 894 resulting in the replacement of glutamic acid with aspartic acid at codon 298 (Glu298Asp) and a variant variable number of 27 bp tandem repeats in intron 4 (VNTR intron 4). Two polymorphisms in the maternal eNOS gene were characterized by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. Preeclamptic pregnant women were evaluated into two subgroups according to the presence of eclampsia. RESULTS: We demonstrated a significant difference in patients with preeclampsia in terms of Glu298Asp/eNOS genotype frequency. G/G homozygotes of Glu298Asp among healthy pregnancies were significantly frequent when T/T homozygotes were significantly frequent among preeclamptic pregnancies. We showed that G/T heterozygotes of Glu298Asp/eNOS gene were significantly frequent among preeclamptic pregnant women who did not develop eclampsia than in preeclamptic pregnant women with eclampsia. CONCLUSION: Glu298Asp polymorphism in the eNOS gene could be an individual's risk factor and may modulate progression to an eclampsia complication of preeclampsia in the Turkish population.

Nitric oxide levels and endothelial nitric oxide synthase gene polymorphisms in Turkish women with idiopathic recurrent miscarriage.

OBJECTIVE: To determine whether endothelial nitric oxide synthase (eNOS) gene polymorphisms are associated with an increased risk for Idiopathic Recurrent Miscarriage (IRM) in the Turkish population and to evaluate the association between Nitric Oxide (NO) levels and eNOS gene polymorphisms in women with IRM. MATERIAL AND METHODS: A total of 120 Turkish women were enrolled in this study in four groups. Of these, 30 women were first trimester pregnant who had IRM (Group I). Thirty healthy multipara women were in the first trimester of pregnancy with no history of abortion (Group II). Thirty women were non pregnant with a history of IRM (Group III). The remaining 30 subjects were healthy multipara non-pregnant women with no history of abortion (Group IV). DNA analysis of four groups were performed for the two polymorphisms using the PCR and/or PCR-RFLPs method and NO levels were measured spectrophotometrically. RESULTS: We observed statistically significant decreased NO levels in the pregnant patient group (p=0.001) while elevated NO levels were measured in the non pregnant patient group (p=0.004). We demonstrated that, while there was no significant difference in terms of VNTR 4/eNOS genotype, there was a marginally significant difference in terms of Glu298Asp/eNOS genotype frequency (p=0.055) in patients with IRM in the Turkish population. We observed no association between NO levels and Glu298Asp/eNOS or VNTR 4/eNOS genotypes in any of the groups. CONCLUSION: The Glu298Asp polymorphism of eNOS could be an intriguing susceptibility factor that modulates an individual's risk of IRM in Turkish population. Further studies to explain the role of the NO pathway in the pathophysiology of IRM are needed.

Gene methylation of SFRP2, P16, DAPK1, HIC1, and MGMT and KRAS mutations in sporadic colorectal cancer.

The aim of this study was to investigate the methylation of the SFRP2, P16, DAPK1, HIC1, and MGMT genes, as well as the mutation of amino acid codons 12 and 13 of the KRAS gene in normal and tumor tissue DNA of patients diagnosed with sporadic colorectal cancer (SCRC). The methylation of gene regions and the KRAS mutations of normal (N) and tumor tissue (T) DNA obtained from 17 patients diagnosed with SCRC and 20 healthy controls were investigated using the polymerase chain reaction and reverse-hybridization methods. There was an Asp mutation in four patients, an Asp and Ser mutations in one patient in codon 12 of the KRAS gene, and an Asp mutation in codon 13 in eight patients. Overall promoter methylation (OPM) in the SFRP2 gene was observed in one N and four T, whereas partial promoter methylation (PPM) was observed in two N and five T. OPM in the P16 gene was present in one T. In the DAPK1 gene, OPM existed in seven T and five N, while PPM was present in two N. In the HIC1 gene, OPM was demonstrated in three T, while PPM was noted in two N; however, no methylation existed in N. In the MGMT gene, OPM occurred in five T and two N, and PPM was present in one T. KRAS mutations in Turkish patients with SCRC are similar to those of other population groups. Methylations in the genes, which underwent methylation analysis, were higher in T in comparison with N, and it has been suggested that significant results would be obtained by making a study with a larger population.

Genetic variation of myeloperoxidase gene contributes to aggressive periodontitis: a preliminary association study in Turkish population.

Myeloperoxidase (MPO) is a lysosomal enzyme found in the azurophilic granules of polymorphonuclear leukocytes. It is involved in the defense against periodontal bacteria, and is also able to mediate inflammatory tissue destruction in aggressive and chronic periodontitis. The aim of this study was to explore the association between MPO-463G/A gene polymorphism and aggressive periodontitis (AgP) and chronic periodontitis (CP). The study included 147 subjects. Probing depth (PD), clinical attachment loss (CAL), plaque index (PI), and gingival index (GI) were recorded as the clinical parameters. Genomic DNA was obtained from the peripheral blood of 32 subjects with AgP, 25 with CP, and 90 reference controls. We genotyped the MPO-463G/A polymorphism using the PCR-RFLP method. All data were analyzed using SPSS version 13.0 for windows. There were no significant differences between the CP patients and controls regarding MPO-463A/G gene polymorphism either in terms of allele frequency or genotype frequency of MPO-463A/G. However, either in terms of allele frequency or genotype frequency of MPO-463A/G, there were significant differences between the AgP patients and the controls. In conclusion, our data suggest that MPO-463G/A may be associated with increased risk of aggressive periodontitis in Turkish patients.

