A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study.

BACKGROUND: The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene-drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed. METHODS: We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, nine community health centres, and 28 community pharmacies in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK). Patients aged 18 years or older receiving a first prescription for a drug clinically recommended in the guidelines of the Dutch Pharmacogenetics Working Group (ie, the index drug) as part of routine care were eligible for inclusion. Exclusion criteria included previous genetic testing for a gene relevant to the index drug, a planned duration of treatment of less than 7 consecutive days, and severe renal or liver insufficiency. All patients gave written informed consent before taking part in the study. Participants were genotyped for 50 germline variants in 12 genes, and those with an actionable variant (ie, a drug-gene interaction test result for which the Dutch Pharmacogenetics Working Group [DPWG] recommended a change to standard-of-care drug treatment) were treated according to DPWG recommendations. Patients in the control group received standard treatment. To prepare clinicians for pre-emptive pharmacogenetic testing, local teams were educated during a site-initiation visit and online educational material was made available. The primary outcome was the occurrence of clinically relevant adverse drug reactions within the 12-week follow-up period. Analyses were irrespective of patient adherence to the DPWG guidelines. The primary analysis was done using a gatekeeping analysis, in which outcomes in people with an actionable drug-gene interaction in the study group versus the control group were compared, and only if the difference was statistically significant was an analysis done that included all of the patients in the study. Outcomes were compared between the study and control groups, both for patients with an actionable drug-gene interaction test result (ie, a result for which the DPWG recommended a change to standard-of-care drug treatment) and for all patients who received at least one dose of index drug. The safety analysis included all participants who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03093818 and is closed to new participants. FINDINGS: Between March 7, 2017, and June 30, 2020, 41 696 patients were assessed for eligibility and 6944 (51·4 % female, 48·6% male; 97·7% self-reported European, Mediterranean, or Middle Eastern ethnicity) were enrolled and assigned to receive genotype-guided drug treatment (n=3342) or standard care (n=3602). 99 patients (52 [1·6%] of the study group and 47 [1·3%] of the control group) withdrew consent after group assignment. 652 participants (367 [11·0%] in the study group and 285 [7·9%] in the control group) were lost to follow-up. In patients with an actionable test result for the index drug (n=1558), a clinically relevant adverse drug reaction occurred in 152 (21·0%) of 725 patients in the study group and 231 (27·7%) of 833 patients in the control group (odds ratio [OR] 0·70 [95% CI 0·54-0·91]; p=0·0075), whereas for all patients, the incidence was 628 (21·5%) of 2923 patients in the study group and 934 (28·6%) of 3270 patients in the control group (OR 0·70 [95% CI 0·61-0·79]; p <0·0001). INTERPRETATION: Genotype-guided treatment using a 12-gene pharmacogenetic panel significantly reduced the incidence of clinically relevant adverse drug reactions and was feasible across diverse European health-care system organisations and settings. Large-scale implementation could help to make drug therapy increasingly safe. FUNDING: European Union Horizon 2020.

Precision Medicine in Antidepressants Treatment.

Precision medicine uses innovative approaches to improve disease prevention and treatment outcomes by taking into account people's genetic backgrounds, environments, and lifestyles. Treatment of depression is particularly challenging, given that 30-50% of patients do not respond adequately to antidepressants, while those who respond may experience unpleasant adverse drug reactions (ADRs) that decrease their quality of life and compliance. This chapter aims to present the available scientific data that focus on the impact of genetic variants on the efficacy and toxicity of antidepressants. We compiled data from candidate gene and genome-wide association studies that investigated associations between pharmacodynamic and pharmacokinetic genes and response to antidepressants regarding symptom improvement and ADRs. We also summarized the existing pharmacogenetic-based treatment guidelines for antidepressants, used to guide the selection of the right antidepressant and its dose based on the patient's genetic profile, aiming to achieve maximum efficacy and minimum toxicity. Finally, we reviewed the clinical implementation of pharmacogenomics studies focusing on patients on antidepressants. The available data demonstrate that precision medicine can increase the efficacy of antidepressants and reduce the occurrence of ADRs and ultimately improve patients' quality of life.

Insulin Metabolism in Polycystic Ovary Syndrome: Secretion, Signaling, and Clearance.

Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in women of reproductive age. Its heterogeneous clinical presentation is characterized by hyperandrogenemia, reproductive changes, polycystic ovary morphology, and insulin resistance (IR). The primary pathophysiological process in its multifactorial etiology has not yet been identified. However, the two most proposed core etiologies are the disruption of insulin metabolism and hyperandrogenemia, both of which begin to intertwine and propagate each other in the later stages of the disease. Insulin metabolism can be viewed as the interconnectedness of beta cell function, IR or insulin sensitivity, and insulin clearance. Previous studies of insulin metabolism in PCOS patients have yielded conflicting results, and literature reviews have focused mainly on the molecular mechanisms and clinical implications of IR. In this narrative review, we comprehensively explored the role of insulin secretion, clearance, and decreased sensitivity in target cells as a potential primary insult in PCOS pathogenesis, along with the molecular mechanism behind IR in PCOS.

The Association of Selected GWAS Reported AD Risk Loci with CSF Biomarker Levels and Cognitive Decline in Slovenian Patients.

Alzheimer's disease (AD) is the most common neurodegenerative disease, with a complex genetic background. Apart from rare, familial cases, a combination of multiple risk loci contributes to the susceptibility of the disease. Genome-wide association studies (GWAS) have identified numerous AD risk loci. Changes in cerebrospinal fluid (CSF) biomarkers and imaging techniques can detect AD-related brain changes before the onset of clinical symptoms, even in the presence of preclinical mild cognitive impairment. In this study, we aimed to assess the associations between SNPs in well-established GWAS AD risk loci and CSF biomarker levels or cognitive test results in Slovenian patients with cognitive decline. The study included 82 AD patients, 28 MCI patients with pathological CSF biomarker levels and 35 MCI patients with normal CSF biomarker levels. Carriers of at least one polymorphic TOMM40 rs157581 C allele had lower Aß42 (p = 0.033) and higher total tau (p = 0.032) and p-tau181 levels (p = 0.034). Carriers of at least one polymorphic T allele in SORCS1 rs1358030 had lower total tau (p = 0.019), while polymorphic SORCS1 rs1416406 allele was associated with lower total tau (p = 0.013) and p-tau181 (p = 0.036). In addition, carriers of at least one polymorphic T allele in BCHE rs1803274 had lower cognitive test scores (p = 0.029). The study findings may contribute to the identification of genetic markers associated with AD and MCI and provide insights into early disease diagnostics.

Serum Calretinin and Genetic Variability as a Prognostic and Predictive Factor in Malignant Mesothelioma.

Calretinin is a promising diagnostic biomarker for malignant mesothelioma (MM), but less is known about its prognostic role. Our aim was to evaluate the association between serum calretinin concentration or genetic factors and the survival or outcome of cisplatin-based chemotherapy in MM. Our study included 265 MM patients. Serum calretinin concentration was determined using ELISA. Patients were genotyped for seven polymorphisms in CALB2, E2F2, MIR335, NRF1, and SEPTIN7 using competitive allele-specific PCR. Nonparametric tests, logistic regression, and survival analysis were used for statistical analysis. Higher serum calretinin concentration was associated with shorter progression-free (PFS) (HR = 1.18 (1.02-1.37), p = 0.023) and overall survival (OS) (HR = 1.20 (1.03-1.41), p = 0.023), but the association was not significant after adjusting for clinical factors (HR = 1.05 (0.85-1.31), p = 0.653 and HR = 1.06 (0.84-1.34), p = 0.613, respectively). SEPTIN7 rs3801339 and MIR335 rs3807348 were associated with survival even after adjustment (HR = 1.76 (1.17-2.64), p = 0.007 and HR = 0.65 (0.45-0.95), p = 0.028, respectively). Calretinin concentration was higher in patients who progressed after treatment with cisplatin-based chemotherapy (1.68 vs. 0.45 ng/mL, p = 0.001). Calretinin concentration above 0.89 ng/mL was associated with shorter PFS and OS from the start of chemotherapy (HR = 1.88 (1.28-2.77), p = 0.001 and HR = 1.91 (1.22-2.97), p = 0.004, respectively), even after adjusting for clinical factors (p < 0.05). MIR335 rs3807348 was associated with a better response to chemotherapy (OR = 2.69 (1.17-6.18), p = 0.020). We showed that serum calretinin is associated with survival and chemotherapy treatment outcomes in MM and could serve as a predictive biomarker.

