Mevalonate kinase gene polymorphisms in ankylosing spondylitis patients: A cross-sectional study.

Objectives: This study aimed to investigate the potential effect of the mevalonate kinase (MVK) gene polymorphisms on the pathogenesis and clinical findings in ankylosing spondylitis (AS) patients. Patients and methods: This cross-sectional study was conducted with 103 participants (63 males, 40 females) between January 2013 and January 2014. Of these, 51 (32 males, 19 females; mean age: 37.3±10.2 years; range, 19 to 60 years) were adult AS patients who met the 1984 Modified New York Criteria, and 52 (31 males, 21 females; mean age: 33.8±12 years; range, 19 to 60 years) were healthy volunteers with similar demographics. MVK gene analysis was performed using polymerase chain reaction sequencing by isolating deoxyribonucleic acids from peripheral blood samples. We determined serum immunoglobulin (Ig)D levels using radial immunodiffusion. We performed physical examinations on the AS patients. The Bath Ankylosing Spondylitis Disease Activity Index and the Bath Ankylosing Spondylitis Functional Index forms were filled and erythrocyte sedimentation rate, C-reactive protein, and IgD levels were recorded. Results: There was no statistically significant difference in the mean age between the groups (p=0.121). The frequency of symptomatic single nucleotide polymorphisms (SNPs), c.769-38 C>T heterozygous, c.769-7 T>G heterozygous, and c.769-38 C>T homozygous were similar between the groups (15/15; p=0.646). Nonsymptomatic SNPs were more common in the patient group, but the difference was not significant (83/58; p>0.05). The rate of having an MVK gene polymorphism was 36 (70.6%) in the AS compared to the 33 (63.4%) in the control group (p>0.05). There were no associations in clinical findings between the AS patients with or without MVK gene polymorphisms. New heterozygous SNPs, I56V A>G, E281D G>D, V80I G>A, and C173Y G>A, were present in four AS patients. Conclusion: The frequency of MVK gene polymorphisms was higher in AS patients than in healthy controls. But there was no statistically significant difference. We determined no effect of the present polymorphisms on AS clinical and laboratory findings.

Killer Cell Immunoglobulin-Like Receptor (KIR) Genotype Distribution in Familial Mediterranean Fever (FMF) Patients.

BACKGROUND Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease predominantly affecting Mediterranean populations. The gene associated with FMF is the MEFV gene, which encodes for a protein called pyrin. Mutations of pyrin lead to uncontrolled attacks of inflammation, and subclinical inflammation continues during attack-free intervals. Killer cell immunoglobulin-like receptor (KIR) genes encode HLA class I receptors expressed by NK cells. The aim this study was to look for immunogenetic determinants in the pathogenesis of FMF and find out if KIR are related to susceptibility to disease or complications like renal amyloidosis. MATERIAL AND METHODS One hundred and five patients with FMF and 100 healthy individuals were involved in the study. Isolated DNA from peripheral blood was amplified by sequence specific PCR probes and analyzed by Luminex for KIR genotypes. Fisher Exact test was used to evaluate the variation of KIR gene distribution. RESULTS All patients and healthy controls expressed the framework genes. An activator KIR gene, KIR2DS2, was significantly more frequent in FMF patients (p=0.036). Renal amyloidosis and presence of arthritis were not associated with KIR genes and genotype. KIR3DL1 gene was more common in patients with high serum CRP (p=0.016). CONCLUSIONS According to our findings, we suggest that presence of KIR2DS2, which is an activator gene for NK cell functions, might be related to the autoinflammation in FMF. The potential effect of KIR genes on amyloidosis and other clinical features requires studies with larger sample sizes.

Mevalonate kinase gene mutations and their clinical correlations in Behçet's disease.

AIM: Genetics is suggested to play a role in the development of Behçet's disease (BD). Shared phenotipic features requires an approach to differential diagnosis from periodic febrile syndromes. We planned to study for mevalonate kinase (MVK) as a candidate for a susceptibility gene for Behçet's disease. METHOD: Consecutive Behçet patients and apperently healthy subjects were included. Severity score of Behçet disease was calculated. Genotyping of mevalonate kinase gene was performed by polymerase chain reaction/sequence-based typing technique. RESULTS: Fifty BD patients (median age: 38.30 ± 11.06 years) and 51 controls (median age: 33.88 ± 12.47 years) were recruited. Three types of mutations have been found: first, a single nucleotide polymorphism (SNP) c.769-38C>T (rs35191208) in 21 of 50 BD patients and in 15 of 51 controls. Both groups were comparable for the frequency of c.769-38C>T (P > 0.05). In all of the cases with c.769-38C>T, a second SNP, c885+24G>A (rs2270374) was also present (previously reported to be in linkage disequilibrium with the first SNP). A third SNP, c.769-7T>G (rs104895331) was found in three of 50 BD patients and in one of the control group. We found this SNP together with c769-38C>T and c.885+24G>A. The neurological involvement was found to be more frequent in the BD patients with c.769-3C>T when compared to the BD patients without this polymorphism (P = 0.012). CONCLUSION: Our results suggested that the effects of MVK mutations in Behçet's disease could be an additional genetic susceptibility factor for the patients with neurological involvement. However, these results need confirmation in larger study populations and in different ethnic groups.

