Could NCOA5 a novel candidate gene for multiple sclerosis susceptibility?

BACKGROUND: Multiple sclerosis (MS) is an inflammatory immune-mediated demyelinating disease that causes a challenging and disabling condition. Environmental and genetic factors play a role in appearing the state of the disease. Recent studies have shown that nuclear cofactor genes may play a role in the pathogenesis of MS. NCOA5 is a nuclear receptor coactivator independent of AF2 that modulates ERa-mediated transcription. This gene is involved in the pathogenesis of diseases such as psoriasis, Behcet's disease, and cancer. METHODS AND RESULTS: We investigated the relationship between the rs2903908 polymorphism of the NCOA5 gene and MS among 157 unrelated MS patients and 160 healthy controls by RT-PCR. The frequencies of the CC, CT, and TT genotypes were 19.87%, 37.82%, and 42.31%, respectively, for the MS group and 5.63%, 43.75%, and 50.62%, respectively, for the control group. The CC genotype and the C allele were found to be significantly higher in the patient group (the p values were 0.0002 and 0.003, respectively). CONCLUSIONS: The fact that the CC genotype was found to be significantly higher in the patient group compared to the control group (p = 0.0002) and that it had a statistically significantly higher OR value (OR, 95% CI = 4.16, 1.91-9.05) suggests that the C allele may recessively predispose to MS for this polymorphism. These results suggest for the first time that the NCOA5 gene may have an effect on the occurrence of MS through different molecular pathways, which are discussed in the manuscript.

Clinical significance of NCOA5 gene rs2903908 polymorphism in Behçet's disease.

Behçet's disease (BD) is an autoimmune multisystemic disease. The precise etiology of BD is not fully understood; however, it is thought that interactions between genetic and environmental factors play an essential role in its pathogenesis. The nuclear receptor coactivator-5 (NCOA5) gene encodes a coregulator for nuclear receptor subfamily 1 group D member 2 (NR1D2) and estrogen receptor 1 and 2 (ESR1 and ESR2). Also, the NCOA5 gene insufficiency leads to an elevated expression of IL-6, and increased levels of IL-6 were found to be related to the pathogenesis of BD. In this study, we aimed to clarify the impact of the NCOA5 rs2903908 polymorphism on susceptibility and clinical findings of BD. This study included 671 participants (300 BD patients and 371 healthy controls). The analyses of NCOA5 rs2903908 polymorphism was performed by using the TaqMan allelic discrimination assay. The frequency of TT genotype of the NCOA5 rs2903908 polymorphism was found significantly higher in BD patients compared to those in healthy controls (p=0.016, OR=1.46, 95 % CI=1.08-1.99). Also, the frequencies of CT genotype was observed significantly higher in BD patients with genital ulceration and uveitis than without genital ulceration and uveitis (p=0.002 and p=0.005, respectively). The most significant association was found between C allele frequencies of BD patients with and without uveitis (p=0.0001). Our study represents for the first time that the NCOA5 rs2903908 polymorphism seemed to be linked to BD susceptibility and clinical findings.

Investigation of CD40 gene rs4810485 and rs1883832 mutations in patients with recurrent aphthous stomatitis.

OBJECTIVES: Recurrent aphthous stomatitis (RAS) is a common painful disorder affecting oral health, mucosa and overall quality of life. The etiopathogenesis of RAS remains unclear. RAS shows a large genetic diversity among the patients. In present study, we investigated whether CD40 gene rs4810485 and rs1883832 are associated with RAS and its clinical findings in Turkish patients. MATERIALS AND METHODS: Genomic DNA obtained from 387 individuals (160 patients with RAS and 227 healthy controls) were used in the study. CD40 gene rs4810485 and rs1883832 mutations were determined by using polymerase chain reaction with the specific primers. RESULTS: There was no statistically significant difference between the groups with respect to genotype and allele distribution (p>0.05, OR 0.94, 95% CI 0.70-1.28, OR 1.01 95% CI 0.75-1.37, respectively). Additionally, there was no statistically significant difference in the combined genotype analysis of CD40 gene rs4810485 and rs1883832 mutations (p>0.05). CONCLUSIONS: According to our results, we found that CD40 gene mutations are not associated with RAS. We are convinced that CD40 gene mutations do not predispose to develop RAS in Turkish population. To our knowledge, this is the first study regarding CD40 gene rs4810485 and rs1883832 mutations investigated in RAS patients.

The IL4-VNTR P1 Allele, IL4-VNTR P2P2 Genotype, and IL4-VNTR_IL6-174CG P2P1-GG Genotype Are Associated with an Increased Risk of Brucellosis.

