Convalescent human plasma candidate reference materials protect against Crimean-Congo haemorrhagic fever virus (CCHFV) challenge in an A129 mouse model.

Crimean-Congo Haemorrhagic Fever Virus (CCHFV) is spread by infected ticks or direct contact with blood, tissues and fluids from infected patients or livestock. Infection with CCHFV causes severe haemorrhagic fever in humans which is fatal in up to 83 % of cases. CCHFV is listed as a priority pathogen by the World Health Organization (WHO) and there are currently no widely-approved vaccines. Defining a serological correlate of protection against CCHFV infection would support the development of vaccines by providing a 'target threshold' for pre-clinical and clinical immunogenicity studies to achieve in subjects and potentially obviate the need for in vivo protection studies. We therefore sought to establish titratable protection against CCHFV using pooled human convalescent plasma, in a mouse model. Convalescent plasma collected from seven individuals with a known previous CCHFV virus infection were characterised using binding antibody and neutralisation assays. All plasma recognised nucleoprotein and the Gc glycoprotein, but some had a lower Gn glycoprotein response by ELISA. Pooled plasma and two individual donations from convalescent donors were administered intraperitoneally to A129 mice 24 h prior to intradermal challenge with CCHFV (strain IbAr10200). A partial protective effect was observed with all three convalescent plasmas characterised by longer survival post-challenge and reduced clinical score. These protective responses were titratable. Further characterisation of the serological reactivities within these samples will establish their value as reference materials to support assay harmonisation and accelerate vaccine development for CCHFV.

Crimean-Congo haemorrhagic fever virus uses LDLR to bind and enter host cells.

Climate change and population densities accelerated transmission of highly pathogenic viruses to humans, including the Crimean-Congo haemorrhagic fever virus (CCHFV). Here we report that the Low Density Lipoprotein Receptor (LDLR) is a critical receptor for CCHFV cell entry, playing a vital role in CCHFV infection in cell culture and blood vessel organoids. The interaction between CCHFV and LDLR is highly specific, with other members of the LDLR protein family failing to bind to or neutralize the virus. Biosensor experiments demonstrate that LDLR specifically binds the surface glycoproteins of CCHFV. Importantly, mice lacking LDLR exhibit a delay in CCHFV-induced disease. Furthermore, we identified the presence of Apolipoprotein E (ApoE) on CCHFV particles. Our findings highlight the essential role of LDLR in CCHFV infection, irrespective of ApoE presence, when the virus is produced in tick cells. This discovery holds profound implications for the development of future therapies against CCHFV.

Systems-level temporal immune-metabolic profile in Crimean-Congo hemorrhagic fever virus infection.

Crimean-Congo hemorrhagic fever (CCHF) caused by CCHF virus (CCHFV) is one of the epidemic-prone diseases prioritized by the World Health Organisation as public health emergency with an urgent need for accelerated research. The trajectory of host response against CCHFV is multifarious and remains unknown. Here, we reported the temporal spectrum of pathogenesis following the CCHFV infection using genome-wide blood transcriptomics analysis followed by advanced systems biology analysis, temporal immune-pathogenic alterations, and context-specific progressive and postinfection genome-scale metabolic models (GSMM) on samples collected during the acute (T0), early convalescent (T1), and convalescent-phase (T2). The interplay between the retinoic acid-inducible gene-I-like/nucleotide-binding oligomerization domain-like receptor and tumor necrosis factor signaling governed the trajectory of antiviral immune responses. The rearrangement of intracellular metabolic fluxes toward the amino acid metabolism and metabolic shift toward oxidative phosphorylation and fatty acid oxidation during acute CCHFV infection determine the pathogenicity. The upregulation of the tricarboxylic acid cycle during CCHFV infection, compared to the noninfected healthy control and between the severity groups, indicated an increased energy demand and cellular stress. The upregulation of glycolysis and pyruvate metabolism potentiated energy generation through alternative pathways associated with the severity of the infection. The downregulation of metabolic processes at the convalescent phase identified by blood cell transcriptomics and single-cell type proteomics of five immune cells (CD4+ and CD8+ T cells, CD14+ monocytes, B cells, and NK cells) potentially leads to metabolic rewiring through the recovery due to hyperactivity during the acute phase leading to post-viral fatigue syndrome.