Role of KIR genes and genotypes in susceptibility to or protection against hepatitis B virus infection in a Turkish cohort.

BACKGROUND: Killer cell immunoglobulin-like receptors (KIRs) are a family of inhibitory and activating receptors expressed by natural killer (NK) cells and regulate NK cell activity in the innate response against viral infections. The aim of this study was to determine the possibility of KIR genes and genotypes as a candidate for susceptibility to or protection against chronic hepatitis B virus (HBV) infection or spontaneous remission of the infection in a Turkish cohort. MATERIAL AND METHODS: The present study was carried out on 37 patients with chronic HBV infection, 36 patients in spontaneous remission of HBV infection, and 85 healthy subjects. Sequence-specific oligonucleotide probes analysis was used to investigate 16 KIR genes. All data were statistically analyzed by the Fisher exact test. RESULTS: The rate of inhibitory KIR2DL3 (p=0.0) and 3DS1 (p=0.0) were higher in the healthy group than the group composed of chronic HBV patients and patients with spontaneous remission. There were no statistically significant differences between the rate of AA and Bx genotypes of chronic HBV patients and patients with spontaneous remission and the control group (p>0.05). CONCLUSIONS: Our results suggest that KIR2DL3 and KIR3DS1 genes could be protector genes for HBV infection and they could be important immuno-genetic markers in determining antiviral immunity in the Turkish population.

Analysis of cytotoxic T lymphocyte antigen-4 (CTLA-4) promoter -318C/T and +49A/G gene polymorphisms in Turkish patients with familial Mediterranean fever.

Either the role of the adaptive immune system or the interaction between innate and adaptive immune systems in familial Mediterranean fever (FMF) is not clear so far. So, we planned to search for the interaction between the innate and adaptive immune systems in the pathogenesis of FMF by investigating polymorphism for CTLA-4 gene, which plays a role in controlling antigen presentation to T cells. We also aimed to investigate whether there is an association between -318C/T and +49A/G polymorphisms in the CTLA-4 gene and the main clinical features of the disease. 75 FMF patients and 179 controls were studied. Polymorphism was detected by the PCR-RFLP technique. The CT genotype and T allele frequencies of the -318C/T polymorphism and the haplotype frequency for the -318T/+49A in the CTLA-4 gene were higher in the FMF (21.3, 21.3, and 10.7 %) when compared with the controls (10.6, 10.6, and 5.3 %; P = 0.029, 0.044, and 0.029). However, these differences did not reach a statistically significant level after the Bonferroni correction. A significant linkage disequilibrium was found between the -318C/T and +49A/G polymorphisms in the CTLA-4 gene (D' = 0.997, r(2) = 0.027, P = 0.0002). Genotype and carrier frequencies of the CTLA-4 gene +49A/G polymorphism were not significantly different between FMF patients and healthy controls. No association was found between the studied polymorphisms and the main clinical features of the disease. Our findings suggest that although not statistically significant, higher frequencies of CTLA-4 gene -318CT genotype, T allele, and -318T/+49A haplotype in FMF patients may be related to the non-autoimmune pathogenesis of FMF.

Different clinical presentation of the hyperimmunoglobulin D syndrome (HIDS) (four cases from Turkey).

Hyperimmunoglobulin D syndrome (HIDS) is one of the autoinflammatory syndromes which are characterized by febrile attacks. Duration and frequency of the febrile attacks, as well as typical organ involvements vary greatly. Recently, it is possible to reach more reliable data by the possibilities that are opened up by molecular genetics in order to highlight the aetiopathogenesis of this group of diseases. Typical patients with HIDS have an onset of disease in the first year of life. Here, we report four Turkish HIDS cases; three of whom, the symptoms started at a later age. The diagnoses were made by relevant clinical symptoms along with MVK mutations detected by DNA sequencing method. As summarised in this article, HIDS could be presented with a broad spectrum of symptoms. Although most of the HIDS patients are reported from Europe and especially Dutch ancestry, case reports are presented from all over the world. For this reason, HIDS should be kept in mind for the differential diagnosis of periodic fever syndromes or before accepting an FMF patient as colchichine resistant. We suppose that the phenomenon of "later-onset HIDS" should shed light into unresolved clinical problems of patients with periodic fever. Especially in countries that FMF is more frequent such as Turkey, even though the symptoms start later than classic cases, HIDS should be kept in mind for differential diagnosis of periodic fever syndromes.