Host genetic variants associated with COVID-19 reconsidered in a Slovak cohort.

We present the results of an association study involving hospitalized coronavirus disease 2019 (COVID-19) patients with a clinical background during the 3rd pandemic wave of COVID-19 in Slovakia. Seventeen single nucleotide variants (SNVs) in the eleven most relevant genes, according to the COVID-19 Host Genetics Initiative, were investigated. Our study confirms the validity of the influence of LZTFL1 and 2'-5'-oligoadenylate synthetase (OAS)1/OAS3 genetic variants on the severity of COVID-19. For two LZTFL1 SNVs in complete linkage disequilibrium, rs17713054 and rs73064425, the odds ratios of baseline allelic associations and logistic regressions (LR) adjusted for age and sex ranged in the four tested designs from 2.04 to 2.41 and from 2.05 to 3.98, respectively. The OAS1/OAS3 haplotype 'gttg' carrying a functional allele G of splice-acceptor variant rs10774671 manifested its protective function in the Delta pandemic wave. Significant baseline allelic associations of two DPP9 variants in all tested designs and two IFNAR2 variants in the Omicron pandemic wave were not confirmed by adjusted LR. Nevertheless, adjusted LR showed significant associations of NOTCH4 rs3131294 and TYK2 rs2304256 variants with severity of COVID-19. Hospitalized patients' reported comorbidities were not correlated with genetic variants, except for obesity, smoking (IFNAR2), and hypertension (NOTCH4). The results of our study suggest that host genetic variations have an impact on the severity and duration of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Considering the differences in allelic associations between pandemic waves, they support the hypothesis that every new SARS-CoV-2 variant may modify the host immune response by reconfiguring involved pathways.

Tuberculosis in Ukrainian War Refugees and Migrants in the Czech Republic and Slovakia: A Molecular Epidemiological Study.

BACKGROUND: The war in Ukraine has led to significant migration to neighboring countries, raising public health concerns. Notable tuberculosis (TB) incidence rates in Ukraine emphasize the immediate requirement to prioritize approaches that interrupt the spread and prevent new infections. METHODS: We conducted a prospective genomic surveillance study to assess migration's impact on TB epidemiology in the Czech Republic and Slovakia. Mycobacterium tuberculosis isolates from Ukrainian war refugees and migrants, collected from September 2021 to December 2022 were analyzed alongside 1574 isolates obtained from Ukraine, the Czech Republic, and Slovakia. RESULTS: Our study revealed alarming results, with historically the highest number of Ukrainian tuberculosis patients detected in the host countries. The increasing number of cases of multidrug-resistant TB, significantly linked with Beijing lineage 2.2.1 (p < 0.0001), also presents substantial obstacles to control endeavors. The genomic analysis identified the three highly related genomic clusters, indicating the recent TB transmission among migrant populations. The largest clusters comprised war refugees diagnosed in the Czech Republic, TB patients from various regions of Ukraine, and incarcerated individuals diagnosed with pulmonary TB specialized facility in the Kharkiv region, Ukraine, pointing to a national transmission sequence that has persisted for over 14 years. CONCLUSIONS: The data showed that most infections were likely the result of reactivation of latent disease or exposure to TB before migration rather than recent transmission occurring within the host country. However, close monitoring, appropriate treatment, careful surveillance, and social support are crucial in mitigating future risks, though there is currently no evidence of local transmission in EU countries.

Resistance patterns and transmission of mono- and polyresistant TB: clinical impact of WGS.