Investigating the effect of ribavirin treatment on genetic mutations in Crimean-Congo haemorrhagic fever virus (CCHFV) through next-generation sequencing.

Crimean-Congo haemorrhagic fever (CCHF) is the most widespread tick-borne viral haemorrhagic fever affecting humans, and yet a licensed drug against the virus (CCHFV) is still not available. While several studies have suggested the efficacy of ribavirin against CCHFV, current literature remains inconclusive. In this study, we have utilised next-generation sequencing to investigate the mutagenic effect of ribavirin on the CCHFV genome during clinical disease. Samples collected from CCHF patients receiving ribavirin treatment or supportive care only at Sivas Cumhuriyet University Hospital, Turkey, were analysed. By comparing the frequency of mutations in each group, we found little evidence of an overall mutagenic effect. This suggests that ribavirin, administered at the acute stages of CCHFV infection (at the World Health Organization-recommended dose) is unable to induce lethal mutagenesis that would cause an extinction event in the CCHFV population and reduce viremia.

The investigation of host genetic variants of toll-like receptor 7 and 8 in COVID-19.

Toll-like receptors (TLRs) recognize infectious agents and play an important role in the innate immune system. Studies have suggested that TLR single nucleotide polymorphisms (SNPs) are associated with poor antiviral responses against SARS-CoV-2. Therefore, we aimed to investigate the relationship of TLR7 and TLR8 (SNPs) with COVID-19 disease prognosis. A total of 120 COVID-19 patients, 40 outpatients, 40 clinical ward patients and 40 intensive care unit (ICU) patients were included in the study. TLR7 (rs179009), TLR8-129 C/G (rs3764879) and TLR8 Met1Val (rs3764880) SNPs were genotyped using the PCR-RFLP method. In female patients, individuals carrying AG genotype and G allele for TLR8 Met1Val SNP were found at a higher frequency in patients hospitalized in the ICU than in patients followed in the clinical ward (p < 0.05). In terms of the other two SNPs, no significant difference was found between the groups in females. Furthermore, in male patients, A allele of TLR7 rs179009 SNP was at a higher frequency in patients who have at least one comorbidity than in patients who have no comorbidity (p < 0.05). Our results suggest that TLR8 Met1Val SNP is important in the COVID-19 disease severity in females. Furthermore, TLR7 rs179009 SNP is important in male patients in the presence of comorbid diseases.

Multi-omics insights into host-viral response and pathogenesis in Crimean-Congo hemorrhagic fever viruses for novel therapeutic target.

The pathogenesis and host-viral interactions of the Crimean-Congo hemorrhagic fever orthonairovirus (CCHFV) are convoluted and not well evaluated. Application of the multi-omics system biology approaches, including biological network analysis in elucidating the complex host-viral response, interrogates the viral pathogenesis. The present study aimed to fingerprint the system-level alterations during acute CCHFV-infection and the cellular immune responses during productive CCHFV-replication in vitro. We used system-wide network-based system biology analysis of peripheral blood mononuclear cells (PBMCs) from a longitudinal cohort of CCHF patients during the acute phase of infection and after one year of recovery (convalescent phase) followed by untargeted quantitative proteomics analysis of the most permissive CCHFV-infected Huh7 and SW13 cells. In the RNAseq analysis of the PBMCs, comparing the acute and convalescent-phase, we observed system-level host's metabolic reprogramming towards central carbon and energy metabolism (CCEM) with distinct upregulation of oxidative phosphorylation (OXPHOS) during CCHFV-infection. Upon application of network-based system biology methods, negative coordination of the biological signaling systems like FOXO/Notch axis and Akt/mTOR/HIF-1 signaling with metabolic pathways during CCHFV-infection were observed. The temporal quantitative proteomics in Huh7 showed a dynamic change in the CCEM over time and concordant with the cross-sectional proteomics in SW13 cells. By blocking the two key CCEM pathways, glycolysis and glutaminolysis, viral replication was inhibited in vitro. Activation of key interferon stimulating genes during infection suggested the role of type I and II interferon-mediated antiviral mechanisms both at the system level and during progressive replication.

