Omer Ates

NRAMP1 (SLC11A1) gene polymorphisms that correlate with autoimmune versus infectious disease susceptibility in tuberculosis and rheumatoid arthritis.

NRAMP1 gene has multiple pleiotropic effects on macrophage activation pathways. These pleiotropic effects may increase resistance to infections such as tuberculosis (TB), but may also lead to susceptibility of autoimmune diseases such as rheumatoid arthritis (RA). It has been hypothesized that allele 3 would be associated with autoimmune diseases, whereas allele 2 would be associated with infectious diseases, and genetic factors that enhanced survival in the epidemics of TB might have led to susceptibility for the development of RA. We analysed four NRAMP1 gene polymorphisms including 5′ promoter (GT)n (rs34448891), INT4 (469 + 14G/C) (rs3731865), 3′UTR (1729 + 55del4) (rs17235416) and D543N (codon 543, Asp to Asn) (rs17235409) in 112 patients with TB, 98 patients with RA, 80 healthy controls for TB and 122 healthy controls for RA using ARMS‐PCR and PCR‐RFLP. We found a significant association between INT4 and RA (P = 0.004, odds ratio: 2.06, 95% CI: 1.24–3.41), but no significant differences between 5′ promoter, D543N, 3′UTR polymorphisms and RA. There were no associations between NRAMP1 gene polymorphisms and TB. Similarly, no significant differences were observed between NRAMP1 polymorphisms and rheumatoid factor positivity and erosive disease in RA and localization of TB. INT4 polymorphism may be associated with RA in Turkish patients.

The association between Interleukin (IL)-4 gene intron 3 VNTR polymorphism and alopecia areata (AA) in Turkish population.

OBJECTIVE Alopecia areata (AA) is hypothesized to be an organ-specific autoimmune disease of hair follicles mediated by T cells. As immunological and genetic factors have been implicated in the pathogenesis of AA, the purpose of the present study was to investigate possible associations between the functional Interleukin (IL)-4 gene intron 3 VNTR polymorphism and AA susceptibility and disease progression in Turkish population. METHODS The study group consisted of 116 unrelated patients with AA and 125 unrelated healthy controls. Genomic DNA was isolated and IL-4 gene 70 bp VNTR polymorphism determined by using polymerase chain reaction (PCR) with specific primers. RESULTS No association was observed between AA patients and controls according to genotype distribution (p=0.051). The allele distribution of IL-4 gene intron 3 VNTR polymorphism was statistically different between AA patients and control group (p=0.026). The frequency of P1 allele in patients was significantly higher than that in the control group. When the P2P2 genotype was compared with P1P2+P1P1 genotypes, a statistically significant difference was observed between patients and controls (p=0.036). Intron 3 VNTR polymorphism in the IL-4 gene was found to be associated with AA susceptibility in Turkish population. CONCLUSION The results suggest that IL-4 VNTR polymorphism in the intron 3 region may be a risk factor for the development of AA among Turkish population. This is the first to report that intron 3 VNTR polymorphism in the IL-4 gene is associated with AA susceptibility.

Common MEFV gene mutations in Turkish patients with Behcet's disease

Behcets disease (BD) is a chronic systemic inflammatory disorder whose etiology has not been fully established yet. The MEditerranean FeVer (MEFV) gene has been identified as the cause of Familial Mediterranean Fever (FMF). BD shows similarities with FMF, in terms of clinical findings and treatments, as well as their geographical and ethnic co-occurrence. In this study we investigated common MEFV gene mutation frequencies in Turkish patients with BD in an area of Turkey where both diseases are frequently encountered. We screened 207 BD patients who had no symptoms and family history for FMF and 200 healthy subjects for five common MEFV gene mutations (E148Q, M680I, M694V, V726A, P369S) and clinical features. Seventy-five patients were found to carry a single MEFV mutation, and six patients were compound heterozygous. The difference in the frequency of the MEFV mutation between the BD and control groups was statistically significant (p<0.001, odds ratio [OR] 2.74, 95% confidence interval [CI] 1.75-4.29). The frequencies of E148Q and M680I mutations were significantly higher in the BD group (p=0.001, p=0.046, respectively). The frequency of uveitis was significantly lower in patients with the mutation than in patients without the mutation (p=0.029, OR 0.54, 95% CI 0.30-0.98). There was no statistical significance between carriers and non-carriers with respect to gender and other manifestations of BD. The frequency of the MEFV mutation was significantly higher in patients with BD compared to the healthy control group. Based on our results, MEFV mutations appear to have a role in the pathogenesis of BD.