Nanoscale Bilirubin Analysis in Translational Research and Precision Medicine by the Recombinant Protein HUG.

Bilirubin is a toxicological biomarker for hemolysis and liver diseases. The current automated diazo method used in clinical chemistry has limited applicability in rodent models and cannot be used in small animals relevant to toxicology, microphysiological systems, cell cultures, and kinetic studies. Here, we present a versatile fluorometric method for nanoscale analysis of bilirubin based on its highly specific binding to the recombinant bifunctional protein HELP-UnaG (HUG). The assay is sensitive (LoQ = 1.1 nM), accurate (4.5% relative standard error), and remarkably robust, allowing analysis at pH 7.4-9.5, T = 25-37 °C, in various buffers, and in the presence of 0.4-4 mg × L-1 serum albumin or 30% DMSO. It allows repeated measurements of bilirubinemia in murine models and small animals, fostering the 3Rs principle. The assay determines bilirubin in human plasma with a relative standard error of 6.7% at values that correlate and agree with the standard diazo method. Furthermore, it detects differences in human bilirubinemia related to sex and UGT1A1 polymorphisms, thus demonstrating its suitability for the uniform assessment of bilirubin at the nanoscale in translational and precision medicine.

Novel and Future Treatment Options in Mesothelioma: A Systematic Review.

Mesothelioma is a rare tumor, frequently associated with asbestos exposure, arising from pleura and peritoneum. Traditionally, diagnosis and treatment have been difficult in a clinical setting. The treatment is based on a trimodal approach involving surgery, chemotherapy, and radiotherapy. The introduction of chemotherapy improved the overall survival. However, the regimen of pemetrexed/cisplatin doublet has not been changed as a standard treatment since 2004. Novel combinations of ipilimumab and nivolumab have only been approved for clinical use in late 2020. The aim of this review was to systematically summarize findings on novel treatment options in mesothelioma. We searched available medical databases online, such as PubMed and Clinicaltrials.gov, to systematically review the literature on novel approaches in immunotherapy, vaccines, and Chimeric Antigen Receptor (CAR)-T cell therapy in mesothelioma. We manually screened 1127 articles on PubMed and 450 trials on ClinicalTrials.gov, and 24 papers and 12 clinical trials published in the last ten years were included in this review. Immunotherapy that was swiftly introduced to treat other thoracic malignancies was slow to reach desirable survival endpoints in mesothelioma, possibly due to limited patient numbers. Novel treatment approaches, such as CAR-T cell therapy, are being investigated. As the incidence of mesothelioma is still rising globally, novel treatment options based on a better understanding of the tumor microenvironment and the genetic drivers that modulate it are needed to support future precision-based therapies.

Glucagon-like Peptide-1 Receptor Agonists in the Management of Type 2 Diabetes Mellitus and Obesity: The Impact of Pharmacological Properties and Genetic Factors.

Glucagon-like peptide-1 (GLP-1) receptor agonists are a new class of antihyperglycemic drugs that enhance appropriate pancreatic ß-cell secretion, pancreatic α-cell (glucagon) suppression, decrease liver glucose production, increase satiety through their action on the central nervous system, slow gastric emptying time, and increase insulin action on peripheral tissue. They are effective in the management of type 2 diabetes mellitus and have a favorable effect on weight loss. Their cardiovascular and renal safety has been extensively investigated and confirmed in many clinical trials. Recently, evidence has shown that in addition to the existing approaches for the treatment of obesity, semaglutide in higher doses promotes weight loss and can be used as a drug to treat obesity. However, some T2DM and obese patients do not achieve a desired therapeutic effect of GLP-1 receptor agonists. This could be due to the multifactorial etiologies of T2DM and obesity, but genetic variability in the GLP-1 receptor or signaling pathways also needs to be considered in non-responders to GLP-1 receptor agonists. This review focuses on the pharmacological, clinical, and genetic factors that may influence the response to GLP-1 receptor agonists in the treatment of type 2 diabetes mellitus and obesity.

Metformin and Insulin Resistance: A Review of the Underlying Mechanisms behind Changes in GLUT4-Mediated Glucose Transport.

