Psychiatrie posledních let se stává medicínským oborem založeným na důkazech. Stále se nám však nedostává spolehlivých možností predikce, které by nám pomohly předpovídat riziko vzniku, průběh a výsledky léčby u závažných duševních nemocí, jako je schizofrenie Stávající modely predikce v psychiatrii lze rozdělit na modely tautologické, heuristické, irelevantní a logické. Logické modely predikce schizofrenie se soustřeďují na studie genetické, zobrazovacích metod (morfologické a funkční) a neuroendokrinní testy. Genetické studie hledají zejména příčiny onemocnění a farmakogenetické prediktory odpovědi na léčbu. Jedním z kandidátských genů je gen pro COMT s dobře známým polymorfizmem, popsaná je také geneticky podmíněná terapeutická odpověď na clozapin. Strukturální a funkční abnormity jsou obvykle spojovány s horším průběhem a nepříznivou odpovědí na léčbu. Neuroendokrinní studie sledují přímo či nepřímo pomocí stimulačních testů funkční stav neurotransmiterových systémů. Příkladem jsou prezentované výsledky d-fenfluraminového testu, který měří vztah mezi aktivitou serotoninergního systému a zlepšením po léčbě antipsychotiky u akutně nemocných se schizofrenií. Uvedené výsledky několika konkrétních studií jsou příkladem úspěšného modelu logické predikce v psychiatrii. Ukazuje se, že na teoretickém podkladě lze postavit hypotézu a následně ji testovat v experimentálních podmínkách. Aplikací zobrazovacích metod, genetických analýz a neuroendokrinních testů v klinické praxi můžeme individualizovat diagnostický a terapeutický přístup k pacientům.
Recently, psychiatry has become an evidence-based field of medicine. However, there is a lack of reliable predictions of risk of onset, course, and outcome for major psychiatric disorders, e.g. schizophrenia. Available prediction models in psychiatry are tautological, heuristic, logical, and irrelevant. Logical models of prediction in schizophrenia are based on genetic, neuroimaging (structural and functional), and neuroendocrine studies. Genetic research searches the causes of illness and pharmacogenetic predictors of treatment response. There are numerous studies of candidate gene encoding COMT polymorphism, or pharmacogenetics of response to clozapine. Neuroanatomical and functional abnormalities are generally associated with unfavorable course, outcome and treatment failure. Neuroendocrine studies measure directly or indirectly, using challenge tests, functional state of neurotransmitter systems. Results of d-fenfluramine challenge test investigating relationship between 5-HT system reactivity and response to antipsychotic treatment in young acute schizophrenia patients are presented. Examples of genetic, neuroimaging, and neuroendocrine studies represent models of successful logical prediction in psychiatry based on the solid theoretical background. Implementation of neuroimaging methods, genetic analyses, and neuroendocrine tests into the clinical practice, may help to individualize diagnostics and treatment of schizophrenia.
- MeSH
- Research Support as Topic MeSH
- Financing, Organized MeSH
- Fluorouracil adverse effects therapeutic use toxicity MeSH
- Genes MeSH
- Humans MeSH
- Mutation drug effects MeSH
- DNA Mutational Analysis statistics & numerical data MeSH
- Drug-Related Side Effects and Adverse Reactions genetics MeSH
- Antineoplastic Agents adverse effects toxicity MeSH
- Pyrimidines metabolism MeSH
- Fluorine Compounds MeSH
- Toxicity Tests MeSH
- Check Tag
- Humans MeSH
OBJECTIVE: Prediction of coronary atherosclerosis in patients with stable angina based on non-invasive examinations. METHODS: Pro-inflammatory markers, heme oxygenase-1 (HO-1) polymorphism, lipid levels, Framingham risk score (FRS), and carotid ultrasound were analyzed and compared to grayscale and virtual histology intravascular ultrasound (VH-IVUS). RESULTS: A total of 101 patients were included, and genetic analysis was performed on 81 patients (80.2%). The HO-1 risk polymorphism was more frequent in patients post-myocardial infarction (61.3% vs 32%; P=.0097), or with diabetes (68.4% vs 35.5%; P=.011) or a higher FRS (21.5 vs 15.7; P=.014). Plaques in patients with the HO-1 risk polymorphism contained less fibro-fatty tissue (17.1% vs 23.2%; P=.005) and more necrotic core (NC; 17.1% vs 12.7%; P=.02) and calcification (10.2% vs 5.7%; P=.035) compared to patients without the HO-1 risk polymorphism. Carotid intima media thickness (P=.05) and carotid bulb plaque (P=.008) predicted plaque burden. The level of Apo A inversely correlated with NC (P=.047; r = -0.27) and was lower in patients with VH-thin-cap fibroatheroma (VH-TCFA; 1.19 mmol/L vs 1.3 mmol/L; P=.04). FRS correlated with NC (P=.007; r = 0.2), with angiographic disease severity (P=.032; r = 0.21) and was higher in patients with VH-TCFA (9.1 vs 7.8; P=.03). CONCLUSION: Carotid ultrasound and HO-1 polymorphism improve coronary atherosclerosis prediction.