Association between TNF-alpha, TGF-beta1, IL-10, IL-6 and IFN-gamma gene polymorphisms and generalized aggressive periodontitis.

OBJECTIVE: The aim of this study was to investigate links among cytokine genetic variants and generalized aggressive periodontitis (GAgP). METHODS: Thirty-five patients with generalized aggressive periodontitis and 85 healthy controls without periodontitis were included in the study. Probing depth (PD), clinical attachment loss (CAL), plaque index (PI), and gingival index (GI) were recorded as clinical parameters. Polymorphisms of IL-6, IL-10, IFN-gamma, TGF-ss1 and TNF-alpha gene were analysed using the polymerase chain reaction sequence-specific primer method (PCR-SSP). RESULTS: No significant differences were observed for IL-6, IL-10, IFN-gamma, and TGF-ss1 cytokine polymorphisms, from the genotype distribution and allele frequency, between GAgP and healthy control groups. In contrast, significant differences were observed in the TNF-alpha gene polymorphism between GAgP and healthy control groups (P = 0.002). CONCLUSION: Our data suggest that TNF-alpha (-308) may be associated with the development of generalized aggressive periodontitis. These results should be replicated in a larger and more diverse population of patients diagnosed with generalized aggressive periodontitis to determine of these findings are generalizable.

The value of XPD and XRCC1 genotype polymorphisms to predict clinical outcome in metastatic colorectal carcinoma patients with irinotecan-based regimens.

BACKGROUND: Previous studies have suggested that DNA repair enzyme polymorphisms may bear prognostic value in metastatic colorectal carcinoma (MCRC). METHODS: We prospectively treated 43 MCRC patients with irinotecan-based regimens (XELIRI or IFL). Allelic variants of the XRCC1 gene at codon 399 and XPD gene at codon 751 were analyzed in lymphocyte DNA by PCR-RFLP. Clinical outcome variables: overall survival (OAS), progression-free survival (PFS) and the occurrence of grade 3 or 4 hematological and gastrointestinal (GIS) toxicities were evaluated. RESULTS: In the univariate analysis for OAS (n = 43) only XPD and XRCC1 polymorphisms were significant (P = 0.05 and P = 0.04, respectively). After adjustment for performance status (ECOG = 0, 1 vs. 2) and disease extent (single vs. multiple metastatic site), XRCC1 genotype and performance status retained significance (HR = 2.85, P = 0.04, and HR = 3.19, P = 0.02, respectively). Gln/Gln genotype was associated with the greatest risk of death. Type of presentation (metastatic vs. local disease at first presentation) was the only significant predictor of PFS in the univariate analysis (n = 40, P = 0.003). After adjustment for performance status and disease extent, type of presentation retained its significance (HR = 4.35, P = 0.003). None of the toxicities was associated with these genotypes. CONCLUSIONS: XRCC1 genotype independently predicted overall survival in metastatic colorectal carcinoma patients treated with irinotecan-based chemotherapy.

Enzyme levels and G-463A polymorphism of myeloperoxidase in chronic lymphocytic leukemia and multiple myeloma.

The aim of this study was to investigate how myeloperoxidase (MPO) G-463A gene polymorphism and enzyme levels varied among patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) and to find the relationship between the MPO gene, enzyme levels, and clinical parameters. We studied the sera from 40 healthy volunteers, patients with CLL (n = 34) and MM (n = 28). In subjects with homozygote GG genotype, MPO levels were higher in the patients with both CLL and MM than in the control group. This difference was statistically significant in patients with CLL. In conclusion, homozygote GG genotype is found to be associated with an increasing amount of serum MPO. In accordance with the results of the study, we assess that the increase in the MPO enzyme level in the patient groups with CLL and MM generated bactericidal effects as well as the increased formation of ROP, thus setting off a pro-cell death pathway and playing a role on the pathogenesis of lymphoproliferative malignancies through this mechanism.

Analysis of myeloperoxidase promotor polymorphism and enzyme activity in Turkish patients with vitiligo.

Vitiligo is an acquired depigmentary disorder characterized by white areas of the skin due to loss of epidermal melanocytes. Oxidative stress and free radicals are suggested as important phenomena in the pathogenesis of vitiligo. Myeloperoxidase is a lysosomal enzyme of polymorphonuclear leukocytes and acts as a catalyst in the production of hypochlorous acid, a powerful oxidant. In this study we analysed enzyme activity and gene polymorphism of myeloperoxidase in patients with vitiligo. Fifty-four patients with vitiligo and 58 healthy controls were enrolled to this study. Patient groups were subdivided according to localization of the lesions; generalized, acrofacial and local. Plasma myeloperoxidase enzyme activity was determined with ELISA and G-463A gene (-463) polymorphism with the PCR-RFLP (AciI) method. The plasma MPO level was significantly lower in vitiligo patients than in the healthy controls (p = 0.005), however, it was not significantly different among subtypes of vitiligo (p = 0.8). A significant difference was not observed for G-463A genotype and allele distribution in patients with vitiligo. In conclusion, the present study is the first study investigating MPO G-463A polymorphism and enzyme levels, which warrants further studies with higher patient numbers and broader polymorphism panels.