Crimean-Congo hemorrhagic fever (CCHF) is an emerging disease that is increasingly spreading to new populations. The condition is now endemic in almost 30 countries in sub-Saharan Africa, South-Eastern Europe, the Middle East and Central Asia. CCHF is caused by a tick-borne virus and can cause uncontrolled bleeding. It has a mortality rate of up to 40%, and there are currently no vaccines or effective treatments available. All viruses depend entirely on their hosts for reproduction, and they achieve this through hijacking the molecular machinery of the cells they infect. However, little is known about how the CCHF virus does this and how the cells respond. To understand more about the relationship between the cell's metabolism and viral replication, Neogi, Elaldi et al. studied immune cells taken from patients during an infection and one year later. The gene activity of the cells showed that the virus prefers to hijack processes known as central carbon and energy metabolism. These are the main regulator of the cellular energy supply and the production of essential chemicals. By using cancer drugs to block these key pathways, Neogi, Elaldi et al. could reduce the viral reproduction in laboratory cells. These findings provide a clearer understanding of how the CCHF virus replicates inside human cells. By interfering with these processes, researchers could develop new antiviral strategies to treat the disease. One of the cancer drugs tested in cells, 2-DG, has been approved for emergency use against COVID-19 in some countries. Neogi, Elaldi et al. are now studying this further in animals with the hope of reaching clinical trials in the future.

Association of MCP-1 promotor polymorphism with disease severity of Crimean-Congo hemorrhagic fever.

Crimean-Congo hemorrhagic fever (CCHF) is a thick-borne viral zoonotic disease. The pathogenesis and the reasons why cases have a mild or severe course in CCHF have not yet been explained. In this study, we investigated the relationship between promoter -2518 A/G single-nucleotide polymorphism (SNP) of the MCP-1 gene and the clinical course of CCHF. The MCP-1-2518 A/G SNP (rs1024611) frequency was examined in 128 virologically/serologically confirmed CCHF patients and 181 healthy controls by using the PCR-RFLP method. When CCHF patients and controls were compared, no significant difference was found between genotype distributions and allele frequencies of the -2518 A/G SNP of MCP-1 gene (P > .05). Compared to the AA genotype, both AG (P = .016; OR = 2.57) and GG genotype (P = .039; OR = 3.43) were found with significantly higher frequencies in mild/moderate cases than in severe cases. Compared to the AG + GG genotype, AA showed a significant risk for severe CCHF (60.0% vs 38.4%, P = .02; OR = 2.41). In contrast, the AG genotype showed a significant protective effect against severe disease compared to AA + GG genotype (29.1% vs 47.9%, P = .013; OR = 2.58). Compared to mild/moderate cases, the A allele was found to be significantly higher in severe cases (0.745 vs 0.623, P = .039; OR = 1.77). However, no significant relationship was found between fatal and nonfatal cases in terms of genotype or allele frequencies (P > .05). In conclusion, both -2518 AA genotype and A allele of MCP-1 were associated with disease severity, and the AG genotype had a protective effect against a severe disease course in CCHF patients.

The Analysis of GJB2, GJB3, and GJB6 Gene Mutations in Patients with Hereditary Non-Syndromic Hearing Loss Living in Sivas.

