Zeliha Emrence

Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease

Behçets disease is a genetically complex disease of unknown etiology characterized by recurrent inflammatory attacks affecting the orogenital mucosa, eyes and skin. We performed a genome-wide association study with 311,459 SNPs in 1,215 individuals with Behçets disease (cases) and 1,278 healthy controls from Turkey. We confirmed the known association of Behçets disease with HLA-B*51 and identified a second, independent association within the MHC Class I region. We also identified an association at IL10 (rs1518111, P = 1.88 × 10−8). Using a meta-analysis with an additional five cohorts from Turkey, the Middle East, Europe and Asia, comprising a total of 2,430 cases and 2,660 controls, we identified associations at IL10 (rs1518111, P = 3.54 × 10−18, odds ratio = 1.45, 95% CI 1.34–1.58) and the IL23R-IL12RB2 locus (rs924080, P = 6.69 × 10−9, OR = 1.28, 95% CI 1.18–1.39). The disease-associated IL10 variant (the rs1518111 A allele) was associated with diminished mRNA expression and low protein production.

Genome-wide association analysis identifies new susceptibility loci for Behcet's disease and epistasis between HLA-B*51 and ERAP1.

Individuals with Behçets disease suffer from episodic inflammation often affecting the orogenital mucosa, skin and eyes. To discover new susceptibility loci for Behçets disease, we performed a genome-wide association study (GWAS) of 779,465 SNPs with imputed genotypes in 1,209 Turkish individuals with Behçets disease and 1,278 controls. We identified new associations at CCR1, STAT4 and KLRC4. Additionally, two SNPs in ERAP1, encoding ERAP1 p.Asp575Asn and p.Arg725Gln alterations, recessively conferred disease risk. These findings were replicated in 1,468 independent Turkish and/or 1,352 Japanese samples (combined meta-analysis P < 2 × 10−9). We also found evidence for interaction between HLA-B*51 and ERAP1 (P = 9 × 10−4). The CCR1 and STAT4 variants were associated with gene expression differences. Three risk loci shared with ankylosing spondylitis and psoriasis (the MHC class I region, ERAP1 and IL23R and the MHC class I–ERAP1 interaction), as well as two loci shared with inflammatory bowel disease (IL23R and IL10) implicate shared pathogenic pathways in the spondyloarthritides and Behçets disease.

Draft Genome Sequence of Halomonas smyrnensis AAD6T

Halomonas smyrnensis AAD6(T) is a Gram-negative, aerobic, exopolysaccharide-producing, and moderately halophilic bacterium that produces levan, a fructose homopolymer with many potential uses in various industries. We report the draft genome sequence of H. smyrnensis AAD6(T), which will accelerate research on the rational design and optimization of microbial levan production.

A genome-wide analysis of lentivector integration sites using targeted sequence capture and next generation sequencing technology

One application of next-generation sequencing (NGS) is the targeted resequencing of interested genes which has not been used in viral integration site analysis of gene therapy applications. Here, we combined targeted sequence capture array and next generation sequencing to address the whole genome profiling of viral integration sites. Human 293T and K562 cells were transduced with a HIV-1 derived vector. A custom made DNA probe sets targeted pLVTHM vector used to capture lentiviral vector/human genome junctions. The captured DNA was sequenced using GS FLX platform. Seven thousand four hundred and eighty four human genome sequences flanking the long terminal repeats (LTR) of pLVTHM fragment sequences matched with an identity of at least 98% and minimum 50 bp criteria in both cells. In total, 203 unique integration sites were identified. The integrations in both cell lines were totally distant from the CpG islands and from the transcription start sites and preferentially located in introns. A comparison between the two cell lines showed that the lentiviral-transduced DNA does not have the same preferred regions in the two different cell lines.

Genomic analysis reveals the biotechnological and industrial potential of levan producing halophilic extremophile, Halomonas smyrnensis AAD6T

Halomonas smyrnensis AAD6T is a gram negative, aerobic, and moderately halophilic bacterium, and is known to produce high levels of levan with many potential uses in foods, feeds, cosmetics, pharmaceutical and chemical industries due to its outstanding properties. Here, the whole-genome analysis was performed to gain more insight about the biological mechanisms, and the whole-genome organization of the bacterium. Industrially crucial genes, including the levansucrase, were detected and the genome-scale metabolic model of H. smyrnensis AAD6T was reconstructed. The bacterium was found to have many potential applications in biotechnology not only being a levan producer, but also because of its capacity to produce Pel exopolysaccharide, polyhydroxyalkanoates, and osmoprotectants. The genomic information presented here will not only provide additional information to enhance our understanding of the genetic and metabolic network of halophilic bacteria, but also accelerate the research on systematical design of engineering strategies for biotechnology applications.

SET oncogene is upregulated in pediatric acute lymphoblastic leukemia

AIMS AND BACKGROUND The SET gene is a target of chromosomal translocations in acute leukemia and encodes a widely expressed multifunctional phosphoprotein. It has been shown that SET is upregulated in BCR-ABL1-positive cell lines, patient-derived chronic myeloid leukemia CD34-positive cells, and some solid tumors. METHODS AND STUDY DESIGN We determined the expression level of SET in 59 pediatric acute lymphoblastic leukemia patients who were BCR-ABL-negative using quantitative real-time reverse-transcriptase-polymerase chain reaction. Results. We showed that SET expression was significantly upregulated in 96.5% of B-acute lymphoblastic leukemia (28 of 29; 16.6 fold) and 93% of T-acute lymphoblastic leukemia (28 of 30; 47.6 fold) patients. This upregulation was not associated with any clinical features or overall and relapse-free survival. CONCLUSIONS Our results showed that SET is significantly overexpressed in pediatric acute lymphoblastic leukemia samples, and an increased level of SET might contribute to leukemic process.

