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Acute myeloid leukaemia (AML) is a neoplasm of immature myeloid cells characterized by various cytogenetic alterations. The present study showed that in addition to the FLT3-ITD and NPM1 mutation status, telomere length (TL) and telomerase reverse transcriptase (TERT) gene polymorphisms may affect risk and overall survival (OS) in AML. TL was longer in healthy controls than in AML patients and positively correlated with age in the patients, but not in healthy subjects. TL was found to be independently affected by the presence of the FLT3-ITD mutation. As for the TERT gene polymorphism, AML patients with the TERT rs2853669 CC genotype were characterized by significantly shorter OS than patients carrying the T allele. Another observation in our study is the difference in TL and OS in patients belonging to various risk stratification groups related to the FLT3-ITD and NPM1 mutation status. Patients with adverse risk classification (mutation in FLT3-ITD and lack of mutation in NPM1) presented with the shortest telomeres and significantly worse OS. In conclusion, OS of AML patients appears to be affected by TERT gene variability and TL in addition to other well-established factors such as age, WBC count, or FLT3-ITD and NPM1 mutation status.

Toll-like receptors (TLRs), NOD-like receptors (NLRs), and RIG-I-like receptors (RLRs) are major elements of the innate immune system that recognize pathogen-associated molecular patterns. Single-nucleotide polymorphisms (SNPs) in the TLR, NLR, and RLR genes may lead to an imbalance in the production of pro- and anti-inflammatory cytokines, changes in susceptibility to infections, the development of diseases, and carcinogenesis. Acute myeloid leukemia (AML) is a bone marrow malignancy characterized by uncontrolled proliferation of transformed myeloid precursors. We retrospectively analyzed 90 AML patients. We investigated the effect of fifteen SNPs located in the genes coding for RLR1 (rs9695310, rs10738889, rs10813831), NOD1 (rs2075820, rs6958571), NOD2 (rs2066845, rs2066847, rs2066844), TLR3 (rs5743305, rs3775296, 3775291), TLR4 (rs4986791, rs4986790), and TLR9 (rs187084, rs5743836). We observed that TLR4 rs4986791, TLR9 rs5743836, and NOD2 rs2066847 were associated with CRP levels, while RLR-1 rs10738889 was associated with LDH level. Furthermore, we found TLR3 rs5743305 AA to be more common in patients with infections. We also found TLR9 rs187084 C to be associated with more favorable risk, and RLR-1 rs9695310 GG with higher age at diagnosis. In conclusion, the current study showed that SNPs in the genes encoding TLRs, NLRs, and RLRs may be potential biomarkers in patients with AML.

Multiple myeloma (MM) is a heterogeneous bone marrow cancer characterized by proliferation of malignant plasma cells in the bone marrow. One of its major symptoms are hypercalcaemia and bone lesions, which may result in pathologic bone fractures. Receptor activator for nuclear factor κB (RANK) and its ligand, RANKL, are part of an activation pathway for osteoclasts and are thus responsible for bone resorption. Furthermore, RANKL expression is increased in multiple myeloma. In the present study, we investigated the role of single nucleotide polymorphisms (SNPs) in the genes coding for RANK (rs1805034, rs8086340), RANKL (rs7325635, rs7988338), and TACI (rs34562254), a receptor for osteoclast-derived pro-survival factors. The study involved 222 patients and 222 healthy individuals, and the analysis included disease susceptibility, survival, bone lesions, calcium levels, and vascular endothelial growth factor levels. Patients with allele RANK rs1805034 C had higher survival (p = .003). This relationship was especially evident in women (p = .006). Furthermore, allele rs1805034 C was associated with slightly lower median age at diagnosis (64.0 vs. 65.5, p = .008). Allele RANKL rs7325635 A correlated with lower progression-free survival (p = .027), and with lack of early progression (p = .023). Additionally, women with allele rs7325635 G were found to have higher calcium blood concentration (p = .040). Allele TACI rs34562254 A was more common in MM patients in more advanced stages (II and III stage International Staging System) at diagnosis (p = .017), and the SNP showed a slight trend towards association in a multivariate analysis (p = .084). Taken together, our results suggest that RANK rs1805034 and RANKL rs7325635 may have a role in MM development and progression.