Genetic variations in tumor necrosis factor alpha, interleukin-10 genes, and migraine susceptibility.

OBJECTIVES Migraine is a very common headache disorder and pathogenesis of the disease is still largely unknown. Cytokine genes have been implicated in migraine susceptibility. The present study was designed to explore the associations of polymorphisms in the tumor necrosis factor alpha (TNF-α), interleukin-10 (IL-10) gene, and IL-10 haplotypes in Turkish migraine patients. METHODS TNF-α-308G/A, IL-10 -1082G/A, -819C/T, and -592C/A polymorphisms in 203 migraine patients and 202 healthy subjects were analyzed by using amplification refractory mutation system-polymerase chain reaction. RESULTS The -308G/A genotypic and -308A allelic frequency of TNF-α polymorphism was higher in migraine patients than healthy controls, and significant association was found between migraine and TNF-α-308G/A polymorphism (Bonferroni correction [Pc]: <0.0001, odds ratio: 2.16, 95% confidence interval: 1.44-3.28). No statistically significant association was found between IL-10 -1082G/A, -819C/T, and -592C/A polymorphisms and haplotypes containing these alleles and migraine. CONCLUSIONS This study reflect that TNF-α-308G/A polymorphism may be one of the many genetic factors for migraine susceptibility in the Turkish population.

NRAMP1 (SLC11A1) variants: genetic susceptibility to multiple sclerosis.

ObjectivesMultiple sclerosis (MS) is an inflammatory, autoimmune demyelinating disease of the central nervous system. Human Natural Resistance Associated Macrophage Protein 1 (NRAMP1) gene polymorphisms have been implicated in the immune mediated diseases susceptibility. This study aimed to investigate the plausible association between NRAMP1 gene and MS susceptibility.MethodsWe analyzed (GT)n, INT4, 3′UTR and D543N polymorphisms of NRAMP1 gene in 100 MS patients and 104 healthy subjects by using amplification refractory mutation system-polymerase chain reaction and sequence analysis.ResultsNo significant association was found between (GT)n, INT4, 3′UTR and D543N polymorphisms and MS. There was also no correlation between NRAMP1 polymorphisms and MS clinical forms.ConclusionsOur findings suggest that NRAMP1 polymorphisms do not play a role in MS susceptibility and clinical finding of MS in Turkish patients.

The BstUI and DpnII Variants of the COL5A1 Gene Are Associated With Tennis Elbow

Background: Tennis elbow entails pain and tenderness over the lateral epicondyle. The exact cause of the condition is not fully understood. Type V collagen is a minor fibrillar collagen that intercalates with type I collagen and forms collagen fibrils. It is encoded by the COL5A1 gene. Sequence variants within COL5A1 3′-UTR have been implicated in musculoskeletal diseases. Purpose: To determine whether rs12722 (BstUI C414T polymorphism) and rs13946 (DpnII C230T polymorphism) of the COL5A1 gene are associated with an increased risk of tennis elbow. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 152 patients with tennis elbow and 195 healthy participants were enrolled in this study. The rs12722 (BstUI C414T) and rs13946 (DpnII C230T) polymorphisms were investigated with the polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) method. Results: There was a significant difference in both BstUI and DpnII genotype frequencies between patients with tennis elbow and healthy participants. The A2 allele of BstUI and the B1 allele of DpnII were significantly underrepresented in the patient group. Conclusion: Individuals with the BstUI A1 allele and DpnII B2 allele of the COL5A1 gene have a high likelihood of developing symptoms of the tennis elbow. This is the first study reporting that rs12722 and rs13946 SNPs (single nucleotide polymorphisms) are genetic risk factors for tennis elbow.

Association of MMP2-1306C/T and TIMP2G-418C polymorphisms in retinal vein occlusion.

