Ассоциация аллельных полиморфизмов гена эндотелиальной NO-синтазы с развитием ишемической болезни сердца (литературный обзор)

Проведений аналіз вітчизняних та закордонних досліджень стосовно вивчення впливу Т-786С, G894T, 4a/b поліморфізмів гену eNOS на ризик розвитку ІХС у представників різних популяцій. Доведена роль Т-786 С поліморфізма гену eNOS у розвитку ІХС у представників японської, української, італійської популяції, причому в останніх він пов’язаний із багатосудинним ураженням. G894T поліморфізм гену eNOS пов’язаний із підвищеним ризиком розвитку ІХС, ішемічних інсультів в італійській, турецькій, азіатській популяціях, а в російській ─ із рестенозами стентів. Доведений зв’язок 4а/4b поліморфізму гену eNOS із виникненням ІХС у турецькій, японській, корейській, афро-американській, іранській, російській популяціях, а в японській популяції ─ гендерна специфіка даної асоціації. В окремих дослідженнях отримані суперечливі дані щодо впливу Т-786 С поліморфізму гену eNOS в турецькій популяції. Не виявлено асоціації 4а/4b поліморфізму гену eNOS у чоловіків Словенії, Фінляндії, G894T поліморфізму гену eNOS у корейській популяції, а у представників білої австралійської популяцій не виявлено асоціації генотипів 4а/4b, G894T, Т-786С поліморфізму гену eNOS із ризиком розвитку ІХС.В статье проведен анализ отечественных и зарубежных исследований, посвященных изучению влияния Т-786С, G894T, 4a/b полиморфизмов гена eNOS на риск развития ИБС у представителей различных популяций. Доказана роль Т-786 С полиморфизма гена eNOS в развитии ИБС у представителей японской, украинськой, итальянской популяции, причем у последних он связан с многососудистым поражением. G894T полиморфизм гена eNOS связан с повышеным риском развития ИХС, ишемических инсультов в итальянской, турецкой, азиатской популяциях, а в российской ─ с рестенозами стентов. Доказана связь 4а/4b полиморфизма гена eNOS с возникновением ИБС в турецкой, японской, корейской, афро-американской, иранськой, российской популяциях, а в японской популяции ─ гендерная специфика данной ассоциации. В отдельных исследованиях получены противоречивые данные о влиянии Т-786 С полиморфизма гена eNOS в турецкой популяции. Не выявлено ассоциации 4а/4b полиморфизма гена eNOS у мужчин Словении, Финляндии, G894T полиморфизма гена eNOS в корейской популяции, а у представителей белой австралийской популяции не выявлено ассоциации генотипов 4а/4b, G894T, Т-786С полиморфизму гену eNOS с риском развития ИБС.The article analyzed Ukrainian and foreign research on the impact study T-786С, G894T, 4a /b polymorphisms of the eNOS gene on the risk of coronary artery disease (CAD) among representatives of different populations. The role of T-786C polimorphism of the eNOS gene was proven in the development of CAD among Japanese, Ukrainian, Italian population, and in the past it is associated with multivessel disease. G894T polymorphism of the eNOS gene is associated with high risk of CAD, ischemic stroke in Italian, Turkish, Asian populations. In the Russian population this polymorphism assotiated with restenosis of stents. The 4a/4b polymorphism of the eNOS gene has significant influence on risk of CAD in Turkish, Japanese, Korean, AfricanAmerican, Iranian and Russian populations. Japanese population has gender specificity of the association. Conflicting data obtained in separate studies of the influence of T-786C polymorphism of the eNOS gene in the Turkish population. There was no association 4a /4b polymorphism of the eNOS gene in men Slovenia’s men and in Finland. Wasn’t identify association of G894T polymorphism of the eNOS gene in Korean population. Wasn’t detected association of genotypes 4a/4b, G894T, T-786S of the eNOS gene polymorphisms with risk of CAD in white Australians. Due to the existence of common pathogenetic mechanisms, involving NO, polymorphism eNOS gene presence may increases the risk of developing COPD. So perspective is study of polymorphisms eNOS gene in patients with COPD and CAD of Ukrainian population. Investigate their role as candidate genes can help to predict and prevent the appearance of comorbid disorders