Objectives: Rapidly diagnosing drug-resistant TB is crucial for improving treatment and transmission control. WGS is becoming increasingly accessible and has added value to the diagnosis and treatment of TB. The aim of the study was to perform WGS to determine the rate of false-positive results of phenotypic drug susceptibility testing (pDST) and characterize the molecular mechanisms of resistance and transmission of mono- and polyresistant Mycobacterium (M.) tuberculosis. Methods: WGS was performed on 53 monoresistant and 25 polyresistant M. tuberculosis isolates characterized by pDST. Sequencing data were bioinformatically processed to infer mutations encoding resistance and determine the origin of resistance and phylogenetic relationship between isolates studied. Results: The data showed the variable sensitivity and specificity of WGS in comparison with pDST as the gold standard: isoniazid 92.7% and 92.3%; streptomycin 41.9% and 100.0%; pyrazinamide 15% and 94.8%; and ethambutol 75.0% and 98.6%, respectively. We found novel mutations encoding resistance to streptomycin (in gidB) and pyrazinamide (in kefB). Most isolates belonged to lineage 4 (80.1%) and the overall clustering rate was 11.5%. We observed lineage-specific gene variations encoding resistance to streptomycin and pyrazinamide. Conclusions: This study highlights the clinical potential of WGS in ruling out false-positive drug resistance following phenotypic or genetic drug testing, and recommend this technology together with the WHO catalogue in designing an optimal individualized treatment regimen and preventing the development of MDR TB. Our results suggest that resistance is primarily developed through spontaneous mutations or selective pressure.

Analysis of Cdx2 VDR gene polymorphism rs11568820 in association with multiple sclerosis in Slovaks.

Vitamin D deficiency is involved in the pathogenesis of multiple sclerosis (MS), a severe autoimmune demyelinating disease of the central nervous system. The gene polymorphism Cdx-2 (rs11568820, G/A) seriously influences the trancriptional activity of the vitamin D receptor (VDR) that binds the vitamin D responsive elements of target genes including HLA-DRB1*15. The aim of the present study in Slovaks was to analyse the association of Cdx-2 variants with the risk of MS and disability progression, and to assess the DRB1*15:01 allele as a possible confounding factor. In total, 493 MS patients and 417 healthy controls were involved in this study. The genotyping of Cdx-2 was performed using restriction analysis; DRB1*15:01 positivity was determined by a high-resolution melting analysis of its surrogate marker rs3135388 (G/A). Our results did not prove any allelic association between Cdx-2 and a risk of MS (minor allele A - 0.181 in patients vs. 0.161 in controls, OR = 1.15, .95 CI = 0.90-1.47, p = 0.289). The logistic regression analysis, adjusted for sex and age, showed no differences in Cdx-2 genotype counts when using an additive, dominant or recessive genetic model (p = 0.351, 0.150, 0.240 respectively). The Cdx-2 variants were also not associated with disease disability progression, evaluated using the Multiple Sclerosis Severity Score. The HLA-DRB1*15:01 allele was found to strongly increase the risk of MS in our study (0.300 in patients vs. 0.101 in controls, OR = 3.83, .95 CI = 2.94-4.99, p = 1.016 × 10-26, dominant genetic model OR = 4.62, .95 CI = 3.40-6.26, p = 9.1 × 10-23). In summary, we found the Cdx-2 as a single genetic marker not to be associated with MS development or progression in Slovaks, independently of HLA-DRB1*15:01 status.

Small-scale variants and large deletions in BRCA1/2 genes in Slovak high-grade serous ovarian cancer.

The role of PARP inhibitors is to prevent the polymerase from repairing the single-strand break that occurred due to tumor growth and thus induce cell apoptosis when the homologous recombination deficiency (HRD) system is disabled. The eliminated system can be monitored especially in patients with serous ovarian epithelial tumors. Current studies still show the highest progression-free survival (PFS) in the examined groups with BRCA mutant status, even though they are also effective in the case of a disrupted HRD system, apart from BRCA genes. The study cohort consists of women diagnosed with high-grade serous ovarian cancer (HGSOC), after at least two lines of chemotherapy and after relapse of the disease, as determined by ESMO standards and guidelines. The commercially available tool SOPHIA DDM™ (SophiaGenetics, Switzerland) was used to classify the variants after sequencing. The most common variants (pathogenic or likely pathogenic) were in BRCA1 c.1067 A>G (rs1799950) and c.5266dupC (rs80357906) and in BRCA2 c.9976 A>T (rs11571833). Large deletions were detected in one and three cases in the BRCA1 and BRCA2 genes, respectively. A mutation in the BRCA1/2 genes was confirmed in 50% of the examined patients. In the study, we focused on the identification of mutated BRCA genes by a commercially available Sophia DDM™ system to identify a pathogenic or probable pathogenic variant in a cohort of patients with HGSOC in the Slovak population, which could result in better management and stratification of the individual.