Metformin is the most commonly used treatment to increase insulin sensitivity in insulin-resistant (IR) conditions such as diabetes, prediabetes, polycystic ovary syndrome, and obesity. There is a well-documented correlation between glucose transporter 4 (GLUT4) expression and the level of IR. Therefore, the observed increase in peripheral glucose utilization after metformin treatment most likely comes from the induction of GLUT4 expression and its increased translocation to the plasma membrane. However, the mechanisms behind this effect and the critical metformin targets are still largely undefined. The present review explores the evidence for the crucial role of changes in the expression and activation of insulin signaling pathway mediators, AMPK, several GLUT4 translocation mediators, and the effect of posttranscriptional modifications based on previously published preclinical and clinical models of metformin's mode of action in animal and human studies. Our aim is to provide a comprehensive review of the studies in this field in order to shed some light on the complex interactions between metformin action, GLUT4 expression, GLUT4 translocation, and the observed increase in peripheral insulin sensitivity.

Optimization of isolation protocol and characterization of urinary extracellular vesicles as biomarkers of kidney allograft injury.

AIMS: Long-term kidney allograft survival requires a personalized approach to allograft injury recognition in a timely and reliable manner. Kidney biopsy is invasive and unsuitable for continuous function assessment. Alternatively, in urine, we find extracellular vesicles (uEVs), stable carriers of kidney pathology signals. Analysis of uEVs and their cargo could allow for more frequent and non-invasive assessment of allograft function. We aimed to optimize the uEVs isolation method applicable for kidney allograft injury biomarker studies. MATERIALS AND METHODS: To this end, we optimized several steps of size-exclusion chromatography (SEC)-based method for uEVs isolation from second morning urine of kidney allograft recipients. uEVs were characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), western analysis, and quantitative PCR. RESULTS: According to TEM and NTA, SEC isolated high concentrations (8.64 × 108 EVs/mL of urine) of EVs that showed typical morphology and mean size (171 nm), but addition of EDTA and filtration step were needed to remove impurities. Additionally, typical EV proteins Hsc70, CD63, flotillin, tubulin, GAPDH, and miR hsa-let-7i were detected in isolated uEVs, further confirming their identity. CONCLUSION: Optimized method based on SEC was effective and adequate in isolating pure EVs from urine of kidney allograft recipients and could be used in future biomarker studies.

Glucocorticoid pathway polymorphisms and diabetes after kidney transplantation.

AIMS: To find possible associations between new-onset diabetes after transplantation and polymorphisms in glucocorticoid pathway. MATERIALS AND METHODS: A total of 290 patients from our national cohort of kidney transplant patients with functioning graft transplanted in 6 consecutive years (2010 - 2015) were included in the study. All patients were genotyped for polymorphisms in genes coding for glucocorticoid receptor (NR3C1 rs33389, rs6198 and rs33388), P-glycoprotein (ABCB1 rs1045642, rs1128503, and rs2032582), and glutathione S-transferase P1 (GSTP1 rs1695 and rs1138272). For interim analysis, clinical data were obtained from medical records for 79 patients. RESULTS: 22.8% of patients developed NODAT in the first post-transplant year. GSTP1 rs1695 and rs1138272 polymorphisms were associated with an increased risk for NODAT. NR3C1 rs6198 polymorphism was associated with higher serum glucose at the end of the first post-transplant year. CONCLUSION: The observed incidence of NODAT in the first post-transplant year is in accordance with the literature data. GSTP1 genotypes leading to decreased conjugation capacity were associated with higher probability of NODAT. As these polymorphisms can be determined already before kidney transplantation, they can help planning early glucocorticoid withdrawal if a favorable post-transplant course permits it.

Treatment Response to SGLT2 Inhibitors: From Clinical Characteristics to Genetic Variations.

SGLT2 (sodium-glucose cotransporter 2) inhibitors are a new class of antihyperglycaemic drugs that act on the proximal tubules of the kidney. They have shown efficacy in the management of diabetes mellitus type 2 and their cardiovascular and renal safety have been extensively investigated and confirmed in clinical trials. However, inter-individual differences in response to treatment with SGLT2 inhibitors may present in everyday clinical practice, and good predictors of glycemic response and the risk for adverse events in an individual patient are lacking. As genetic variability of SGLT2 may influence the treatment response, pharmacogenetic information could support the choice of the most beneficial treatment strategy in an individual patient. This review focuses on the clinical and genetic factors that may influence the treatment response to SGLT2 inhibitors in type 2 diabetes patients with comorbid conditions.