OBJECTIVES: The aim of the present study was to investigate the presence of GJB2, GJB3, and GJB6 gene mutations in non-syndromic sensorineural hearing loss (NSHL) cases living in Sivas region, to provide appropriate genetic counseling for cases who were found to have mutation, and to contribute to decrease the frequency of mutant allele in the next generation and plan treatment and rehabilitation with early diagnosis. MATERIALS AND METHODS: The study included 53 unrelated cases that were diagnosed with congenital NSHL between June 2009 and March 2010. Multiplex ligation-dependent probe amplification method was used for genotyping of GJB2, GJB3, and GJB6 gene mutations. RESULTS: Heterozygous 35delG variant was determined in 1.9% (n=1) of cases, homozygous 35delG in 15.1% (n=8), heterozygous IVS1+1G>A mutation in 1.9% (n=1), compound heterozygous in 3.8% (n=2), and homozygous IVS1+1G>A variant in 3.8% (n=2). None of the cases had mutation in GJB3 and GJB6 genes. Mutated allele frequencies in the present study were found to be 17.9% for 35delG and 6.6% for IVS1+1G>A. CONCLUSION: The present study showed that 35delG mutation is the most common variant in the Sivas region, and that IVS1+1G>A mutation should be investigated in hearing loss. Another result of the present study was that genetic analyzes would allow early diagnosis of hearing impairments particularly when infants whose parents have consanguinity do not pass the newborn hearing screening.

Genetic variants in the microRNA machinery gene (Dicer) have a prognostic value in the management of endometrial cancer.

AIM: Although several associations were found between Dicer rs3742330 single nucleotide polymorphism (SNP) and development and prognosis of some epithelial cancers, relationship between the SNP rs3742330 and endometrial cancer (EC) has not yet been studied. We aimed to investigate the prognostic role of rs3742330 SNP of Dicer gene in EC patients. SUBJECTS AND METHODS: A total of 80 EC patients and 80 control subjects included in the study. Real-time polymerase chain reaction and the allele discrimination technique was used for genotyping of rs3742330 SNP. RESULTS: There was no significant difference between EC patients and control subjects with regard to the genotype and allele frequencies for Dicer rs3742330 SNP (P > 0.05). Despite Dicer rs3742330 SNP had no prognostic value in terms of stage, grade, lymphovascular invasion, myometrial invasion, tumor size, and histopathology; malignant peritoneal cytology has been detected higher in the patients bearing AA genotype compare with AG genotype (P = 0.023). Higher recurrence rate and shorter time to recurrence were found in patients bearing AG and GG genotype compare with AA genotype (P = 0.009). CONCLUSION: Dicer rs3742330 AG and GG genotypes may have the potential to be used as a predictor of poor prognosis in the management of EC case.

Association of vitamin D receptor gene TaqI, FokI and ApaI variants with arteriovenous fistula failure in hemodialysis patients.

PURPOSE: We investigated the influence of the vitamin D receptor gene TaqI (rs731236), ApaI (rs7975232), and FokI (rs2228570) polymorphisms in arteriovenous fistula failure in hemodialysis patients. METHODS: This study was carried out with 54 patients who experienced two or more fistula failures in the late period after arteriovenous fistula operation and 58 control patients with no history of arteriovenous fistula failure in 3 years or longer. The polymerase chain reaction-restriction fragment length polymorphism method was used to determine the vitamin D receptor TaqI, FokI, and ApaI polymorphisms. RESULTS: For vitamin D receptor gene TaqI and Fok1 polymorphisms, no significant association was found between the two groups ( p > 0.05). However, a statistically significant association was determined for ApaI polymorphism between the two groups ( p = 0.02). In patients, ApaI AA, AC, and CC genotype frequencies were found as 21 (38.9%), 32 (59.3%), and 1 (1.8%), respectively. However, genotype frequencies of AA, AC, and CC in the control group were 29 (50%), 22 (37.9%), and 7 (12.1%), respectively. In all three polymorphisms, no significant difference was found between the two groups in terms of allele frequencies ( p > 0.05). CONCLUSION: Vitamin D receptor ApaI AC genotype may be a possible cardiovascular risk factor for the development of arteriovenous fistula failure.

Frequency of familial Mediterranean fever (MEFV) gene mutations in patients with biopsy-proven primary glomerulonephritis.