Polymorphisms in the gene encoding CYP1A2 influence prostate cancer risk and progression.

The role of the cytochrome P450 1A2 (CYP1A2) rs2472299, rs2470890 and rs11072508 polymorphisms in prostate cancer risk, disease progression and tumour development remains unclear. The potential associations of these three CYP1A2 polymorphisms and haplotypes with prostate cancer susceptibility and its clinicopathological characteristics were therefore investigated. The present case-control study consisted of 522 patients with prostate cancer and 554 healthy controls. High-resolution melting analysis was used to determine the CYP1A2 polymorphisms. No significant association in prostate cancer risk was seen for CYP1A2 rs2472299 and rs11072508. However, a significantly decreased risk of prostate cancer was found for CYP1A2 rs2470890 [odds ratio (OR), 0.67; P=0.02] in the recessive model. After analysis of the associations of clinical status and these three CYP1A2 polymorphisms, the CYP1A2 rs2470890 and rs11072508 polymorphisms showed a positive association with a higher Gleason score (rs2470890 OR, 1.36, P=0.04 in the allelic model; rs11072508 OR, 1.37, P=0.04 in the allelic model and OR, 1.60, P=0.03 in the dominant model). All three polymorphisms showed a significant positive association with pathological T stage in the additive, allelic and dominant genetic models (P<0.05). Haplotype analysis revealed that the most common haplotypes 'GTT' and 'ACC' were significantly associated with pathological T stages 3 and 4 (OR, 0.62; P=0.02 and OR, 1.54; P=0.03, respectively). A significant association was found between the 'GTT' haplotype and the Gleason score (OR, 0.71; P=0.03). In conclusion, these CYP1A2 polymorphisms and haplotypes have the potential to predict prostate cancer disease progression.

Systematic Genomic Surveillance of SARS-CoV-2 Virus on Illumina Sequencing Platforms in the Slovak Republic-One Year Experience.

To explore a genomic pool of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the pandemic, the Ministry of Health of the Slovak Republic formed a genomics surveillance workgroup, and the Public Health Authority of the Slovak Republic launched a systematic national epidemiological surveillance using whole-genome sequencing (WGS). Six out of seven genomic centers implementing Illumina sequencing technology were involved in the national SARS-CoV-2 virus sequencing program. Here we analyze a total of 33,024 SARS-CoV-2 isolates collected from the Slovak population from 1 March 2021, to 31 March 2022, that were sequenced and analyzed in a consistent manner. Overall, 28,005 out of 30,793 successfully sequenced samples met the criteria to be deposited in the global GISAID database. During this period, we identified four variants of concern (VOC)-Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2) and Omicron (B.1.1.529). In detail, we observed 165 lineages in our dataset, with dominating Alpha, Delta and Omicron in three major consecutive incidence waves. This study aims to describe the results of a routine but high-level SARS-CoV-2 genomic surveillance program. Our study of SARS-CoV-2 genomes in collaboration with the Public Health Authority of the Slovak Republic also helped to inform the public about the epidemiological situation during the pandemic.

The potential use of miRNAs in the diagnosis and prediction of metastatic lung carcinoma.

Lung carcinoma is the "top killer" of all malignancies in the world. Early diagnosis of lung carcinoma significantly improves patient survival. Screening with biomarkers from peripheral blood could detect more patients at an early stage of the disease. MicroRNAs (miRNAs) could be a possible biomarker. These are 21-23 nucleotide long single-stranded RNA molecules playing an important role in the post-transcriptional regulation of gene activity. Individual miRNAs have the potential to regulate genes responsible for cell proliferation, differentiation, apoptosis, regulate cell cycle in cooperation with pro-oncogenes and tumor suppressor genes. In our study, we determined miRNA expression levels in individual samples of lung carcinoma patients and in a healthy control group. We used the reverse transcription method followed by qRT-PCR. The expression levels of the investigated miRNAs were evaluated in the QIAGEN GeneGlobe Data center software. We demonstrated the significance of miR-126 and let-7g as biomarkers of lung carcinoma in all clinical stages studied. We also observed significantly increased expression of miR-143 and miR-145 at the distant metastasis stage, and significantly decreased expression of miR-133a in the N2 disease group of lung carcinoma patients (N2 disease represents disease with metastases in the ipsilateral mediastinal and/or subcarinal lymph nodes or node). The investigated miRNAs showed no clear potential for detecting potentially resectable (N0-N1), locally advanced (N2) and distant organ metastatic (M1) lung carcinoma.

