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Background: Methotrexate is the most frequently administered first-line treatment for rheumatoid arthritis (RA). The disease-modifying effects of methotrexate are mainly associated with enhanced release of free adenosine. The downstream anti-inflammatory effects of adenosine are mediated via its binding to adenosine receptor 2A (ADORA2A) and 3 (ADORA3). Many clinically important single nucleotide polymorphisms (SNPs) were reported in ADORA2A and ADORA3 genes., Objectives: To investigate whether tagging ADORA2A and ADORA3 polymorphisms influences methotrexate treatment in RA., Methods: In total, 212 RA patients treated with methotrexate were genotyped for tagging ADORA2A (rs2298383, rs8141793, rs2236624, rs5751876, rs35320474, and rs17004921) and ADORA3 SNPs (rs2298191, rs1544223, rs78594984, rs35511654, rs2229155, rs3393, and rs3394)., Results: RA patients who carried ADORA3 rs35511654 G allele showed a tendency toward better response to methotrexate treatment (P = 0.054). Carriers of ADORA2A polymorphic allele rs2298383 (P = 0.011), rs2236624 (P = 0.027), rs5751876 (P = 0.018), and rs35320474 (P = 0.026) were less likely to experience methotrexate induced adverse events. All associations remained significant after adjustment for clinical factors. The effects of these polymorphisms were also significant in haplotype analyses., Conclusions: Polymorphisms in the ADORA2A gene may influence methotrexate treatment response and may be considered as a potential biomarker for methotrexate treatment in rheumatoid arthritis.

Molecular mechanisms of Parkinson's disease (PD) have already been investigated in various different omics landscapes. We reviewed the literature about different omics approaches between November 2005 and November 2017 to depict the main pathological pathways for PD development. In total, 107 articles exploring different layers of omics data associated with PD were retrieved. The studies were grouped into 13 omics layers: genomics-DNA level, transcriptomics, epigenomics, proteomics, ncRNomics, interactomics, metabolomics, glycomics, lipidomics, phenomics, environmental omics, pharmacogenomics, and integromics. We discussed characteristics of studies from different landscapes, such as main findings, number of participants, sample type, methodology, and outcome. We also performed curation and preliminary synthesis of multiple omics data, and identified overlapping results, which could lead toward selection of biomarkers for further validation of PD risk loci. Biomarkers could support the development of targeted prognostic/diagnostic panels as a tool for early diagnosis and prediction of progression rate and prognosis. This review presents an example of a comprehensive approach to revealing the underlying processes and risk factors of a complex disease. It urges scientists to structure the already known data and integrate it into a meaningful context.