Sleep bruxism (SB) and obstructive sleep apnea (OSA) are co-occurring sleep conditions. The study aimed to evaluate the association of selected single-nucleotide polymorphisms (SNPs) occurring within the genes of the serotonin and dopamine pathways in SB and OSA and investigate the relationship between them. The study group included 100 Caucasian patients. SB and OSA were diagnosed in 74 and 28 patients, respectively. In addition, 125 unrelated Caucasian healthy blood donors served as randomly selected controls to enable comparison of polymorphisms. The following SNPs were analyzed: rs2770304 and rs6313 within the serotonin receptor encoding gene (HTR2A), rs4680 polymorphism of the catechol-O-methyltransferase (COMT) gene, and rs686 within the dopamine receptor (DRD1) encoding gene. The prevalence of the DRD1 rs686 G variant (GG homozygosity) was found to be high in the study group compared to the control group. Bruxism episode index (BEI) was found to be significantly increased in the HTR2A rs6313 TT homozygotes compared to the heterozygous patients. Moreover, within a group of the HTR2A rs2770304 TT homozygous cases, a statistically significant correlation was observed between BEI and apnea–hypopnea index. These results indicate that DRD1 rs686 may potentially affect predisposition to SB, that HTR2A rs6313 SNP may be involved in SB pathogenesis, and that HTR2A rs2770304 polymorphism might contribute to the association between SB and OSA. This suggests a possible genetic contribution to the etiology of primary SB.

The molecular mechanisms of telomerase reverse transcriptase (

Introduction: Sleep bruxism (SB) is a widespread masticatory muscle activity during sleep and affects approximately 13.2% of the general population. Telomerase reverse transcriptase (TERT) plays a role in preventing the shortening of the telomere. This prospective, observational study aimed to investigate the relationship between single nucleotide polymorphism (SNP) of TERT and the severity of SB and to identify the independent risk factors for SB. Methods: A total of 112 patients were diagnosed by performing one-night polysomnography based on the guidelines of the American Academy of Sleep Medicine. TERT SNP was detected by real-time quantitative polymerase chain reaction (qPCR). Results: Statistical analysis showed the lack of relationship between the rs2853669 polymorphism of TERT and severity of SB (p > 0.05). However, the study showed that patients with allele T in the 2736100 polymorphism of TERT had a lower score on the phasic bruxism episode index (BEI). Based on the receiver operating characteristic (ROC) curve, the value of phasic BEI was 0.8 for the differential prediction for the presence of allele T in the locus. The sensitivity and specificity were 0.328 and 0.893, respectively. The regression analysis showed that lack of TERT rs2736100 T allele, male gender, and arterial hypertension are the risk factors for the higher value of phasic BEI. Conclusion: The SNP of the TERT gene affects phasic SB intensity. The absence of TERT rs2736100 T allele, male sex, and arterial hypertension are independent risk factors for phasic SB.

Background: The human telomerase reverse transcriptase (TERT) gene encodes the catalytic subunit of telomerase that is essential for maintenance of telomere length. We aimed to find out whether variability within the TERT gene could be associated with telomere length and development of the disease in non-treated patients with chronic lymphocytic leukemia (CLL). Materials and methods: Telomere length, rs2736100, rs2853690, rs33954691, rs35033501 single-nucleotide polymorphisms, and variable number of tandem repeats (VNTR-MNS16A) were assessed in patients at diagnosis. In addition, blood donors served as controls for the polymorphism studies. Results: The minor rs35033501 A variant was more frequent among CLL patients than in healthy controls (OR=3.488, p=0.039). CLL patients over 60 years of age were characterized with lower disease stage at diagnosis (p=0.001 and p=0.008, for the Rai and Binet criteria, respectively). The MNS16A VNTR-243 short allele was more frequent in patients with a low disease stage (p=0.020 and p=0.028, for the Rai and Binet staging system) and also among older patients having longer telomeres (p=0.046). Patients with Rai 0-I stage were characterized with longer telomeres than those with more advanced disease (p=0.030). This relationship was especially pronounced in patients carrying the rs2736100 C allele, independently of the criteria used, ie, Binet (p=0.048) or Rai (p=0.001). Conclusion: Our results showed that the genetic variation within the TERT gene seems to play a regulatory role in CLL and telomere length.