Risk genetic polymorphism and haplotype associated with papillary thyroid cancer and their relation to associated diseases in Slovak population.

BACKGROUND: Risk for developing papillary thyroid carcinoma (PTC), the most common endocrine malignancy, is thought to be mediated by lifestyle, environmental exposures and genetic factors. Recent progress in the genome-wide association studies of thyroid cancer leads to the identification of several genetic variants conferring risk to this malignancy across different ethnicities. METHODS AND RESULTS: We set out to elucidate the impact of selected single nucleotide polymorphisms (SNPs) on papillary thyroid carcinoma risk and to evaluate the interactions of these genetic variants with associated diseases for the first time in the Slovak population. Six SNPs (rs966423, rs2439302, rs965513, rs116909374, rs1537424 and rs944289) were genotyped in 86 patients with PTC and 99 healthy control subjects. The association analysis and multivariable modelling of PTC risk by the genetic factors, supplemented with a rigorous statistical validation, were performed. One of the six SNPs rs966423 (DIRC3, OR=1.51, p=0.03) was significantly associated with PTC. Next two SNPs rs965513 (PTCSC2, OR=1.34) and rs116909374 (MBIP, OR=0.44) showed a suggestive association. Haplotype TTC (SNPs located on chromosome 14q13) showed a suggestive association with PTC (p=0.07, OR=1.55). In the PTC group, significant associations were observed between rs966423 (DIRC3) and ischemic heart diseases (p=0.009), rs965513 (PTCSC2) and diabetes mellitus (p=0.04) and haplotype 14q13 and musculoskeletal diseases. Next three associations rs966423 (DIRC3) and arterial hypertension; rs116909374 (MBIP) and other benign diseases; rs1537424 (MBIP) and disorder lipid metabolism, rs965513 (PTCSC2) and anti-Tg (thyroglobulin antibody) showed suggestive associations. CONCLUSION: These results indicate that germline variants not only predispose to PTC, but may also be related to other risk factors, including associated diseases. However, these associations were only moderate, and further multi-ethnic studies are required to evaluate the usefulness of these germline variants in the clinical stratification of PTC patients (Tab. 8, Ref. 37).

The Common Haplotype GATGACA in Surfactant-Protein B Gene Is Protective for Respiratory Distress Syndrome in Preterm Neonates.

Background: Respiratory distress syndrome (RDS), a disorder of primary surfactant deficiency resulting in pulmonary insufficiency, remains a significant problem for preterm neonates. Associations between genetic variants of surfactant proteins and RDS have been reported, but haplotypes of the surfactant protein B gene (SFTPB) have not been studied. The aim of the study was to prove the hypothesis that certain haplotypes of SFTPB may be protective or risk factors for RDS. Methods: The study was performed with 149 preterm infants, born <34 weeks of gestation, with 86 infants with mild RDS or without RDS (control group) and 63 infants with severe RDS (patient group). RDS was considered severe if multiple doses of exogenous surfactant and/or mechanical ventilation within the first 72 h of life were needed. The venous blood sample was used for the analysis of gene polymorphisms associated with RDS, genotyping, and haplotype estimation. Multivariate logistic regression analysis and the odds ratio were calculated to detect the contribution of the studied variables to the development of RDS. Results: A new association of the common single nucleotide polymorphism (SNP) rs2304566 with RDS in premature infants was detected. Analysis of rs2304566 polymorphisms using a logistic regression model showed that there are two significant predictors inversely related to the occurrence of RDS (Apgar score of 5 min, CT and TT genotype in rs2304566 polymorphism). Gestational age, birth weight, and sex have border significance. Moreover, in the patient group, the frequency of the GATGACA haplotype in the SFTPB gene was lower (p = 0.037), and the GATGGCA haplotype was higher (p = 0.059) in comparison with the control group. Conclusion: The common haplotype GATGACA of the SFTPB gene can be protective against RDS in preterm infants. The trend of a higher frequency of GATGGCA in the SFTPB gene in infants with severe RDS suggests that this haplotype may be a risk factor for RDS susceptibility.