Primary glomerulopathies are those disorders that affect glomerular structure, function, or both in the absence of a multisystem disorder. We aimed to evaluate the frequency of MEFV gene mutation to show possible coexistence of FMF in patients diagnosed with biopsy-proven primary glomerulonephritis (GN). A total of 64 patients with biopsy-proven primary GN were included in the study. MEFV gene mutations examined retrospectively. The mean age of patients was 39.6 ± 13.4 (range 18-69), 35 of patients were female and 29 of patients were male. Of the 64 patients, 17 were mesangial proliferative glomerulonephritis (MsPGN), 15 were IgA nephropathy (IgAN), 12 were membranous glomerulonephritis (MGN), 11 were focal segmental glomerulosclerosis (FSGS), three were membranous proliferative glomerulonephritis (MPGN), three were immune complex glomerulonephritis (ICGN), two were minimal change disease (MCD), and one was IgM nephropathy (IgMN). MEFV gene mutation was detected in 35.9% (23) of these patients. The most frequently detected mutations were E148Q and M694V. Twelve cases (18.75% of GN patients) with MEFV gene mutation were diagnosed as FMF phenotype I. The frequency of MEFV gene mutation was detected at a high rate of 35.9%. Further studies with larger populations are needed to clarify the importance of these mutations on clinical progression of glomerulonephritis.

SDF-1/CXCL12 and CXCR4 gene variants, and elevated serum SDF-1 levels are associated with preeclampsia.

OBJECTIVE: We aimed to compare the frequencies of stromal cell-derived factor-1 (SDF-1) 3'A and CXCR4 single-nucleotide polymorphisms (SNPs) and serum SDF-1 levels in patients with preeclampsia (PE). METHODS: In total, 89 women with PE and 89 control women were included in the study. Genotyping was done by polymerase chain reaction-restriction fragment length polymorphism method. Enzyme-linked immunosorbent assay method was used to measure serum SDF-1 level. RESULTS: For SDF-1 3'A SNP, the frequency of GA genotype, total number of GA and AA genotypes, and the A allele frequency was higher in PE patients than controls (p = 0.04, 0.023, and 0.029, respectively). For CXCR4 SNP, the frequency of CT genotype, total number of CT and TT genotypes, and the T allele frequency were higher in PE patients than controls (p = 0.04, 0.006, and 0.005, respectively). SDF-1 serum level was detected higher in preeclamptic women compared with controls (p = 0.001). In PE patients, there was no significant association between serum SDF-1 levels and genotypes of SDF-1 3'A SNP. SDF-1 level was significantly higher in patients bearing CXCR4 CT genotype than CC genotype (p = 0.001). Furthermore, SDF-1 levels in patients bearing CT+TT genotype were found higher than that of patients with CC genotypes (p = 0.001). CONCLUSION: Results of our study suggest that SDF-1 3'A and CXCR4 polymorphisms and elevated serum SDF-1 levels may have a role in the development of PE.

KRAS, BRAF oncogene mutations and tissue specific promoter hypermethylation of tumor suppressor SFRP2, DAPK1, MGMT, HIC1 and p16 genes in colorectal cancer patients.

BACKGROUND: Colorectal cancer is a serious disease that causes significant morbidity and mortality in developed countries. Genetic changes, such as mutations in proto-oncogenes and DNA repair genes, and loss of function in the tumor suppressor genes cause colorectal cancer development. Abnormal DNA methylation is also known to play a crucial role in colorectal carcinogenesis. OBJECTIVE: In this study, frequencies of KRAS and BRAF mutations, promoter hypermethylation profiles of SFRP2, DAPK1, MGMT, HIC1 and p16 genes, and possible associations between hypermethylation of these genes and KRAS and BRAF mutations were aimed to find out. METHODS: Ninety three colorectal cancer tissues and 14 normal colon mucosas were included in the study. Common twelve KRAS gene mutation were investigated with using reverse-hybridization strip assay method. BRAF V600E mutations were investigated with RFLP method. Hypermethylation status of five tumor suppressor genes were detected by using reverse-hybridization strip assay method after bisulfite modification of DNA. RESULTS: KRAS and BRAF mutation frequencies were determined as 54.84% and 12.9%, respectively. Promoter hypermethylation frequencies of tumor suppressor genes SFRP2, DAPK1, MGMT, HIC1 and p16 were determined as 66.7%, 45.2%, 40.9%, 40.9% and 15.1%, respectively. Statistically significant associations were found between BRAF mutation and SFRP2 and p16 tumor suppressor genes hypermethylation (SFRP2; p= 0.005, p16; p= 0.016). Compared to rectum, SFRP2 (p= 0.017) and MGMT (p= 0.013) genes have statistically significantly higher promoter hypermethylation in colon. CONCLUSIONS: Results of the current study have confirmed that KRAS mutations and SFRP2 hypermethylation can be used as genetic markers in colorectal cancer.