In this study, associations between IL-4, IL-6, and macrophage migration inhibitory factor (MIF) polymorphisms and susceptibility to brucellosis were investigated. Consecutive adult patients with no known treatment against brucellosis and who did not have any other autoimmune and/or chronic disorders, were included in this study (n = 120, Group I). Age and sex-matched controls who had no other autoimmune and/or chronic disorders were also included (n = 120, healthy volunteers, Group II). The IL4_P2P2 genotype, IL4_P1 allele, and IL4_variable number of tandem repeats (VNTR)_IL6-174CG compound genotype were found to be more frequent in the patient group than in control subjects. There were significant differences between the patients and controls with respect to the frequencies of the IL4_P2P2 genotype (77.5% versus 87.5%; p = 0.001; OR, 0.36; 95% confidence interval [CI], 0.21-0.62) and the IL4_P1 allele (12.1% versus 6.7%; p = 0.030; OR, 0.92; CI, 1.02-3.64). The IL4-VNTR_IL6-174CG compound genotype was also present at a significantly higher frequency in the patient group than in control subjects (11.7% versus 4.2%; p = 0.027, OR, 3.04; CI, 1.06-8.68). No statistically significant differences in the frequencies of the IL-6-174, MIF-173, IL-4_P1P1, and IL4_P2P1 genotypes were observed between patients and control subjects. The IL4_VNTR P1 allele, P2P2 genotypes, and IL4-VNTR_IL6-174CG P2P1-GG genotypes are common in southern Turkey, and carriers of these polymorphisms are susceptible to brucellosis.

Relationship between major depressive disorder and ACE gene I/D polymorphism in a Turkish population

Abstract Background Major depressive disorder (MDD) is a complex disease and a significant health problem that is prevalent across the world. Angiotensin-converting enzyme (ACE) has an important role in renin-angiotensin system (RAS) and converts inactive angiotensin I to a potent vasopressor and aldosterone-stimulating peptide angiotensin II. Levels of ACE in plasma vary according to the insertion/deletion (I/D) polymorphism of ACE gene. Objective The aim of the current study was to examine the influence ACE gene I/D variations on the risk of MDD. Methods In the present case-control study, we analyzed ACE I/D polymorphism in 346 MDD patients and 210 healthy subjects using polymerase chain reaction technique. Results Comparing the two groups, no significant difference was observed with regard to either genotype distributions or allele frequencies of the I/D polymorphism of ACE gene. Discussion Our findings suggest that the ACE I/D polymorphism is not associated with MDD in Turkish case-control study. Further studies are still needed.

Associations of rs4810485 and rs1883832 polymorphisms of CD40 gene with susceptibility and clinical findings of Behçet's disease.

There are evidences that besides geographic tendency, interactions between genetic and environmental factors play an essential role in the pathogenesis of Behçet's disease (BD). In this study, we have evaluated the associations between rs4810485 and rs1883832 single nucleotide polymorphism (SNP)s of CD40 gene with the susceptibility and clinical findings of BD. Two hundred and eighty-five patients with BD and 225 age-matched healthy controls were enrolled in this study. The clinical findings of patients were noted. The distributions of genotypes, alleles, combined genotypes and haplotypes of these two SNPs in BD patients were compared with those in healthy controls. In further evaluation, we evaluated the patients with and without any of clinical findings with regarding to distribution of genotypes and alleles of these two SNPs. There was no significant difference concerning frequencies of genotypes, alleles, combined genotypes and haplotypes of rs4810485 and rs1883832 between patients and controls (p > 0.05 for all). Frequency of GT genotype of CD40 rs4810485 polymorphism was found to be significantly higher in patients with skin lesions (p < 0.05, OR 1.65, 95 % CI 1.02-2.64). Also, we have found significantly higher frequencies of CC genotype and C allele of CD40 rs1883832 polymorphism in patients with genital ulcers (p < 0.05 for both, OR 2.30, 95 % CI 1.07-4.94 and OR 1.78, 95 % CI 1.06-2.97, respectively). However, these significances were disappeared after Bonferroni correction. We suggest that differences in the expression levels of CD40 because of different genotypes of these two SNPs may take part in the development of skin lesions or genital ulcers in patients with BD.

Possible association of FAS and FASLG polymorphisms with the risk of idiopathic azoospermia in southeast Turkey.