Inconsistency of the results regarding the genetic variability within genes coding for receptor activator of nuclear factor κB (RANK) and its ligand (RANKL) in rheumatoid arthritis (RA) prompted us to study the RANK and RANKL polymorphisms as potential biomarkers associated with disease predisposition and response to anti-TNF treatment in a group of Polish patients with RA. This study enrolled 318 RA patients and 163 controls. RANK (rs8086340, C > G; rs1805034, C > T) and RANKL (rs7325635, G > A; rs7988338 G > A) alleles were determined by real-time PCR with melting curve analysis and related with clinical parameters. In addition, RANKL serum levels were measured by ELISA. The RANK rs8086340-G allele was overrepresented among patients as compared to controls (OD = 1.777, p = 0.038). C-reactive protein (CRP) levels were significantly (p RANK rs8086340 polymorphism and were higher in the CC-homozygotes at the baseline while lower in the GG-carriers at the 12th week of the treatment. At the latter time point RANKL rs7325635-GG-positive patients also showed significantly lower CRP concentrations. Higher alkaline phosphatase levels before induction of anti-TNF therapy were observed in RANK rs8086340 and RANK rs1805034 CC homozygotes (p = 0.057 and p = 0.035, respectively). The GG homozygosity of both RANKL single nucleotide polymorphisms was significantly associated with the number of swollen joints (rs7988338 and rs7325635, before and at the 12th week of therapy, respectively, p RANK and RANKL genes affect RA susceptibility and anti-TNF treatment outcome.

Promoter region of the telomerase reverse transcriptase gene (TERTp) constitutes a regulatory element capable to affect TERT expression (TE), telomerase activity (TA) and telomere length (TL). TERTp mutation status, TL, TA and TE were assessed in 27 in vitro cultured human cell lines, including 11 solid tumour, 13 haematological and 3 normal cell lines. C228T and C250T TERTp mutations were detected in 5 solid tumour and none of haematological cell lines (p = 0.0100). As compared to other solid tumour cell lines, those with the presence of somatic mutations were characterized by: shorter TL, lower TA and TE. Furthermore, cell lines carrying TERTp mutations showed a linear correlation between TE and TA (R = 0.9708, p = 0.0021). Moreover, haematological cell lines exhibited higher TE compared to solid tumour cell lines (p = 0.0007). TL and TA were correlated in both solid tumour (R = 0.4875, p = 0.0169) and haematological (R = 0.4719, p = 0.0095) cell lines. Our results based on the in vitro model suggest that oncogenic processes may differ between solid tumours and haematological malignancies with regard to their TERT gene regulation mechanisms.