Relationship between cardiorespiratory phase coherence during hypoxia and genetic polymorphism in humans.

KEY POINTS: High altitude-induced hypoxia in humans evokes a pattern of breathing known as periodic breathing (PB), in which the regular oscillations corresponding to rhythmic expiration and inspiration are modulated by slow periodic oscillations. The phase coherence between instantaneous heart rate and respiration is shown to increase significantly at the frequency of periodic breathing during acute and sustained normobaric and hypobaric hypoxia. It is also shown that polymorphism in specific genes, NOTCH4 and CAT, is significantly correlated with this coherence, and thus with the incidence of PB. Differences in phase shifts between blood flow signals and respiratory and PB oscillations clearly demonstrate contrasting origins of the mechanisms underlying normal respiration and PB. These novel findings provide a better understanding of both the genetic and the physiological mechanisms responsible for respiratory control during hypoxia at altitude, by linking genetic factors with cardiovascular dynamics, as evaluated by phase coherence. ABSTRACT: Periodic breathing (PB) occurs in most humans at high altitudes and is characterised by low-frequency periodic alternation between hyperventilation and apnoea. In hypoxia-induced PB the dynamics and coherence between heart rate and respiration and their relationship to underlying genetic factors is still poorly understood. The aim of this study was to investigate, through novel usage of time-frequency analysis methods, the dynamics of hypoxia-induced PB in healthy individuals genotyped for a selection of antioxidative and neurodevelopmental genes. Breathing, ECG and microvascular blood flow were simultaneously monitored for 30 min in 22 healthy males. The same measurements were repeated under normoxic and hypoxic (normobaric (NH) and hypobaric (HH)) conditions, at real and simulated altitudes of up to 3800 m. Wavelet phase coherence and phase difference around the frequency of breathing (approximately 0.3 Hz) and around the frequency of PB (approximately 0.06 Hz) were evaluated. Subjects were genotyped for common functional polymorphisms in antioxidative and neurodevelopmental genes. During hypoxia, PB resulted in increased cardiorespiratory coherence at the PB frequency. This coherence was significantly higher in subjects with NOTCH4 polymorphism, and significantly lower in those with CAT polymorphism (HH only). Study of the phase shifts clearly indicates that the physiological mechanism of PB is different from that of the normal respiratory cycle. The results illustrate the power of time-evolving oscillatory analysis content in obtaining important insight into high altitude physiology. In particular, it provides further evidence for a genetic predisposition to PB and may partly explain the heterogeneity in the hypoxic response.

Generating evidence for precision medicine: considerations made by the Ubiquitous Pharmacogenomics Consortium when designing and operationalizing the PREPARE study.

OBJECTIVES: Pharmacogenetic panel-based testing represents a new model for precision medicine. A sufficiently powered prospective study assessing the (cost-)effectiveness of a panel-based pharmacogenomics approach to guide pharmacotherapy is lacking. Therefore, the Ubiquitous Pharmacogenomics Consortium initiated the PREemptive Pharmacogenomic testing for prevention of Adverse drug Reactions (PREPARE) study. Here, we provide an overview of considerations made to mitigate multiple methodological challenges that emerged during the design. METHODS: An evaluation of considerations made when designing the PREPARE study across six domains: study aims and design, primary endpoint definition and collection of adverse drug events, inclusion and exclusion criteria, target population, pharmacogenomics intervention strategy, and statistical analyses. RESULTS: Challenges and respective solutions included: (1) defining and operationalizing a composite primary endpoint enabling measurement of the anticipated effect, by including only severe, causal, and drug genotype-associated adverse drug reactions; (2) avoiding overrepresentation of frequently prescribed drugs within the patient sample while maintaining external validity, by capping drugs of enrolment; (3) designing the pharmacogenomics intervention strategy to be applicable across ethnicities and healthcare settings; and (4) designing a statistical analysis plan to avoid dilution of effect by initially excluding patients without a gene-drug interaction in a gatekeeping analysis. CONCLUSION: Our design considerations will enable quantification of the collective clinical utility of a panel of pharmacogenomics-markers within one trial as a proof-of-concept for pharmacogenomics-guided pharmacotherapy across multiple actionable gene-drug interactions. These considerations may prove useful to other investigators aiming to generate evidence for precision medicine.