To investigate the association of the genetic variants of FAS/FASLG cell death pathway genes in male infertility, we genotyped the FAS -670A/G, -1377G/A, and FASLG -124A/G single-nucleotide polymorphisms (SNPs) by real-time polymerase chain reaction in 108 infertile men with idiopathic azoospermia and in 125 proven fertile controls. The distribution of genotypes and alleles for SNPs at FAS -1377G/A and FASLG -124A/G loci were determined not to be statistically different between the case and control groups. However, the genotype frequencies of SNPs, FAS -670AA and FAS -670AG, were found to be significantly different between the case and control groups. Whereas the FAS -670AA genotype might be regarded as a higher predisposition for idiopathic azoospermia, FAS -670AG could be interpreted to mean that this genotype provides protection against idiopathic azoospermia. The study of combined genotype and haplotype frequencies has found statistically significant differences between case and control subjects for some combinations. The AA-GG binary genotype for the FAS670 and FAS1377 loci couple, in particular, may have a high degree of predisposition to idiopathic azoospermia. Our results suggest that FAS -670A/G SNP may be a genetic predisposing factor of idiopathic azoospermia among southeastern Anatolian men. Larger studies are needed to verify these findings. Furthermore, our data indicated a possible linkage between the FAS and FASLG genes and idiopathic azoospermia.

Effects of interleukin (IL)-6 gene polymorphisms on recurrent aphthous stomatitis.

Recurrent aphthous stomatitis (RAS) is a common disease with oral ulceration in which cytokines are thought to play an important role. High levels of interleukin (IL)-6, a pro-inflammatory cytokine have been detected in the circulation of ulcer tissue. The purpose of the present study was to investigate if the IL-6 gene polymorphisms are associated with RAS or clinical characteristics of RAS in a cohort of Turkish population. 184 RAS patients and 150 healthy controls were included in the study. The genotypes of IL-6 gene -572G>C and -174G>C polymorphisms were determined using polymerase chain reaction based restriction fragment length polymorphism analysis. The genotype frequencies of -572G>C polymorphism showed statistically significant differences between RAS patients and controls (p = 0.01). Frequencies of GG + GC genotypes and G allele of -572G>C polymorphism were found higher in RAS patients (p = 0.0001, OR 10.8, 95 % CI 2.79-70.5; p = 0.0008, OR 2.06, 95 % CI 1.35-3.17, respectively). The genotype frequencies of -174G>C polymorphism also showed statistically significant differences between RAS patients and controls (p < 0.0001). Frequencies of GG genotype and G allele of -174G>C polymorphism were found higher in RAS patients (p < 0.0001, OR 4.87, 95 % CI 3.06-7.85; p < 0.0001, OR 3.82, 95 % CI 2.64-5.59, respectively). GG-GG combined genotype and G-G haplotype of -174G>C to -572G>C loci were also significantly higher in RAS patients (p < 0.0001 and p = 1.5 × 10(-8), respectively). After stratifying clinical and demographical characteristics of RAS patients according to IL-6 gene polymorphisms, an association was observed between family history of RAS and -174G>C polymorphism (p = 0.011). Susceptibility effects of both IL-6 gene -572G>C and -174G>C polymorphisms for RAS were observed. Further studies are necessary to prove the association of IL-6 gene polymorphisms with RAS.

Potential genotoxic effect of 186Re-HEDP on human lymphocyte cells: in-vitro evaluation with micronucleus-FISH analysis.

AIM: Systemic and local therapies can be used to treat painful bone metastases. It has been shown that certain pharmaceuticals such as 186Re (rhenium-186) are effective in the treatment of pains caused by bone metastasis and a correlation between bone metastases and T cells has also been shown. The aim of this study was to investigate the genotoxic effect of 186Re-1,1-hydroxyethylidenediphosphonate (186Re-HEDP) on the cultured peripheral blood lymphocytes using an micronucleus (MN)-fluorescence in-situ hybridization assay. METHODS: Two lymphocyte cultures, with and without 186Re-HEDP, were set up from 20 healthy individuals. MN frequencies were determined by a classical cytokinesis-blocked micronucleus assay and samples with the highest MN frequencies were used for fluorescent in-situ hybridization analyses with the 'all human centromeres' probe. RESULTS: Our results show a significant increase in the MN frequency in 186Re-treated lymphocytes compared with the untreated group (P<0.001). The frequencies of centromere-positive [CEN(+)] and centromere-negative [CEN(-)] MN in the 186Re-treated and untreated groups were found to be similar; however, the ratio of CEN(-)/CEN(+) MN frequency was lower in 186Re-treated samples. CONCLUSION: These preliminary results support the idea that 186Re-HEDP is a highly genotoxic radiopharmaceutical and shows a proaneugenic effect. Causing genotoxicity in lymphocytes, especially in T cells, that regulate bone metastases and tumor growth in bone, might be a mechanism of this pharmaceutical to reduce the pain of patients.