Acute myeloid leukemia (AML) is a bone marrow malignancy characterized by uncontrolled proliferation of transformed myeloid precursors. It is the most common acute leukemia and is a highly heterogeneous disease. AML leads to impaired hematopoiesis, which may result in increased risk of infection. Toll-like receptors (TLRs) are major elements of the innate immune system which recognize pathogen-associated molecular patterns. They also have a role in autoimmune diseases and cancer through their recognition of endogenous danger-associated molecular patterns. Various TLRs were found to be expressed in AML cells, and their expression was found to affect growth, differentiation, and immunostimulatory capacity in AML. We retrospectively analysed 90 patients (48 females and 42 males) with diagnosis of AML, hospitalized in Department and Clinic of Hematology, Blood Neoplasms and Bone Marrow Transplantation of Wroclaw Medical University. The median age of patients was 62 (range:18-81). Infectious complications after induction chemotherapy occurred in 62 patients. In the present study, we detected the effect of seven single nucleotide polymorphisms (SNPs) located in the genes coding for TLR3 (rs5743305, rs3775296, 3775291), TLR4 (rs4986791, rs4986790) and TLR9 (rs187084, rs5743836). DNA was isolated from samples of peripheral blood taken on EDTA. Melting curve genotyping with the use of LightSNiP asays(TIB MOLBIOL, Germany) was employed to determining TLR3, TLR4 and TLR9 genotypes, and the reactions were performed LightCycler 480 device (Roche Applied Science, Germany).Statistical analyses were performer using Real Statistics Resource Pack for Microsoft Excel. We found that TLR3 rs5743305 AA homozygosity was more common in AML patients with infectious complications than in patients unaffected by infections (p=0.015). TLR4 rs4986791 C and TLR9 rs5743836 C were associated with lower levels of the inflammation marker CRP (p=0.015 and p=0.048, for rs4986791 and rs5743836, respectively), TLR4 rs4986791 C and was less frequently detected among patients with CRP>5 (p=0.028). We also found TLR9 rs187084 C to be more common in patients with adverse cytogenetic risk according to ELN criteria (0.012). Additionally, a trend for higher prevalence of extramedullary disease was observed for carriers of TLR3 rs3775296 T (p=0.054), TLR3 3775291 GG (p=0.068), TLR4 rs4986790 G (p=0.078), as well as TLR9 rs187084 TT (p=0.053). In conclusion, our results suggest that SNPs in the genes coding for TLR3, TLR4 and TLR9 may be implicated in clinical outcome of AML and is related with increased risk of infectious complications. Disclosures Wróbel: BMS: Honoraria; Roche: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; BeiGene: Honoraria.

Background: Psoriatic arthritis (PsA) is a multifactorial chronic inflammatory disease manifested by joint inflammation and cutaneous psoriasis. The precise etiology of PsA remains unknown, however both genetic and environmental factors contribute to development of this immune-mediated disease. Objectives: This present study aimed to assess whether polymorphism within gene coding for major histocompatibility complex (MHC) class I chain-related a (MICA) proteins could be a prognostic factor of PsA. Methods: For this purpose 77 PsA patients and 234 controls were enrolled to the study on MICA polymorphic variants. Genotyping for MICA rs1051792 (Met/Val; G>A) was performed using a LightSNiP assay. In addition the MICA serum levels were studied in 66 patients and 99 controls employing Luminex assay. Results: Interestingly, MICA polymorphism was found to affect the susceptibility to PsA. The presence of the a (Val) variant was found to increase the risk of PsA (OR= 1.932, p=0.022). No significant differences were detected between MICA serum levels in patients and controls. However, patients carrying this risk variant (A allele) characterized with lower MICA serum levels as compared GG homozygotes (p=0.018) Conclusion: These results imply that MICA polymorphism may constitute a risk factor of PsA and be associated with MICA serum levels in PsA patients. Supported by the National Science Centre (Poland) grant: 2016/21/B/NZ5/01901. Disclosure of interests: None declared

Background: The human telomerase reverse transcriptase (TERT) gene encodes the catalytic subunit of telomerase that is essential for maintenance of telomere length. We aimed to find out whether variability within the TERT gene could be associated with telomere length and development of the disease in non-treated patients with chronic lymphocytic leukemia (CLL). Materials and methods: Telomere length, rs2736100, rs2853690, rs33954691, rs35033501 single-nucleotide polymorphisms, and variable number of tandem repeats (VNTR-MNS16A) were assessed in patients at diagnosis. In addition, blood donors served as controls for the polymorphism studies. Results: The minor rs35033501 A variant was more frequent among CLL patients than in healthy controls (OR=3.488, p=0.039). CLL patients over 60 years of age were characterized with lower disease stage at diagnosis (p=0.001 and p=0.008, for the Rai and Binet criteria, respectively). The MNS16A VNTR-243 short allele was more frequent in patients with a low disease stage (p=0.020 and p=0.028, for the Rai and Binet staging system) and also among older patients having longer telomeres (p=0.046). Patients with Rai 0–I stage were characterized with longer telomeres than those with more advanced disease (p=0.030). This relationship was especially pronounced in patients carrying the rs2736100 C allele, independently of the criteria used, ie, Binet (p=0.048) or Rai (p=0.001). Conclusion: Our results showed that the genetic variation within the TERT gene seems to play a regulatory role in CLL and telomere length.