Angiotensin-Converting Enzyme (ACE) I/D and Alpha-Adducin (ADD1) G460W Gene Polymorphisms in Turkish Patients with Severe Chronic Tinnitus.

OBJECTIVE: Tinnitus is described as a disturbing sound sensation in the absence of external stimulation. We aimed to investigate whether there is any relationship between severe chronic tinnitus and angiotensin-converting enzyme (ACE) I/D and α-adducin (ADD1) G460W gene polymorphisms. MATERIALS AND METHODS: The patient group and control group consisted of 89 and 104 individuals, respectively. The evaluation of tinnitus was performed using the Strukturiertes Tinnitus-Interview (STI). The Tinnitus Handicap Inventory (THI) was used to evaluate the tinnitus severity. Polymerase chain reaction (PCR) and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) techniques were used for genotyping. RESULTS: With regard to the ACE I/D polymorphism, there was no significant difference in genotype and allele frequencies between the patient group and control group. However, a statistically significant difference was found in genotype (p<0.01) and allele frequencies (p=0.021) of the ADD1 G460W gene polymorphism. Combined genotype analysis showed that the ACE II /ADD1 GW genotype was statistically significantly higher in the patient group than in the control group (X2: 7.15, p=0.007). The odds ratio value of the GW genotype was 2.5 (95% CI=1.4-4.7) (p<0.01). CONCLUSION: Our results demonstrate an association between ADD1 G460W gene polymorphism and susceptibility to severe chronic tinnitus. It was found that the GW genotype increased the disease risk by 2.5-fold compared with other genotypes. This indicates that ADD1 G460W polymorphism could be an important factor in the pathophysiology of tinnitus.

Renalase gene polymorphism is associated with increased blood pressure in preeclampsia.

BACKGROUND: Renalase is a novel enzyme that degrades circulating catecholamines. We aimed to investigate the role of rs2576178 and rs10887800 polymorphisms of the renalase gene in preeclampsia (PE) patients METHODS: This case-control study consisted of 110 women with PE and 102 normotensive controls. PCR-RFLP method was used for determination of renalase gene polymorphisms. RESULTS: Allele frequency and genotype distribution of rs10887800 polymorphism were found statistically significantly higher in women with PE (p<0.05). Also G allele and GG genotype of rs10887800 polymorphism were found higher in women with severe PE than that of mild PE (p<0.05). There was no significant difference for rs2576178 polymorphism in terms of allele frequency and genotype distribution (p>0.05). In PE patients, systolic blood pressure (SBP) means according to rs10887800 genotypes were found statistically significantly higher (GG vs AA; p=0.001) and (GG vs GA; p=0.001). Similarly, diastolic blood pressure (DBP) means were found statistically significantly higher in PE patients (GG vs GA: p=0.001); (GG vs AA: p=0.004). For rs2576178 polymorphism, SBP means were found as (GG vs AA; p=0.012, GG vs GA; p>0.05) in PE patients. DBP means were not significant according to rs2576178 genotypes in PE patients (p>0.05). CONCLUSIONS: The findings of the present study suggest that blood pressure may be increased by GG genotype and G allele of rs10887800 polymorphism and the polymorphism may increase the susceptibility to PE.

Associations of fractalkine receptor (CX3CR1) and CCR5 gene variants with hypertension, diabetes and atherosclerosis in chronic renal failure patients undergoing hemodialysis.