Whole genome sequencing of multidrug-resistant Mycobacterium tuberculosis isolates collected in the Czech Republic, 2005-2020.

The emergence and spread of resistant tuberculosis (TB) pose a threat to public health, so it is necessary to diagnose the drug-resistant forms in a clinically short time frame and closely monitor their transmission. In this study, we carried out a first whole genome sequencing (WGS)-based analysis of multidrug resistant (MDR) M. tuberculosis strains to explore the phylogenetic lineages diversity, drug resistance mechanisms, and ongoing transmission chains within the country. In total, 65 isolates phenotypically resistant to at least rifampicin and isoniazid collected in the Czech Republic in 2005-2020 were enrolled for further analysis. The agreement of the results obtained by WGS with phenotypic drug susceptibility testing (pDST) in the determination of resistance to isoniazid, rifampicin, pyrazinamide, streptomycin, second-line injectables and fluoroquinolones was more than 80%. Phylogenetic analysis of WGS data revealed that the majority of MDR M. tuberculosis isolates were the Beijing lineage 2.2.1 (n = 46/65; 70.8%), while the remaining strains belonged to Euro-American lineage. Cluster analysis with a predefined cut-off distance of less than 12 single nucleotide polymorphisms between isolates showed 19 isolates in 6 clusters (clustering rate 29.2%), located mainly in the region of the capital city of Prague. This study highlights the utility of WGS as a high-resolution approach in the diagnosis, characterization of resistance patterns, and molecular-epidemiological analysis of resistant TB in the country.

Anti-tuberculosis drug resistance in Slovakia, 2018-2019: The first whole-genome epidemiological study.

OBJECTIVE: The resistance of Mycobacterium (M.) tuberculosis to antituberculosis drugs poses a major threat to global public health. Whole genome sequencing (WGS) is an increasingly preferred method in the diagnostics and monitoring of the transmission dynamics of resistant forms of tuberculosis (TB). The aim of the study was to, for the first time, use the sequencing-based analysis to study the transmission and resistance patterns of a systematic and recent collection of extensively drug resistant (XDR) and multidrug resistant tuberculosis (MDR-TB) isolates and to expand our knowledge about drug resistant (DR) TB epidemiological dynamics in Slovakia. DESIGN: A total of 495 patients with pulmonary TB, who were referred to National Reference Laboratory for Mycobacteriology (Vysné Hágy, Slovakia) in the years 2018-2019, were studied. Out of the total of 495 patients, 4 XDR-TB (0.8%) and 8 (1.6%) MDR-TB isolates were identified by conventional drug susceptibility testing on Löwenstein-Jensen solid medium and subjected to whole genome sequencing. Sequencing data were evaluated for molecular-epidemiological analysis and identification of resistance patterns. RESULTS: Phylogenetic and cluster analysis showed extensive recent transmission events and the predominance of Euro-American lineage 4.7 in Slovakia. However, phylogenetic analysis revealed the circulation of several lineages that originally occurred in Eastern European countries. Resistance patterns for first- and second-line antituberculosis drugs characterized by whole genome sequencing were in high concordance with the results of phenotypic drug susceptibility testing. CONCLUSION: Forty percent of at least MDR-TB isolates were not genetically linked, indicating that appropriate measures should be taken to monitor and prevent the spread of drug-resistant tuberculosis within the country as well as in other regions.

Comparison of SARS-CoV-2 Detection by Rapid Antigen and by Three Commercial RT-qPCR Tests: A Study from Martin University Hospital in Slovakia.