- MeSH
- Apolipoproteins A blood MeSH
- Biomarkers MeSH
- Physical Examination MeSH
- Genetic Predisposition to Disease epidemiology MeSH
- Heme Oxygenase-1 genetics MeSH
- Carotid Intima-Media Thickness MeSH
- Middle Aged MeSH
- Humans MeSH
- Carotid Artery Diseases ultrasonography MeSH
- Coronary Artery Disease * epidemiology genetics pathology MeSH
- Polymorphism, Genetic * MeSH
- Predictive Value of Tests MeSH
- Risk Factors MeSH
- Aged MeSH
- Angina, Stable * diagnosis genetics pathology MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Comparative Study MeSH
OBJECTIVES: Our study aims to find the relationship between metabolic enzyme thiopurine S-methyltransferase (TPMT) gene polymorphisms and clinical output of the therapy with azathioprine. We focused on patients who experienced leucopenia caused by high blood levels of active azathioprine metabolites. DESIGN: Our group consists of 87 patients who have been treated by azathioprine. 21 individuals experienced leucopenia during treatment with standard dose of azathioprine. We have used PCR-REA and "real-time" PCR methods for genotype detection G238C, G460G and A719G substitutions in TPMT gene. RESULTS: We have found statistical association between the presence of non-standard TPMT alleles and adverse event associated with azathioprine treatment - leucopenia (p=0.0033). CONCLUSION: Our results confirm that TPMT genotyping prior to the treatment with azathioprine could predict patients with genetic predisposition for serious leucopenia and seems to be a useful genetic marker for individualisation of the therapy.
- MeSH
- Alleles MeSH
- Azathioprine adverse effects blood MeSH
- Adult MeSH
- Genetic Predisposition to Disease MeSH
- Genotype MeSH
- Polymorphism, Single Nucleotide MeSH
- Leukopenia chemically induced MeSH
- Humans MeSH
- Methyltransferases genetics MeSH
- Polymerase Chain Reaction MeSH
- Polymorphism, Genetic MeSH
- Sequence Analysis, DNA MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
- MeSH
- Bayes Theorem MeSH
- Carcinoma, Ovarian Epithelial genetics MeSH
- Genetic Predisposition to Disease MeSH
- Polymorphism, Single Nucleotide MeSH
- Humans MeSH
- Breast Neoplasms * MeSH
- Ovarian Neoplasms * epidemiology genetics MeSH
- Prospective Studies MeSH
- Risk Factors MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Although genetic variation at chromosome 9p21.3 is associated with incident cardiovascular disease, it is unclear whether screening for this polymorphism improves risk prediction. OBJECTIVE: To determine whether knowledge of variation at chromosome 9p21.3 provides predictive information beyond that from other readily available risk factors. DESIGN: Prospective cohort study. SETTING: United States. PATIENTS: 22 129 female white health professionals participating in the Women's Genome Health Study, initially without any major chronic disease, who were prospectively followed over a median of 10.2 years for incident cardiovascular disease. MEASUREMENTS: Polymorphism at rs10757274 in chromosome 9p21.3 and additional cardiovascular disease risk factors (blood pressure, smoking status, diabetes, blood levels of cholesterol, high-sensitivity C-reactive protein, and family history of premature myocardial infarction). RESULTS: Polymorphism at rs10757274 was associated with an adjusted hazard ratio for incident cardiovascular disease of 1.25 (95% CI, 1.04 to 1.51) for the AG genotype and 1.32 (CI, 1.07 to 1.63) for the GG genotype. However, the addition of the genotype to a prediction model based on traditional risk factors, high-sensitivity C-reactive protein, and family history of premature myocardial infarction had no effect on model discrimination as measured by the c-index (0.807 to 0.809) and did not improve the Net Reclassification Improvement score (-0.2%; P = 0.59) or the Integrated Discrimination Improvement score (0.0; P = 0.18). Limitation: Study participants were all white women. CONCLUSION: In this large prospective cohort of white women, genetic variation in chromosome 9p21.3 was associated with incident cardiovascular disease but did not improve on the discrimination or classification of predicted risk achieved with traditional risk factors, high-sensitivity C-reactive protein, and family history of premature myocardial infarction.