PURPOSE: We aimed to investigate the associations of fractalkine receptor (CX3CR1) V249I, T280M and CCR5-59029 A/G gene polymorphisms in chronic renal failure (CRF) subjects undergoing hemodialysis and to evaluate possible associations of these polymorphisms with hypertension (HT), diabetes mellitus (DM) and atherosclerosis (AS). METHODS: A total of 225 CRF subjects undergoing hemodialysis and 201 healthy controls were enrolled in the study. CRF subjects were divided into three major subgroups according to comorbidities including HT (n = 127), DM (n = 65) and AS (n = 33). Genotyping was done using polymerase chain reaction-restriction fragment length polymorphism method. RESULTS: The II genotype and I allele frequencies of CX3CR1 V249I polymorphism were found significantly more frequent in CRF subjects, CRF subjects with DM and CRF subjects with AS compared with controls (p < 0.05 for all comparisons). G allele frequency of CCR5 polymorphism was found significantly more prevalent in CRF subjects with DM than that of controls. Further, GG genotype and G allele frequencies of CCR5 polymorphism were significantly more prevalent in CRF subjects with AS compared with controls (p < 0.05). We also explored these polymorphisms among CRF subjects with and without following comorbidities: HT, DM, AS. We found significant association between CRF subjects with HT and without HT in terms of genotype and allele frequencies of V249I polymorphism (p < 0.05). CX3CR1 T280M polymorphism was not found significantly different in none of the comparisons. CONCLUSION: These data demonstrate possible associations between CX3CR1 V249I and CCR5-59029 A/G polymorphisms and/or HT, DM and AS in CRF subjects.

Prevalence of Fabry Disease in Familial Mediterranean Fever Patients from Central Anatolia of Turkey.

Fabry disease (FD) is a progressive, X-linked inherited disorder of glycosphingolipid metabolism due to deficient or absent lysosomal alpha-galactosidase A (AGALA) activity. FD and familial Mediterranean fever (FMF) have typical clinical similarities, and both diseases may progress to end-stage renal diseases. In this study, we aimed to determine the prevalence of FD in patients with FMF from Central Anatolia of Turkey. The study group consisted of 177 FMF patients, followed up by the Adult and Pediatric Nephrology Clinic of Cumhuriyet University Hospital. Screening for AGALA activity was performed by the dry blood spot method. Mutation analysis for GLA gene was carried out for patients having an AGALA enzyme activity value lower than the normal reference value. Low AGALA activity was detected in 23 (13 %) patients. Heterozygous GLA gene mutation c.[937G>T] p.[D313Y] was detected in one female patient (0.56 %). The patient was a 53-year-old female with proteinuria and who had undergone left nephrectomy; her glomerular filtration rate (GFR) by scintigraphy was found to be 70 ml/min. She had M694V mutation and no clinical manifestation of FD. In our study, the prevalence rate of FD was found as 0.56 % in FMF patients. The similarities between the symptoms of FMF and FD might lead to a diagnostic dilemma in physicians at countries where FMF is observed frequently. Although the prevalence of FD is rare, physicians should keep in mind that FD has an ambiguous symptomology pattern of FMF.

Relationship between IFNA1, IFNA5, IFNA10, and IFNA17 gene polymorphisms and Crimean-Congo hemorrhagic fever prognosis in a Turkish population range.