The global pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is having a tremendous impact on the global economy, health care systems and the lives of almost all people in the world. The Central European country of Slovakia reached one of the highest daily mortality rates per 100,000 inhabitants in the first 3 months of 2021, despite implementing strong prophylactic measures, lockdowns and repeated nationwide antigen testing. The present study reports a comparison of the performance of the Standard Q COVID-19 antigen test (SD Biosensor) with three commercial RT-qPCR kits (vDetect COVID-19-MultiplexDX, gb SARS-CoV-2 Multiplex-GENERI BIOTECH Ltd. and Genvinset COVID-19 [E]-BDR Diagnostics) in the detection of infected individuals among employees of the Martin University Hospital in Slovakia. Health care providers, such as doctors and nurses, are classified as "critical infrastructure", and there is no doubt about the huge impact that incorrect results could have on patients. Out of 1231 samples, 14 were evaluated as positive for SARS-CoV-2 antigen presence, and all of them were confirmed by RT-qPCR kit 1 and kit 2. As another 26 samples had a signal in the E gene, these 40 samples were re-isolated and subsequently re-analysed using the three kits, which detected the virus in 22, 23 and 12 cases, respectively. The results point to a divergence not only between antigen and RT-qPCR tests, but also within the "gold standard" RT-qPCR testing. Performance analysis of the diagnostic antigen test showed the positive predictive value (PPV) to be 100% and negative predictive value (NPV) to be 98.10%, indicating that 1.90% of individuals with a negative result were, in fact, positive. If these data are extrapolated to the national level, where the mean daily number of antigen tests was 250,000 in April 2021, it points to over 4700 people per day being misinterpreted and posing a risk of virus shedding. While mean Ct values of the samples that were both antigen and RT-qPCR positive were about 20 (kit 1: 20.47 and 20.16 for Sarbeco E and RdRP, kit 2: 19.37 and 19.99 for Sarbeco E and RdRP and kit 3: 17.47 for ORF1b/RdRP), mean Ct values of the samples that were antigen-negative but RT-qPCR-positive were about 30 (kit 1: 30.67 and 30.00 for Sarbeco E and RdRP, kit 2: 29.86 and 31.01 for Sarbeco E and RdRP and kit 3: 27.47 for ORF1b/RdRP). It confirms the advantage of antigen test in detecting the most infectious individuals with a higher viral load. However, the reporting of Ct values is still a matter of ongoing debates and should not be conducted without normalisation to standardised controls of known concentration.

Germline Mutations in DNA Repair Genes in Patients With Metastatic Castration-resistant Prostate Cancer.

BACKGROUND/AIM: The aim of this study was to analyse the genetic profiles of metastatic castration-resistant prostate cancer (mCRPC) by using next generation sequencing to identify variants with pathogenic potential in nine DNA repair genes - BRCA1, BRCA2, RAD50, RAD51, RAD51C/D, ATM and ATR. MATERIALS AND METHODS: Isolated genomic DNA from peripheral blood of 50 patients with mCRPC was used for the sequencing of 111 genes associated with hereditary cancer on an Illumina platform. Identified variants were tested in Integrative Genomic Viewer, their clinical significance confirmed in databases and their potential impact on protein function predicted by in silico tools. RESULTS: From nine analysed DNA repair genes, we identified 14 relevant variants; three pathogenic variants - BRCA2 (rs80359306), RAD50 (rs786201531) and ATM (rs1555099760), and eleven other variants with pathogenic potential. CONCLUSION: The pathogenic variants identified in this study are located in evolutionarily conserved regions of proteins and are highly likely to affect DNA repair efficiency.

Common gene haplotypes of gelatinases and their tissue inhibitors in abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) involves complex dynamic remodeling processes in the aortic wall. Gelatinases (MMP2 and MMP9) and their respective tissue inhibitors (TIMP1 and TIMP2) play a crucial role during extracellular matrix (ECM) turnover in aortic tissue. In this study we characterized associations between the haplotypes of genes encoding gelatinase/inhibitor pairs and pathways involved in AAA, a total of 100 AAA patients and 192 controls were enrolled. For males, a significant decrease in the distribution of the minor G allele of the TIMP2 rs8082025 was observed in AAA patients (p = 0.01, 23.1% controls vs. 13.1% AAA). In addition, in males, the major TIMP2 GA haplotype was associated with AAA (86.9% AAA vs. 76.9% control; p = 0.009, OR = 1.997), whereas the TIMP2 GG haplotype (7.7% AAA vs. 13.9% control) was associated with protection against AAA (p = 0.046, OR = 0.518). The minor GAGC MMP9 haplotype was related to AAA for all study subjects as well as the males only subset (p = 0.011, OR = 2.202 and p = 0.025, OR = 2.156, respectively). Small differences in the distribution of gene haplotypes could be associated with different levels of gene expression and in turn influence gelatinases activity in AAA.

