The role of CD247 polymorphisms in Bulgarian patients with systemic lupus erythematosus

Decreased expression of the TCR ζ-chain has been reportedin several autoimmune and inflammatory diseases. Recent evidence suggeststhat this deficiency may be due to polymorphisms in the CD247gene. A total 52 patients with systemic lupus erythematosus (SLE) and95 healthy controls of Bulgarian ethnicity were genotyped for 837C&gt;G,rs1052230, 844A&gt;T, and rs1052231 using a TaqMan genotyping assay.None of the two polymorphisms appeared associated with the diseases.On the other hand, we have found that the -837GG genotype and the Gallele were associated with hematological disease. The -844AA genotypeand the A allele appeared associated with the hematological disease aswell. The -843AA genotype and the A allele were found to be associatedwith antinuclear antibody (ANA) tests and immunological disease. Anassociation was found between the -837G allele and arthritis. The AGhaplotype was found to be associated with hematological disease, ANA,and immunological disease. Our preliminary data confirm the previousfindings that the CD247 polymorphisms are mainly associated with theclinical outcome of the disease and less with susceptibility.</p

Detection of different colistin resistance mechanisms among multidrug resistant Klebsiella pneumoniae isolates in Bulgaria

The more frequent usage of colistin resulted in an increase of colistin resistance due to lipopolysaccharide modifications. The aim of this study was to reveal the prevalence and mechanisms of colistin resistance among multidrug-resistant Klebsiella pneumoniae isolates collected in Bulgaria. One hundred multidrug resistant K. pneumoniae isolates were collected in a period between 2017 and 2018. Among them, 29 colistin resistant and 8 heteroresistant isolates were observed and further investigated. Clonal relatedness was detected by RAPD and MLST. Carbapenemases, two component system phoQ/phoP, pmrA/B, and mgrB were investigated by PCR amplification and Sanger sequencing. Among 37 colistin nonsusceptible isolates, we detected 25 NDM-1 producers. The isolates belonged mainly to ST11 (80%), and also to ST147, ST35, ST340, ST219 (1-2 members per clone). Nine colistin resistant isolates showed changes in mgrB. IS903B-like elements truncated mgrB in five isolates. In two isolates, premature stopcodon (Q30stopcodon) was observed and another two isolates did not amplify mgrB, possibly due to bigger deletion or insertion. No isolates showed phoQ/phoP and pmrA/B mutations except for pmrB (four isolates had R256G). All isolates with IS903B insertions belonged to ST11 clone. The mgrB alterations play major role in colistin resistance in K. pneumoniae isolates studied in the current work. We report truncation of mgrB by IS903 like element in colistin resistant NDM-1 producing K. pneumoniae ST11 clone in Bulgaria

MOLECULAR EPIDEMIOLOGY OF MULTIDRUG RESISTANT ENTEROBACTER CLOACAE BLOOD ISOLATES FROM A UNIVERSITY HOSPITAL

urpose: to evaluate the epidemiological relationship between 3rd generation cephalosporin resistant Enterobacter cloacae blood isolates collected from patients in the University Hospital in Varna city during the period March 2014 and January 2017 and to characterize the ESBLs production in these isolates. Materials and methods: a total of 47 consecutive (nonduplicate) 3rd generation cephalosporin resistant isolates of Enterobacter cloacae, obtained from blood samples of patients admitted in different wards in Varna University Hospital, were investigated. Antimicrobial susceptibility to set of antimicrobial agents was tested by disc diffusion method and Phoenix (BD), and the results were interpreted according to EUCAST guidelines 2017. Identification of ESBL encoding genes was performed by PCR and sequencing. Isolates were genotyped by ERIC PCR. Results: The antimicrobial susceptibility in the whole collection of isolates, shown in decreasing order, is as follows: amikacin, 97.8% < levofloxacin, 76.6% < trimethoprime/ sulphometoxazole, 40.4% < ciprofloxacin, 19% < gentamicin, 8.4% < cefepime, 4.2% < piperacillin/ tazobactam, tobramycin, 2.1%. Multidrug resistance was detected in 70.2% of the isolates. The most widespread enzyme was CTX-M-15, found in 95.5% (n=43). Nine different ERIC types were detected. The dendrogram of similarity revealed three main clones of E. cloacae: Clone I, comprising two closely related subclones (ERIC type A and Aa) (similarity coefficient 0.92), was predominant, detected in Haematology (n=9), Haemodialysis (n=8), ICU (n=6), Cardio surgery (n=3), Pulmonology (n=4) and Gastroenterology (n=1); Clones II (ERIC type C) and III were presented by 5, and 3 isolates with identical profiles, obtained from patients, hospitalized in different wards. The ERIC profiles K, L, M and P, were found in single isolates only and were interpreted as sporadic. Conclusions: multi-drug resistance in E. cloacae was associated with successful intrahospital dissemination of three CTX-M-15 producing E. cloacae clones. Clone I was predominant, demonstrating high cross-transmission, epidemic and invasive potential. BlaCTX-M-15 was identified as a major mechanism of resistance to 3rd generation cephalosporins in E. cloacae

IL-1RN VNTR Polymorphism in Adult Dermatomyositis and Systemic Lupus Erythematosus