Purpose: The voltage-gated sodium channel SCN1A mutations are involved in epileptogenesis and may be associated with different epilepsy phenotypes. The SCN1A channel is also an important antiepileptic drug (AED) target. The aim of this study was to investigate if the SCN1A c.3184A>G/p.Thr1067Ala polymorphism modifies the epilepsy risk or is associated with the responsiveness to AEDs in Slovenian children and adolescents with epilepsy., Methods: In total, 216 paediatric patients with epilepsy were consecutively recruited during routine outpatient follow-up visits between January 2011 and December 2014. All patients and 95 healthy controls, all Central European Caucasians, were genotyped for the SCN1A c.3184A>G/p.Thr1067Ala polymorphism. Clinical data on all patients were collected retrospectively. The response to AEDs was classified as seizure remission (a minimum of one year of seizure freedom before inclusion) or no remission. Univariate and multivariate logistic regression was used to determine the association of genotypes with binary outcomes., Results: 114 patients (52.8%) had achieved remission, while 102 (47.2%) had failed to do so. Carriers of at least one polymorphic SCN1A c.3184A>G/p.Thr1067Ala G allele tended to have a lower epilepsy risk (OR=0.38, 95% CI=0.18-0.79, P=0.010) and were significantly more likely to achieve remission (OR=2.00, 95% CI=1.16-3.46, P=0.013). Girls were less likely to achieve remission (P=0.055). Patients in remission tended to be older at first seizure in comparison to the group failing to achieve remission (OR=1.06, 95% CI=0.99-1.14, P=0.099), but this association did not reach statistical significance., Conclusion: The polymorphic SCN1A c.3184A>G/p.Thr1067Ala G allele was associated with a lower risk of epilepsy and a higher remission rate in Slovenian children and adolescents with epilepsy., (Copyright © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Purpose: The aim of this study was to investigate if common functional antioxidant polymorphisms are associated with epilepsy after neonatal hypoxic-ischemic encephalopathy (HIE). The antioxidant enzymes manganese superoxide dismutase (SOD2), glutathione peroxidase 1 (GPX1) and catalase (CAT) represent the primary defence mechanism against reactive oxygen species (ROS). Evidence suggests that genetic variants in antioxidant enzymes could influence susceptibility to epilepsy, but to date the relationship between them remains unclear., Methods: The study comprised 214 patients with epilepsy (64 with and 150 without neonatal HIE) as well as 95 healthy controls. Genomic DNA was isolated from buccal swabs or venous blood samples and genotyped for SOD2 rs4880, GPX1 rs1050450 and CAT rs1001179 using real-time PCR-based methods., Results: The investigated polymorphisms influenced neither the overall risk of epilepsy nor the risk of epilepsy after HIE in comparison with healthy controls. Furthermore, no significant difference in genotype distribution was observed between patients with drug-resistant epilepsy and patients in remission in either the group with epilepsy but without HIE or in the group with epilepsy and HIE, although the frequency of drug-resistant cases was higher in the latter group (p=0.009, OR=2.52; 95% CI=1.22-4.15)., Conclusion: According to this study, common GPX1, SOD2 and CAT polymorphisms do not influence the overall risk of epilepsy after HIE and its drug resistance., (Copyright © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Background: Tacrolimus has a narrow therapeutic drug window but high inter- and intrapatient variability. Our aim is to construct a model able to predict optimal maintenance tacrolimus predose concentration (C 0 ) in kidney transplant patients. Here we present our study design and genotype and variant allele frequencies for the selected single nucleotide polymorphisms of genes involved in tacrolimus metabolism in our national cohort of kidney transplant recipients., Methods: In the observational part of the study, we intend to determine allelic variants of CYP3A4, CYP3A5, and ABCB1 gene in a national cohort of 700 kidney transplants recipients. Clinical and laboratory data of this historic cohort will be added to assess patient's immunologic risk. Based on these data, a prediction model will be constructed that will be validated in a prospective randomized study in 60 de-novo kidney transplant recipients., Results: Our interim cross-sectional observational results show higher variability of ABCB1 genotypes when compared to CYP3A genes, with more than two thirds of the population carrying at least one polymorphic allele. On the other hand, less than 1% of our transplant recipients possess the CYP3A genotype, which requires high daily tacrolimus dose., Conclusions: Due to high inter- and intrapatient tacrolimus variability, a patient-tailored approach to define the optimal maintenance tacrolimus C 0 for each individual patient is needed. Our model will rely on individual pharmacogenomic and clinical data to cover different patient-specific risk factors for adverse outcomes.
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The existing antipsychotic therapy is based on dopamine hyperfunction and glutamate hypofunction hypotheses of schizophrenia. Adenosine receptors (ADORA) have a neuromodulatory role and can control dopaminergic and glutamatergic systems. To elucidate the effect of ADORA polymorphisms on psychopathological symptoms and adverse effects in patients with schizophrenia on long-term antipsychotic treatment, we examined 127 nonacute schizophrenia outpatients in a cross-sectional study using the Positive and Negative Symptoms Scale, Simpson-Angus Scale, Barnes Akathisia Rating Scale, and Abnormal Involuntary Movement Scale. All patients were genotyped for 18 polymorphisms in ADORA1, ADORA2A, and ADORA3. We found an association between ADORA1 rs3766566 and psychopathological symptoms (p = 0.006), in particular, with positive psychopathological symptoms (p = 0.010) and general psychopathological symptoms (p = 0.023), between ADORA2A rs2298383 and general psychopathological symptoms (p = 0.046), and between ADORA2A rs5751876 and akathisia (p = 0.015). Haplotype analysis showed an association between ADORA1 CTCAACG haplotype and overall psychopathological symptoms (p = 0.019), positive psychopathological symptoms (p = 0.021), and akathisia (p = 0.028). ADORA2A TCCTC haplotype was associated with parkinsonism (p = 0.014). ADORA3 CACTAC was associated with akathisia (p = 0.042), whereas CACTAT was associated with akathisia (p = 0.045) and tardive dyskinesia (p = 0.023). The results of this first comprehensive study on ADORA polymorphisms in patients with nonacute schizophrenia receiving long-term antipsychotic therapy suggest an important neuromodulatory role of ADORA receptors in both psychopathological symptoms and adverse effects of antipsychotics.

This study investigated the associations between single nucleotide polymorphisms in the neurodevelopmental Disrupted In Schizophrenia 1 (DISC1 ), neuregulin 1 (NRG1), brain-derived neurotrophic factor (BDNF) and NOTCH4 genes and the clinical symptoms and the occurrence of treatment-resistant schizophrenia in the Slovenian population. We included 138 schizophrenia patients, divided into treatment-responsive and treatment-resistant group and 94 healthy blood donors. All subjects were genotyped for eight polymorphisms (DISC1 rs6675281, DISC1 rs821616, NRG1 rs3735781, NRG1 rs3735782, NRG1 rs10503929, NRG1 rs3924999, BDNF rs6265, NOTCH rs367398) and investigated for associations with clinical variables. NOTCH4 rs367398 AA/AG was significantly associated with worse Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression (CGI) score. NOTCH4 rs367398 was not statistically significantly associated with the occurrence of treatment-resistant schizophrenia after the correction for multiple testing. Our data indicate that NOTCH4 polymorphism can influence clinical symptoms in Slovenian patients with schizophrenia.

