Nihan Bozkurt

Significance of MEFV gene R202Q polymorphism in Turkish familial Mediterranean fever patients

OBJECTIVE Familial Mediterranean fever (FMF) is an autosomal recessive disorder characterized by recurrent attacks of fever and inflammation in the peritoneum, synovium, or pleura, accompanied by pain. The disease is associated with mutations in the Mediterranean fever (MEFV) gene, which encodes for the pyrin protein. The aim of this study was to explore the frequency and clinical significance of the R202Q (c.605G>A) polymorphism in exon 2 of the MEFV gene in a cohort of Turkish patients with FMF. METHODS The study included 191 patients with FMF and 150 healthy controls. Genomic DNA was isolated and genotyped using polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) assay for the MEFV gene R202Q polymorphism. RESULTS The genotype and allele frequencies of R202Q polymorphism showed a statistically significant difference between FMF patients and controls (p<0.0001 and p=0.0004, respectively) and especially the homozygous AA genotype was significantly higher in FMF patients than healthy controls (p=0.0002; odds ratio=6.27; 95% CI=2.1-18.3). However no significant association was observed between clinical and demographic features of FMF patients and R202Qpolymorphism. CONCLUSION The results of this study showed that there was a high association between MEFV gene R202Q polymorphism and FMF. R202Q polymorphism should be included in routine molecular diagnosis of FMF patients.

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.

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.

MDR1 gene polymorphisms may be associated with Behçet's disease and its colchicum treatment response

Behçets disease (BD) is a chronic multisystem disorder. Infectious agents, immune system mechanisms, and genetic factors are implicated in the etiopathogenesis of BD, which remains to be explained. The human MDR1 (ABCB1) gene encoder P-glycoprotein (P-gp) plays a key role in drug disposition, serves as a protective mechanism against xenobiotics, and provides additional protection for the brain, testis, and fetus. We investigated the genotype and haplotype distributions of three MDR1 gene polymorphisms (C1236T, G2677T/A, and C3435T) in 104 BD patients and 130 control subjects. The genotyping analysis was performed by using PCR-RFLP methods. No statistically significant differences were found for the genotypic and allelic distributions of three individual single nucleotide polymorphisms (SNPs) in the MDR1 gene between BD patients and control subjects in this study (p>0.05). However, combined genotype and haplotype frequencies have found statistically significant differences between BD and control subjects for some combinations (p<0.05). The CC-GG binary genotype for C1236T-G2677T/A loci couple in particular may have a high degree of predisposition to BD (p=0.009; OR, 3.03; 95% CI, 1.41-6.54). Furthermore, significant differences between colchicine-responsive and -nonresponsive groups were found. Genotypic and allelic distributions of C3435T and G2677T/A loci, as well as their genotype and haplotype combinations, were found to have statistically significant differences (p<0.05). The TT genotype for the C3435T locus (p=0.001; OR, 6.59; 95% CI, 1.86-23.30) and T allele (p=0.009; OR, 2.09; 95% CI, 1.18-3.70) plays a substantial role in the colchicine response. Our study showed that MDR1 genes and their polymorphisms may affect a patients BD susceptibility and colchicine response.

Common Mediterranean fever (MEFV) gene mutations associated with ankylosing spondylitis in Turkish population

Ankylosing spondylitis (AS) is a common inflammatory rheumatic disease. Mediterranean fever (MEFV) gene, which has already been identified as being responsible for familial Mediterranean fever (FMF), is also a suspicious gene for AS because of the clinical association of these two diseases. The aim of this study was to explore the frequency and clinical significance of MEFV gene mutations (M694V, M680I, V726A, E148Q and P369S) in a cohort of Turkish patients with AS. Genomic DNAs of 103 AS patients and 120 controls were isolated and genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. There was a statistically significant difference of the MEFV gene mutation carrier rates between AS patients and healthy controls (p = 0.004, OR: 2.5, 95% CI: 1.32–4.76). This association was also observed in allele frequencies (p = 0.005, OR: 2.3, 95% CI: 1.27–4.2). A relatively higher frequency was observed for M694V mutation in AS patients than controls (10.7% versus 4.2% , p = 0.060). There were no significant differences between MEFV mutation carriers and non-carriers with respect to the clinical and demographic characteristics. The results of this study suggest that MEFV gene mutations are positively associated with a predisposition to develop AS.

Clinical symptoms in fibromyalgia are associated to catechol-O-methyltransferase (COMT) gene Val158Met polymorphism.

Abstract 1. Fibromyalgia syndrome (FMS) is a common chronic widespread pain syndrome mainly affecting women. The aim of this study was to explore the frequency and clinical significance of catechol-O-methyltransferase (COMT) gene Val158Met polymorphism in a large cohort of Turkish patients with FMS. 2. The study included 379 FMS patients and 290 controls. Genomic DNA was isolated and genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analyses. 3. The genotype frequencies of Val158Met polymorphism showed a small difference between FMS patients and healthy controls (p = 0.047), however, the Met/Met genotype was significantly higher in FMS patients than healthy controls (p = 0.016). No difference was observed for allele frequencies between two groups. Stratification analysis according to clinical features for this disease reveals that weight, FMS Impact Questionnaire score, algometry and Raynaud’s syndrome, were detected to have statistically significant associations with Val158Met polymorphism (p = 0.037, p = 0.042, p = 0.039 and p = 0.033, respectively). Pain sensitivity, measured by algometry, was statistically higher in patients with Met/Met genotype than the patients with Val/Val and Val/Met genotypes (p = 0.017). 4. The results of this study suggested that COMT gene Val158Met polymorphism is positively associated with FMS and play a relevant role in the clinical symptoms of the disease.

Methylenetetrahydrofolate reductase C677T mutation in patients with alopecia areata in Turkish population.

OBJECTIVE Methylene-tetrahydrofolate reductase (MTHFR) is a key enzyme regulating folate metabolism and it is thought to influence DNA methylation and nucleic acid synthesis. Mutations in the MTHFR gene have been associated with several autoimmune disorders in previous studies. Alopecia areata (AA) is considered to be a tissue-specific autoimmune disease as the hair follicle has been targeted and antibodies to their own hair follicle structures have been developed. Since there is a common shared pathway between AA and other autoimmune disorders, we aimed to investigate a possible association between the MTHFR gene C677T mutation and AA susceptibility in the Turkish population. METHODS The study included 136 patients affected by AA and 130 healthy controls. Genomic DNA was isolated and genotyped using a polymerase chain reaction (PCR)-based restriction fragment length polymorphism (RFLP) assay for the MTHFR gene C677T mutation. RESULTS The distributions of genotype and allele frequencies of MTHFR gene C677T mutation were statistically different between AA patients and the control group (p=0.036 and p=0.011, respectively). High differences were also observed when the patients and controls were compared according to CC versus CT+TT (p=0.012). CT+TT genotypes and T allele of MTHFR gene C677T mutation were found to be a susceptibility factor for AA in the Turkish population. CONCLUSION The results suggest that MTHFR gene C677T mutation may have an effect on the risk of alopecia areata in the Turkish population. This is the first study reporting the association between the MTHFR (C677T) genotype and AA.