Crimean-Congo hemorrhagic fever (CCHF) is a fatal emerging acute viral infection. Not much is known regarding the pathogenic mechanisms and the reasons behind severe or mild disease courses in CCHF. IFN-alpha (IFNA) is one of the essential cytokines in the immune system. Existence of single nucleotide gene polymorphisms (SNPs) in cytokines can cause susceptibility or resistance to viral agents and different clinical courses. Hence, the relationship between SNPs in genes encoding cytokines (IFNA1 -1823G/A (rs1332190), IFNA5 -2529T/A (rs758236), IFNA10 Cys20stop (rs10119910), and IFNA17 Ile184Arg (rs9298814) SNPs and disease susceptibility were investigated. The associations between SNPs and CCHF prognosis were also studied. Total 150 patients with CCHF and 170 healthy individuals were enrolled. Genotyping was performed by PCR-RFLP methods. The frequency of IFNA1 -1823 (rs1332190) GG genotype was significantly higher in control subjects than CCHF patients (20% vs. 8%; P = 0.01). For IFNA17 Ile184Arg (rs9298814) polymorphism, CCHF patients having TG genotype had a higher frequency than the control subjects (38% vs. 32.4%; P = 0.039). The distribution of TT + TG genotype frequencies was also significantly higher in CCHF group than the controls (97.3% vs. 91.8%; P = 0.049). Genotype and allele frequencies for IFNA subtypes between fatal and survivors were the same (P > 0.05). Genotype and allele frequencies between severe and mild/moderate CCHF patients were also the same (P > 0.05). The results show that IFNA1 rs1332190 and IFNA17 rs9298814 SNPs may play an important role in CCHF susceptibility. Determining the existence of other connections for IFNA SNPs and CCHF severity and fatality requires further investigations.

Glutathione-S-Transferase Variants are not Associated With Increased Carotid Intima-Media Thickness in Turkish Familial Mediterranean Fever Patients.

OBJECTIVES: This study aims to evaluate the carotid intima-media thickness (CIMT) in patients diagnosed with Familial Mediterranean fever (FMF) and investigate whether there is a relationship between glutathione-S-transferase (GST) gene polymorphisms and CIMT. PATIENTS AND METHODS: Sixty FMF patients (17 males, 43 females; mean age: 31.43±11.36 years; range 18 to 45 years) and 60 healthy controls (22 males, 38 females; mean age: 29.8±5.82 years; range 18 to 40 years) were enrolled in this study. Polymerase chain reaction-restriction fragment length polymorphism methods were carried out to assess GST polymorphisms. CIMT was measured by carotid ultrasonography. Biochemical parameters were also evaluated using biochemical methods. RESULTS: Right and left CIMT of FMF patients were statistically significantly higher than that of control group (CIMT right p=0.001 and CIMT left: p=0.033). There was no significant association in terms of GST polymorphisms between FMF and control groups. No significant association was observed between GST polymorphisms and CIMT. Low density lipoprotein, erythrocyte sedimentation rate, and fibrinogen levels were significantly higher in the patient group (p<0.05). The difference between groups was not significant in terms of other biochemical parameters (p>0.05). CONCLUSION: Although no significant association was observed between GST polymorphisms and CIMT in FMF patients and controls, CIMT was statistically significantly higher in FMF patients compared to controls.

Aldosterone Synthase CYP11B2 Gene Promoter Polymorphism in a Turkish Population With Chronic Kidney Disease.

INTRODUCTION: It has been shown that gene polymorphisms influence the development and progression of chronic kidney disease (CKD). Many studies have indicated that aldosterone synthase CYP11B2 gene polymorphism (-344C>T) influences the aldosterone level, urinary aldosterone excretion, blood pressure, and left ventricular size and mass. We aimed to investigate whether there is an effect of CYP11B2 -344 C>T polymorphism on the development of CKD in a Turkish population. MATERIAL AND METHODS: A total of 240 patients with stage 5 CKD and 240 age- and sex-matched healthy individuals were included in the study. Genotyping of CYP11B2 gene -344 T>C promoter polymorphism was carried out using polymerase chain reaction and restriction fragment length polymorphism methods. RESULTS: No significant differences were found in the genotype distribution of CYP11B2 -344 C>T polymorphism between the patients and controls; however, -344 C>T polymorphism was significantly more frequent among the CKD patients with diabetes mellitus as compared to those with it (P = .02). Diabetic CKD patients with TC genotype had a 2-fold increased risk for development of the disease than the CKD patients without diabetes mellitus (odds ratio, 2.21; 95% confidence interval, 1.04 to 4.67). CONCLUSIONS: Our study suggests that the CYP11B2 gene -344 C>T polymorphism may have an effect on the development of CKD in diabetic patients.