- MeSH
- Financing, Organized MeSH
- Genotype MeSH
- Polymorphism, Single Nucleotide MeSH
- Kaplan-Meier Estimate MeSH
- Cardiovascular Diseases epidemiology genetics MeSH
- Middle Aged MeSH
- Humans MeSH
- Chromosomes, Human, Pair 9 genetics MeSH
- Follow-Up Studies MeSH
- Probability MeSH
- Proportional Hazards Models MeSH
- Prospective Studies MeSH
- Risk Factors MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Female MeSH
AIMS: The aim of the study was to investigate genetic variants predicting cardiovascular events in patients with dyslipidemia and compare its relationship with common risk factors including hyperlipidemia, metabolic syndrome, history of acute myocardial infarction, thrombosis, obesity, and smoking. MATERIALS AND METHODS: Five hundred two individuals divided into six groups corresponding with the risk factors and a control group of normolypidemic patients were analyzed for the presence of eight mutations and polymorphisms (endothelial nitric oxide synthase -786T → C and G894T; lymphotoxin A C804A; angiotensin-converting enzyme [ACE] ins/del; human platelet antigen 1 a/b; beta-fibrinogen -455G → A; apolipoprotein B [ApoB] R3500Q; APOE E2/E3/E4) using the ViennaLab CVD Strip assay. RESULTS: ACE deletions are the most frequent genetic variants in risk groups of dyslipidemic patients (from 58% in cardiovascular events to 51% in smokers). We found a strong relationship between genetic variants and risk factors. G894T is significantly associated with smoking (value of odds ratio [OR] = 1.62, p = 0.04), and ACE deletions are negatively associated with cardiovascular events (OR = 0.62, p = 0.03). CONCLUSION: Significant associations between genetic variants predicting cardiovascular events and common risk factors in dyslipidemic patients were found.
- MeSH
- Peptidyl-Dipeptidase A genetics MeSH
- Adult MeSH
- Dyslipidemias genetics MeSH
- Genetic Predisposition to Disease MeSH
- Genetic Variation MeSH
- Genotype MeSH
- Cardiovascular Diseases genetics MeSH
- Smoking genetics MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Mutation MeSH
- Polymorphism, Genetic MeSH
- Predictive Value of Tests MeSH
- Risk Factors MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Nitric Oxide Synthase Type III genetics MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
The purpose of our study was to evaluate a possible correlation between genetic polymorphisms in ATM and TGFB1 genes and late toxicity of chemoradiotherapy for locally advanced cervical cancer. Fifty five patients with FIGO stage IIB and higher without a disease recurrence with a mean follow up of 6 years were included. Late toxicity was assessed by EORTC/RTOG late toxicity criteria. Univariate and multivariate logistic regression model was used for statistical analysis. Degree of association between polymorphisms and late toxicity of chemotherapy was assessed on the basis of phi-coefficient () as well. We did not find any association between 5557G>A polymorphism in the ATM gene or single TGFB1 polymorphisms and late toxicity. TGFB1 compound homozygosity (-1552delAGG, -509C>T, L10P) was a significant predictive factor of grade III-IV and any grade of complications in both univariate and multivariate logistic regression analyses and statistical significance of association between polymorphisms and late toxicity of chemoradiotherapy was confirmed also by the evaluation of phi-coefficient (). We conclude that haplotypes instead of single nucleotide polymorphic sites in the genes may better characterize the individual radiosensitivity.
- MeSH
- Ataxia Telangiectasia Mutated Proteins * genetics MeSH
- Chemoradiotherapy * adverse effects MeSH
- Adult MeSH
- Haplotypes MeSH
- Middle Aged MeSH
- Humans MeSH
- Logistic Models MeSH
- Uterine Cervical Neoplasms * genetics therapy MeSH
- Polymorphism, Genetic * MeSH
- Aged MeSH
- Transforming Growth Factor beta1 * genetics MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