Matrix metalloproteinases (MMPs) are large groups of zinc-dependent proteases that play an important role in many diseases and pathological processes such as cancer, angiogenesis, atherosclerosis, and vascular disease. Also, it was found that the expression of MMPs was high during the initial period of thrombosis in a rat model of traumatic deep vein thrombosis. Moreover, the presence of metalloproteinase activity and endogenous inhibitor activity in vitrectomy samples are associated with neovascularization of several retinal diseases such as exudative age related maculopathy, proliferative diabetic retinopathy, and central retinal vein occlusion. In this study, we aimed to investigate the possible association of the matrix metalloproteinase 2-1306C/T (rs 243865) and tissue inhibitors of matrix metalloproteinase 2 G-418C (rs 8179090) polymorphisms with the risk of retinal vein occlusion (RVO). Genomic DNA was extracted from peripheral leukocytes from ethylenediaminetetraacetic acid anticoagulated blood. Genotyping of the MMP2-1306C/T and TIMP2G-418C polymorphisms were performed using real-time polymerase chain reaction. The MMP2-1306 T allele carriers (CT + TT) had a significantly increased risk of RVO compared with the CC homozygotes (p < 0.001, odds ratio = 4.78; 95% CI = 2.85-8.09). After adjusting for hypertension, diabetes, hypertriglyceridemia, and hypercholesterolemia, MMP2-1306 T allele carriers (CT + TT) also had a significantly increased risk of RVO (B = 1.453; p < 0.001; odds ratio = 4.275; 95% CI:2.529-7.224). MMP2-1306C/T, but not TIMP2G-418C, gene variants are a risk factor for the development of retinal vein occlusion.

Association of angiotensin converting enzyme (ACE) gene I/D polymorphism and rheumatoid arthritis.

We sought to determine the frequency of I/D polymorphism genotypes of angiotensin converting enzyme gene in Turkish patients with rheumatoid arthritis. Genomic DNA obtained from 256 individuals (110 patients with rheumatoid arthritis and 146 healthy controls) was used in the study. ACE gene I/D polymorphism genotypes were determined using polymerase chain reaction using I and D allele-specific primers. There was a statistically significant difference between the groups with respect to genotype distribution (p=0.001). A significant difference was found in frequencies of ACE I/D alleles between patients and controls, with RA patients having a higher representation of D and lower representation of I alleles compared to controls (p<0.001). As a result of our study, angiotensin converting enzyme gene I/D polymorphism DD genotype could be a genetic marker in rheumatoid arthritis in the Turkish study population.

Genetic association of 5-HT1A and 5-HT1B gene polymorphisms with migraine in a Turkish population

Migraine, a very common headache disorder, is regarded as a polygenic disease and serotonergic pathways appear to play a major role in its pathogenesis. The present study was designed to explore the associations of polymorphisms of 5-hydroxytryptamine (serotonin) receptor 1A (5-HT1A) and 5-hydroxytryptamine receptor 1B (5-HT1B) genes in Turkish migraine patients. 5-HT1A C-1019G (rs6295) promoter and 5-HT1B G861C (rs6296) exon polymorphisms in 203 migraine patients and 202 healthy subjects were analyzed by using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Allele and genotype frequencies were not significantly different between migraine patients and healthy subjects for both the 5-HT1A C-1019G promoter and 5-HT1B G861C exon polymorphisms. Our data do not support the hypothesis that 5-HT1A C-1019G and 5-HT1B G861C polymorphisms have effects on migraine.

Association between fibromyalgia syndrome and polymorphism of the IL-4 gene in a Turkish population.

PURPOSE Fibromyalgia (FM) syndrome is a form of non-articular rheumatism characterized by long term and widespread musculoskeletal pain, morning stiffness, sleep disturbance, paresthesia, and pressure hyperalgesia at characteristic sites, called soft tissue tender points. The etiology of FM is still obscure. Genetic factors may predispose individuals to FM. Cytokines may play a role in the pathophysiology of FM. The aim of this study was to investigate the interleukin-4 (IL-4) 70 bp VNTR variations in Turkish patients with FM and evaluate if there was an association with clinical features, especially between these polymorphisms. METHODS The study included 300 patients with FM and 270 healthy controls. Genomic DNA was isolated and genotyped using polymerase chain reaction (PCR) for the IL-4 gene 70 bp VNTR polymorphisms. RESULTS There was statistically significant difference between the groups with respect to IL-4 genotype distribution and allele frequencies (p<0.0001). The homozygous P1P1 genotype and P1 allele were significantly higher in FM patients than in healthy controls (p=0.04; OR: 3.25, 95% CI: 1-10, p<0.0001; OR:4.84, 95% CI:3-7.7). There was not any difference between the groups respect to IL-4 genotype distribution and allele frequencies (p>0.05) and clinical characteristics. CONCLUSION Our findings suggest that there is an association of IL-4 gene 70 bp VNTR polymorphism with susceptibility of a person for development of FM. As a result, further studies are necessary to determine whether IL-4 may be a genetic marker for FM in the Turkish population.