Веб-ресурс для перегляду 3D моделей з використанням технології WebGL

У першому розділі досліджується актуальність проблеми, проводиться аналіз існуючих аналогів. Другий розділ присвячений формування мети дипломної роботи та задач проекту, вибору засобів реалізації та плануванню робіт. У третьому розділі виконується проектування веб-ресурсу, де наведені діаграми у нотації IDF0 та Use Case.Останній розділ присвячений детальному опису практичної реалізації проекту: виконання прототипування веб-сторінки, розмітка та форматування веб-ресурсу, налаштування та перевірка працездатності веб-браузера з WebGL, опис реакції на дії користувача, розробка функцій маніпуляцій над моделлю. Результатом проведеної роботи є розроблений веб-ресурс, який дозволяє користувачу обирати одну із чотирьох моделей для візуалізації на веб-сторінці та виконувати базові маніпуляції з нею

Exercise SBP response and incident depressive symptoms: The Maastricht Study

Objective : An exaggerated exercise SBP, which is potentially modifiable, may be associated with incident depressive symptoms via an increased pulsatile pressure load on the brain. However, the association between exaggerated exercise SBP and incident depressive symptoms is unknown. Therefore, we examined whether exaggerated exercise SBP is associated with a higher risk of depressive symptoms over time. Methods : We used longitudinal data from the population-based Maastricht Study, with only individuals free of depressive symptoms at baseline included (n = 2121; 51.3% men; age 59.5 +/- 8.5 years). Exercise SBP was measured at baseline with a submaximal exercise cycle test. We calculated a composite score of exercise SBP based on four standardized exercise SBP measures: SBP at moderate workload, SBP at peak exercise, SBP change per minute during exercise and SBP 4 min after exercise. Clinically relevant depressive symptoms were determined annually at follow-up and defined as a Patient Health Questionnaire score of at least 10. Results : After a mean follow-up of 3.9 years, 175 participants (8.3%) had incident clinically relevant depressive symptoms. A 1 SD higher exercise SBP composite score was associated with a higher incidence of clinically relevant depressive symptoms [hazard ratio: 1.27 (95% confidence interval: 1.04-1.54)]. Results were adjusted for age, sex, education level, glucose metabolism status, lifestyle, cardiovascular risk factors, resting SBP and cardiorespiratory fitness. Conclusion : A higher exercise SBP response is associated with a higher incidence of clinically relevant depressive symptoms

Multiple inflammatory biomarker detection in a prospective cohort study: a cross-validation between well-established single-biomarker techniques and electrochemiluminescense-based multi-array platform

Background - In terms of time, effort and quality, multiplex technology is an attractive alternative for well-established single-biomarker measurements in clinical studies. However, limited data comparing these methods are available. Methods - We measured, in a large ongoing cohort study (n = 574), by means of both a 4-plex multi-array biomarker assay developed by MesoScaleDiscovery (MSD) and single-biomarker techniques (ELISA or immunoturbidimetric assay), the following biomarkers of low-grade inflammation: C-reactive protein (CRP), serum amyloid A (SAA), soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1). These measures were realigned by weighted Deming regression and compared across a wide spectrum of subjects’ cardiovascular risk factors by ANOVA. Results - Despite that both methods ranked individuals’ levels of biomarkers very similarly (Pearson’s r all=0.755) absolute concentrations of all biomarkers differed significantly between methods. Equations retrieved by the Deming regression enabled proper realignment of the data to overcome these differences, such that intra-class correlation coefficients were then 0.996 (CRP), 0.711 (SAA), 0.895 (sICAM-1) and 0.858 (sVCAM-1). Additionally, individual biomarkers differed across categories of glucose metabolism, weight, metabolic syndrome and smoking status to a similar extent by either method. Conclusions - Multiple low-grade inflammatory biomarker data obtained by the 4-plex multi-array platform of MSD or by well-established single-biomarker methods are comparable after proper realignment of differences in absolute concentrations, and are equally associated with cardiovascular risk factors, regardless of such differences. Given its greater efficiency, the MSD platform is a potential tool for the quantification of multiple biomarkers of low-grade inflammation in large ongoing and future clinical studies