Analysis of association of ADORA2A and ADORA3 polymorphisms genotypes/haplotypes with efficacy and toxicity of methotrexate in patients with Rheumatoid arthritis.

Adenosine receptors ADORA2A and ADORA3 are part of the adenosine-mediated antiinflammatory pathway and are overexpressed in patients with Rheumatoid arthritis (RA). Methotrexate (MTX) antiinflammatory effects are partially mediated via increased release of adenosine into extracellular space. Polymorphisms in ADORA2A and ADORA3 genes may have an impact on the efficacy and toxicity of MTX in RA patients. The study included 127 RA patients. Treatment efficacy was estimated using the changes in Disease activity score (DAS28) after 6 months of MTX monotherapy, according to EULAR response criteria. Patients with good and moderate response were classified as "responders", and with a poor response as "nonresponders". Adverse effects were collected during the follow-up period. Genotyping for polymorphisms within ADORA2A gene (rs2298383, rs2236624, rs5751876, rs17004921) and ADORA3 gene (rs2298191, rs1544223, rs3393) was performed using the KASPar assays. Among patients 112 (88.19%) were responders (18.8% good, 81.2% moderate). We observed no association between analyzed genotypes or alleles and MTX response by EULAR criteria but carriers of ADORA2A rs17004921 T allele (CT + TT) had a higher DAS28 decrease after 6 months of treatment than patients with CC genotype (p = 0.013). Adverse effects were reported in 31 patients (24.41%). Bone erosions were present in 82 (64.6%) patients. Haplotype block was observed among all 3 analyzed polymorphisms within ADORA3 gene and TAA haplotype was associated with bone erosions (29% vs 15.6%, p = 0.023) and hepatotoxicity (51.3% vs 21.6%, p = 0.013). According to our study, ADORA3 TAA haplotype may be associated with bone erosions and hepatotoxicity in RA patients treated with MTX.

Clinical and Clinical-Pharmacogenetic Models for Prediction of the Most Common Psychiatric Complications Due to Dopaminergic Treatment in Parkinson's Disease.

BACKGROUND: The most common psychiatric complications due to dopaminergic treatment in Parkinson's disease are visual hallucinations and impulse control disorders. Their development depends on clinical and genetic factors. METHODS: We evaluated the simultaneous effect of 16 clinical and 34 genetic variables on the occurrence of visual hallucinations and impulse control disorders. Altogether, 214 Parkinson's disease patients were enrolled. Their demographic, clinical, and genotype data were obtained. Clinical and clinical-pharmacogenetic models were built by The Least Absolute Shrinkage and Selection Operator penalized logistic regression. The predictive capacity was evaluated with the cross-validated area under the receiver operating characteristic curve (AUC). RESULTS: The clinical-pharmacogenetic index for prediction of visual hallucinations encompassed age at diagnosis (OR = 0.99), rapid eye movement (REM) sleep behavior disorder (OR = 2.27), depression (OR = 1.0002), IL6 rs1800795 (OR = 0.99), GPX1 s1050450 (OR = 1.07), COMT rs165815 (OR = 0.69), MAOB rs1799836 (OR = 0.97), DRD3 rs6280 (OR = 1.32), and BIRC5 rs8073069 (OR = 0.94). The clinical-pharmacogenetic index for prediction of impulse control disorders encompassed age at diagnosis (OR = 0.95), depression (OR = 1.75), beta-blockers (OR = 0.99), coffee consumption (OR = 0.97), NOS1 rs2682826 (OR = 1.15), SLC6A3 rs393795 (OR = 1.27), SLC22A1 rs628031 (OR = 1.19), DRD2 rs1799732 (OR = 0.88), DRD3 rs6280 (OR = 0.88), and NRG1 rs3924999 (OR = 0.96). The cross-validated AUCs of clinical and clinical-pharmacogenetic models for visual hallucinations were 0.60 and 0.59, respectively. The AUCs of clinical and clinical-pharmacogenetic models for impulse control disorders were 0.72 and 0.71, respectively. The AUCs show that the addition of selected genetic variables to the analysis does not contribute to better prediction of visual hallucinations and impulse control disorders. CONCLUSIONS: Models could be improved by a larger cohort and by addition of other types of Parkinson's disease biomarkers to the analysis.