Polymorphisms in the cytokine genes and their natural antagonists are thought to influence the predisposition to dermatomyositis (DM) and systemic lupus erythematosus (SLE). A variable number tandem repeat (VNTR) polymorphism of 86 bp in intron 2 of the interleukin-1 receptor antagonist (IL-1RN) gene leads to the existence of five different alleles which cause differences in the production of both IL-1RA (interleukin-1 receptor antagonist) and IL-1 . The aim of this case-control study was to investigate the association between the IL-1RN VNTR polymorphism and the susceptibility to DM and SLE in Bulgarian patients. Altogether 91 patients, 55 with SLE and 36 with DM, as well as 112 unrelated healthy controls, were included in this study. Only three alleles were identified in both patients and controls ((1) four repeats, (2) two repeats, and (3) five repeats). The IL-1RN * 2 allele ( = 0.02, OR 2.5, and 95% CI 1.2-5.4) and the 1/2+2/2 genotypes were found prevalent among the SLE patients ( = 0.05, OR 2.6, and 95% CI 1-6.3). No association was found between this polymorphism and the ACR criteria for SLE as well as with the susceptibility to DM. Our results indicate that the IL-1RN VNTR polymorphism might play a role in the susceptibility of SLE but not DM

Marked intrafamilial variability of exocrine and endocrine pancreatic phenotypes due to a splice site mutation in GATA6

The objective of this study was to describe the clinical characteristics of syndromic neonatal diabetes in a family with a GATA6 mutation. A girl, currently aged 12 years 3 months, was born with intrauterine growth retardation: weight 1600 g (–4.3 SDS) at term. After birth, foramen ovale and patent ductus arteriosus (PDA) were diagnosed by echocardiography. Diabetes was diagnosed on the 9th day after birth. Exocrine pancreatic insufficiency was clinically diagnosed at about 2 years of age and pancreatic agenesis was revealed later by magnetic resonance imaging. Her father had undergone surgery during infancy for PDA and had developed insulin dependent diabetes at 12 years of age. Ultrasound revealed a thin pancreas with normal length and anatomical structure. He has subclinical exocrine pancreatic insufficiency, low insulin needs and no late complications of diabetes up to the age of 40 years. Sequencing of GATA6 identified a heterozygous splicing mutation, 1136-2A>G, in the girl and her father. Testing of the paternal grandparents showed that the mutation was likely to have arisen de novo in the father. Identification of a GATA6 mutation explains the cardiac anomalies and diabetes in this family. This case highlights the marked intrafamilial variability of both exocrine and endocrine pancreatic phenotypes in patients with GATA6 mutations.This article is freely available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site

Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression

Associations between single nucleotide polymorphisms (SNPs) at 5p15 and multiple cancer types have been reported. We have previously shown evidence for a strong association between prostate cancer (PrCa) risk and rs2242652 at 5p15, intronic in the telomerase reverse transcriptase (TERT) gene that encodes TERT. To comprehensively evaluate the association between genetic variation across this region and PrCa, we performed a fine-mapping analysis by genotyping 134 SNPs using a custom Illumina iSelect array or Sequenom MassArray iPlex, followed by imputation of 1094 SNPs in 22 301 PrCa cases and 22 320 controls in The PRACTICAL consortium. Multiple stepwise logistic regression analysis identified four signals in the promoter or intronic regions of TERT that independently associated with PrCa risk. Gene expression analysis of normal prostate tissue showed evidence that SNPs within one of these regions also associated with TERT expression, providing a potential mechanism for predisposition to disease

Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohort.

BACKGROUND: Epidemiological studies have observed a positive association between an earlier age at sexual development and prostate cancer, but markers of sexual maturation in boys are imprecise and observational estimates are likely to suffer from a degree of uncontrolled confounding. To obtain causal estimates, we examined the role of pubertal development in prostate cancer using genetic polymorphisms associated with Tanner stage in adolescent boys in a Mendelian randomization (MR) approach. METHODS: We derived a weighted genetic risk score for pubertal development, combining 13 SNPs associated with male Tanner stage. A higher score indicated a later puberty onset. We examined the association of this score with prostate cancer risk, stage and grade in the UK-based ProtecT case-control study (n = 2,927), and used the PRACTICAL consortium (n = 43,737) as a replication sample. RESULTS: In ProtecT, the puberty genetic score was inversely associated with prostate cancer grade (odds ratio (OR) of high- vs. low-grade cancer, per tertile of the score: 0.76; 95 % CI, 0.64-0.89). In an instrumental variable estimation of the causal OR, later physical development in adolescence (equivalent to a difference of one Tanner stage between pubertal boys of the same age) was associated with a 77 % (95 % CI, 43-91 %) reduced odds of high Gleason prostate cancer. In PRACTICAL, the puberty genetic score was associated with prostate cancer stage (OR of advanced vs. localized cancer, per tertile: 0.95; 95 % CI, 0.91-1.00) and prostate cancer-specific mortality (hazard ratio amongst cases, per tertile: 0.94; 95 % CI, 0.90-0.98), but not with disease grade. CONCLUSIONS: Older age at sexual maturation is causally linked to a reduced risk of later prostate cancer, especially aggressive disease.This work was supported by the World Cancer Research Fund (2011/419) and Cancer Research UK (C18281/A19169). The Integrative Epidemiology Unit (IEU) is supported by the MRC and the University of Bristol (G0600705, MC_UU_12013/19), and the Integrative Cancer Epidemiology Programme is supported by Cancer Research UK programme grant C18281/A19169. The National Institute for Health Research (NIHR) Bristol Nutrition Biomedical Research Unit is funded by the NIHR and is a partnership between University Hospitals Bristol NHS Foundation Trust and the University of Bristol. The ProtecT study is supported by the UK NIHR Health Technology Assessment (HTA) Programme (HTA 96/20/99; ISRCTN20141297). Funding for PRACTICAL and the iCOGS infrastructure came from: the European Community’s Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/ A16565), the National Institutes of Health (CA128978), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 – the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. We acknowledge support from the NIHR to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust.This is the final version of the article. It first appeared from BioMed Central via http://dx.doi.org/10.1186/s12916-016-0602-