Background: Osteosarcoma patients are commonly treated with cisplatin-based preoperative and postoperative chemotherapy. Cisplatin binds to DNA and forms both intrastrand and interstrand crosslinks, inhibiting DNA replication. Glutathione-S-transferases (GSTs) participate in cisplatin detoxification, while several independent DNA repair mechanisms repair cisplatin-induced lesions. The aim of our study was to investigate the influence of genetic variability of DNA repair mechanisms and GSTs on efficacy and toxicity of cisplatin-based chemotherapy in osteosarcoma patients., Methods: A total of 66 osteosarcoma patients were genotyped for ERCC1, ERCC2, NBN, RAD51, XRCC3, and GSTP1 polymorphisms, as well as GSTM1 and GSTT1 gene deletion. We determined the influence of polymorphisms on survival and treatment outcome using Cox regression and logistic regression., Results: Carriers of at least one polymorphic ERCC2 rs1799793 allele had longer event-free survival (EFS) (P=0.006; hazard ratio (HR)=0.28; 95% confidence interval (CI)=0.11-0.70). Polymorphic GSTP1 rs1138272 allele was associated with both shorter EFS and OS (P=0.005; HR=3.67; 95%CI=1.47-9.16; and P=0.004; HR=3.52; 95%CI=1.51-8.22, respectively). Compared to the reference NBN CAA haplotype, NBN CGA haplotype was associated with shorter EFS (P=0.001; HR=4.12; 95%CI=1.77-9.56)., Conclusions: Our results suggest that DNA repair polymorphisms and GST polymorphisms could be used as predictive factors for cisplatin-based chemotherapy in osteosarcoma patients and could contribute to treatment personalization., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Cytotoxic activity of most chemotherapeutic agents is based on their ability to induce DNA damage. Interstrand crosslinks are among the most detrimental forms of DNA damage as both DNA strands are affected. As translesion polymerases participate in their repair, they may be important for response to chemotherapeutic agents that induce such lesions, including commonly used cisplatin. Altered expression of translesion polymerase genes REV1 and REV3L may modify sensitivity to cisplatin. As osteosarcoma patients are commonly treated with cisplatin-based chemotherapy, our aim was to investigate if REV1 and REV3L polymorphisms influence survival of osteosarcoma patients treated with cisplatin-based chemotherapy. We determined the genotypes of common functional tag REV1 and REV3L polymorphisms in 66 osteosarcoma patients. Cox regression was used for survival analysis. Carriers of at least one polymorphic REV1 rs3087403 allele had significantly shorter EFS and overall survival (OS) (p = 0.004; HR = 3.79; 95%CI = 1.53-9.35 and p < 0.001; HR = 4.44; 95%CI = 1.92-10.27, respectively). Combination of REV1 rs3087403 and REV3L rs462779 polymorphisms was also significantly associated with shorter OS (ptrend<0.001) and shorter EFS (ptrend = 0.003). The results of this first study on polymorphisms in translesion polymerase genes in osteosarcoma suggest they could help predict outcome of cisplatin-based chemotherapy in osteosarcoma patients.

Aim: We evaluated the influence of genetic variability in translesion polymerases REV1 and REV3L on the outcome of cisplatin treatment in malignant mesothelioma patients., Materials & Methods: In total, 139 malignant mesothelioma patients were genotyped for seven tag SNPs in REV1 and REV3L. Logistic regression and Cox regression were used to assess the influence of SNPs on treatment outcome., Results: Polymorphic REV1 rs3087403 allele and REV1 TGT haplotype were associated with increased risk for leukopenia (p = 0.013 and p = 0.047, respectively) and neutropenia (p = 0.048 and p = 0.024, respectively). REV3L rs465646, rs462779 and REV3L CCGG haplotype were significantly associated with longer overall survival (p = 0.007, p = 0.022 and p = 0.013, respectively)., Conclusion: Our results suggest for the first time that REV1 and REV3L SNPs might serve as potential predictive markers of outcome of cisplatin-based chemotherapy. Original submitted 7 October 2013; Revision submitted 15 January 2014.

Malignant pleural mesothelioma is an incurable cancer strongly associated with asbestos exposure and characterised by poor response to treatment. The inhibitor-of-apoptosis protein family member survivin is involved in apoptosis and proliferation and is expressed in cancer cells only. The aims of the present study were to elucidate whether survivin expression is associated with tumour cell apoptosis and proliferation and to assess the prognostic and predictive value of survivin expression in malignant pleural mesothelioma. Archival pleural mesothelioma tissue samples from 101 patients were immunohistochemically analysed for nuclear expression of survivin, for proliferation with the use of Ki-67 as marker and for apoptosis using active caspase-3 as a marker. Staining results and clinical data were included in a survival analysis. Survivin was highly expressed in tumour cell nuclei in all samples and this correlated positively with both apoptosis and proliferation, but did not have a significant prognostic value. We found significantly higher survivin expression in patients who responded to chemotherapy compared to patients with progressive disease. Survivin expression might contribute to treatment response prediction, but survivin expression in malignant pleural mesothelioma did not have prognostic significance.