Genetic variability of serotonin pathway associated with schizophrenia onset, progression, and treatment.

Schizophrenia (SZ) onset and treatment outcome have important genetic components, however individual genes do not have strong effects on SZ phenotype. Therefore, it is important to use the pathway-based approach and study metabolic and signaling pathways, such as dopaminergic and serotonergic. Serotonin pathway has an important role in brain signaling, nevertheless, its role in SZ is not as thoroughly examined as that of dopamine pathway. In this study, we reviewed serotonin pathway genes and genetic variations associated with SZ, including variations at DNA, RNA, and epigenetic level. We obtained 30 serotonin pathway genes from Kyoto encyclopedia of genes and genomes and used these genes for the literature review. We extracted 20 protein coding serotonin pathway genes with genetic variations associated with SZ onset, development, and treatment from 31 research papers. Genes associated with SZ are present on all levels of serotonin pathway: serotonin synthesis, transport, receptor binding, intracellular signaling, and reuptake; however, regulatory genes are poorly researched. We summarized common challenges of genetic association studies and presented some solutions. The analysis of reported serotonin pathway-SZ associations revealed lack of information about certain serotonin pathway genes potentially associated with SZ. Furthermore, it is becoming clear that interactions among serotonin pathway genes and their regulators may bring further knowledge about their involvement in SZ.

Genetic variability of inflammation and oxidative stress genes does not play a major role in the occurrence of adverse events of dopaminergic treatment in Parkinson's disease.

BACKGROUND: Inflammation and oxidative stress are recognized as important contributors to Parkinson's disease pathogenesis. As such, genetic variability in these pathways could have a role in susceptibility for the disease as well as in the treatment outcome. Dopaminergic treatment is effective in management of motor symptoms, but poses a risk for motor and non-motor adverse events. Our aim was to evaluate the impact of selected single-nucleotide polymorphisms in genes involved in inflammation and oxidative stress on Parkinson's disease susceptibility and the occurrence of adverse events of dopaminergic treatment. METHODS: In total, 224 patients were enrolled, and their demographic and clinical data on the disease course were collected. Furthermore, a control group of 146 healthy Slovenian blood donors were included for Parkinson's disease' risk evaluation. Peripheral blood was obtained for DNA isolation. Genotyping was performed for NLRP3 rs35829419, CARD8 rs2043211, IL1ß rs16944, IL1ß rs1143623, IL6 rs1800795, CAT rs1001179, CAT rs10836235, SOD2 rs4880, NOS1 rs2293054, NOS1 rs2682826, TNF-α rs1800629, and GPX1 rs1050450. Logistic regression was used for analysis of possible associations. RESULTS: We observed a nominally significant association of the IL1ß rs1143623 C allele with the risk for Parkinson's disease (OR = 0.59; 95%CI = 0.38-0.92, p = 0.021). CAT rs1001179 A allele was significantly associated with peripheral edema (OR = 0.32; 95%CI = 0.15-0.68; p = 0.003). Other associations observed were only nominally significant after adjustments: NOS1 rs2682826 A allele and excessive daytime sleepiness and sleep attacks (OR = 1.75; 95%CI = 1.00-3.06, p = 0.048), SOD2 rs4880 T allele and nausea/vomiting (OR = 0.49, 95%CI = 0.25-0.94; p = 0.031), IL1ß rs1143623 C allele and orthostatic hypotension (OR = 0.57, 95%CI = 0.32-1.00, p = 0.050), and NOS1 rs2682826 A allele and impulse control disorders (OR = 2.59; 95%CI = 1.09-6.19; p = 0.032). We did not find any associations between selected polymorphisms and motor adverse events. CONCLUSIONS: Apart from some nominally significant associations, one significant association between CAT genetic variability and peripheral edema was observed as well. Therefore, the results of our study suggest some links between genetic variability in inflammation- and oxidative stress-related pathways and non-motor adverse events of dopaminergic treatment. However, the investigated polymorphisms do not play a major role in the occurrence of the disease and the adverse events of dopaminergic treatment.

ADORA2A Polymorphisms Influence Methotrexate Adverse Events in Rheumatoid Arthritis.

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.