The association of rs703842 variants in CYP27B1 with multiple sclerosis susceptibility is influenced by the HLA-DRB1*15:01 allele in Slovaks.

In this study, we analysed the association of rs703842 in CYP27B1 gene with multiple sclerosis (MS) risk and disability progression in a group of 496 MS patients and 521 controls. For the first time in Central European Slovak population, we found the rs703842 allele C to be protective factor against MS development (p = 1.09 × 10-5). Moreover, the risky genotypes TT and TC were showed to be associated with an increased MS risk, and this was aggravated by the homozygous carriage of the HLA-DRB1*15:01 allele (OR = 2.82 vs. 4.86, p < .0001). No association of rs703842 with MS disability progression or calcidiol serum level was found.

Glycoprotein VI Gene Variants Affect Pregnancy Loss in Patients With Platelet Hyperaggregability.

The aim of our study was to evaluate GP6 gene in patients with sticky platelet syndrome (SPS) and fetal loss. Platelet aggregability was tested with platelet-rich plasma using PACKS-4 aggregometer (Helena Laboratories). High-resolution melting analysis on LightCycler 480 II (Roche Diagnostics) was used for single-nucleotide polymorphism (SNP) genotyping. We examined 64 patients with SPS and 54 control participants. We found significantly higher occurrence of 5 SNPs in patients with SPS versus controls (rs1671152, rs1654433, rs1613662, rs1654416, and rs2304167). Moreover, the haplotype analysis showed a significantly higher occurrence of 7 haplotypes in patients with SPS compared to controls (acgg and aagg in GP6_5reg haplotype; ccgt in GP6_3reg haplotype; gg and ta in GP6_REG haplotype; SKTH and PEAN in GP6_PEAN haplotype). Our results, especially higher occurrence of 4 nonsynonymous variants within the coding region, support the idea that GP6 polymorphisms are associated with the platelet hyperaggregability accompanied by fetal loss.

Association of Genetic Variability in Selected Genes in Patients With Deep Vein Thrombosis and Platelet Hyperaggregability.

The aim of this study was to evaluate the genetic variability of the selected single nucleotide polymorphisms (SNPs) and examine the association between these SNPs and risk for deep vein thrombosis (DVT) in patients with sticky platelet syndrome (SPS). We examined 84 patients with SPS and history of DVT and 101 healthy individuals. We were interested in 2 SNPs within platelet endothelial aggregation receptor 1 (PEAR1) gene (rs12041331 and rs12566888), 2 SNPs within mkurine retrovirus integration site 1 gene (rs7940646 and rs1874445), 1 SNP within Janus kinase 2 gene (rs2230722), 1 SNP within FCER1G gene (rs3557), 1 SNP within pro-platelet basic protein (rs442155), 4 SNPs within alpha2A adrenergic receptor 2A (ADRA2A; rs1800545, rs4311994, rs11195419, and rs553668), and 1 SNP within sonic hedgehog gene (rs2363910). We identified 2 protective SNPs within PEAR1 gene and 1 risk SNP within ADRA2A gene (PEAR1: rs12041331 and rs12566888; ADRA2A: rs1800545). A haplotype analysis of 4 SNPs within ADRA2A gene identified a risk haplotype aagc ( P = .003). Moreover, we identified 1 protective haplotype within PEAR1 gene (AT, P = .004). Our results support the idea that genetic variability of PEAR1 and ADRA2A genes is associated with platelet hyperaggregability manifested as venous thromboembolism. The study also suggests a possible polygenic type of SPS heredity.