TT polymorphism in rs2165241 and rs1048661 region in lysyl oxidase like-1 gene may have a role in stress urinary incontinence physiopathology

Aim:  In experimental studies, lysyl oxidase like‐1 (LOX‐L1) (−/−) mice were shown to have similar pelvic floor dysfunction to female rats. LOX‐L1 levels in endopelvic fascia decrease as a result of increasing births in women with pelvic prolapse. For these reasons, we investigated the LOX‐L1 gene polymorphism, which has an important role in connective tissue and collagenous metabolism in stress urinary incontinence (SUI).

Natural Killer Cell Subsets and Their Functional Activity in Behçet’s Disease

ABSTRACT Background: Behçet’s disease (BD) is a rare, chronic autoinflammatory disorder of unknown origin. Natural killer (NK) cells are one of the major immunoregulatory cell groups of the innate immune system, but their role in BD pathogenesis is not well documented. Objectives: We aimed to investigate the role of NK cell subsets and their cytokine secretion and cytotoxic activity in patients with BD. Patients and methods: The study group consisted of BD patients who had only mucocutaneous involvement, and they were compared with healthy subjects. BD patients were divided into two groups according to their frequencies of oral ulcerations. NK cell cytotoxicity was determined using CD107a expression and a CFSE-based cytotoxicity test. Expression of NK cell receptors and surface markers and the intracellular IL-5, IL-10, IL-17, and IFN-γ levels in CD16+ NK cells were assessed by flow cytometry. Results: Although the cytokine secretion pattern was different, no difference was obtained in cytotoxic activity, expression of activatory receptors, or degranulation of NK cells. Conclusion: Increases in NK1/NK2 ratio and CD16+IFN-γ+ NK1 cells might support the idea of a biased IFN-γ dominant immune response in the mucocutaneous involvement of BD pathogenesis. Although the cytokine secretion pattern was different, no difference was obtained in cytotoxic activity, expression of activatory receptors, or degranulation of NK cells.

Pathological and immunological features of autoinflammatory syndrome associated with lymphedema (AISLE)

Background We recently described a new autoinflammatory syndrome associated with lymphedema (AISLE), and a frameshift mutation in the MDFIC gene was identified by homozygosity mapping and targeted sequencing using DNA samples of a consanguineous Turkish family as the cause of this syndrome. The same mutation in the MDFIC gene was identified in an Italian patient with similar clinical findings. Clinical findings of these patients are characterized by recurrent attacks of fever, erythematous/urticarial rash with hyperesthesia, myalgia, serositis, chylous serosal effusions, edema/lymphedema on the face and extremities. These patients gradually developed a permanent lymphedema in the same areas affected during attacks. On the other hand, there is limited information about the functions of MDFIC gene, which include transcriptional regulator interacting with cellular transcription factors, including such as axin and wnt/b-catenin signaling pathway. Although, its expression has been documented in immune cells, no clear function has been described in immune mediated or inflammatory conditions.

OP0078 The TNFRSF1A and MEFV Gene Mutations in the Secondary Amyloidosis Without FMF and HPFS Symptoms

Background Familial Mediterranean Fever (FMF) is an autoinflammatory disease with recurrent attacks of fever, serositis and arthritis. The most frequently complication of FMF is amyloidosis, which causes frequently mortality and morbidity. The pathogenesis of amyloidosis is unknown. In the other hand other chronic inflammatory disorders may cause secondary amyloidoses. Except SAA, it was not found a common genetic susceptibility for the secondary amyloidoses associated with different inflammatory disorders. Objectives We aimed in this study to investigate the role of MEFV gene and TNFRSF1A gene in the pathogenesis of amyloidosis which is not associated with FMF or other hereditary periodic fever syndromes (HPFS). Methods The study group is consisted of 47 FMF patients without amyloidosis, 42 FMF patients with amyloidosis, 37 patients with AA amyloidosis without FMF or other HPFS and 45 healthy controls. We analyzed the TNFRSF1A gene exon 2-5 and MEFV gene exon 10 mutations with sequencing in all patients. Results We found increased frequency of rs116336305 SNP in TNFRSF1A gene in the FMF without amyloidosis group. An interesting finding was that this SNP was not found in amyloidosis group (p=0.003, OR:0.809, %95 CI:0, 708-0929). No other mutation was found in the TNFRSF1A gene. The M694V mutation carrier rate is increased in the AA amyloidosis group without any FMF symptoms in comparison with healthy controls (p=0,042, OO:8,52, %95 CI: 0,98-74,3, %16,2 vs %2.2). There was no difference in the carrier rate of other MEFV mutations between these groups. Conclusions This study reveals that rs116336305 mutation rate is increased in AAA and there is no amyloidosis in patients with this mutation. This data should be verified with larger patients groups. In the other hand we found increased M694V carrier rate in secondary amyloidosis group without FMF symptomes. These results suggest that M694V mutation should be investigated in the patients with proteinuria and without FMF symptomes, especially in those populations with high carrier MEFV mutation carrier rate. Disclosure of Interest None Declared