Functional genomics analysis identifies T and NK cell activation as a driver of epigenetic clock progression

Background Epigenetic clocks use DNA methylation (DNAm) levels of specific sets of CpG dinucleotides to accurately predict individual chronological age. A popular application of these clocks is to explore whether the deviation of predicted age from chronological age is associated with disease phenotypes, where this deviation is interpreted as a potential biomarker of biological age. This wide application, however, contrasts with the limited insight in the processes that may drive the running of epigenetic clocks. Results We perform a functional genomics analysis on four epigenetic clocks, including Hannum's blood predictor and Horvath's multi-tissue predictor, using blood DNA methylome and transcriptome data from 3132 individuals. The four clocks result in similar predictions of individual chronological age, and their constituting CpGs are correlated in DNAm level and are enriched for similar histone modifications and chromatin states. Interestingly, DNAm levels of CpGs from the clocks are commonly associated with gene expression in trans. The gene sets involved are highly overlapping and enriched for T cell processes. Further analysis of the transcriptome and methylome of sorted blood cell types identifies differences in DNAm between naive and activated T and NK cells as a probable contributor to the clocks. Indeed, within the same donor, the four epigenetic clocks predict naive cells to be up to 40 years younger than activated cells. Conclusions The ability of epigenetic clocks to predict chronological age involves their ability to detect changes in proportions of naive and activated immune blood cells, an established feature of immuno-senescence. This finding may contribute to the interpretation of associations between clock-derived measures and age-related health outcomes.Molecular Epidemiolog

Genome-wide identification of genes regulating DNA methylation using genetic anchors for causal inference

BACKGROUND: DNA methylation is a key epigenetic modification in human development and disease, yet there is limited understanding of its highly coordinated regulation. Here, we identify 818 genes that affect DNA methylation patterns in blood using large-scale population genomics data. RESULTS: By employing genetic instruments as causal anchors, we establish directed associations between gene expression and distant DNA methylation levels, while ensuring specificity of the associations by correcting for linkage disequilibrium and pleiotropy among neighboring genes. The identified genes are enriched for transcription factors, of which many consistently increased or decreased DNA methylation levels at multiple CpG sites. In addition, we show that a substantial number of transcription factors affected DNA methylation at their experimentally determined binding sites. We also observe genes encoding proteins with heterogenous functions that have widespread effects on DNA methylation, e.g., NFKBIE, CDCA7(L), and NLRC5, and for several examples, we suggest plausible mechanisms underlying their effect on DNA methylation. CONCLUSION: We report hundreds of genes that affect DNA methylation and provide key insights in the principles underlying epigenetic regulation

Genome-wide identification of genes regulating DNA methylation using genetic anchors for causal inference

Background DNA methylation is a key epigenetic modification in human development and disease, yet there is limited understanding of its highly coordinated regulation. Here, we identify 818 genes that affect DNA methylation patterns in blood using large-scale population genomics data. Results By employing genetic instruments as causal anchors, we establish directed associations between gene expression and distant DNA methylation levels, while ensuring specificity of the associations by correcting for linkage disequilibrium and pleiotropy among neighboring genes. The identified genes are enriched for transcription factors, of which many consistently increased or decreased DNA methylation levels at multiple CpG sites. In addition, we show that a substantial number of transcription factors affected DNA methylation at their experimentally determined binding sites. We also observe genes encoding proteins with heterogenous functions that have widespread effects on DNA methylation, e.g.,NFKBIE,CDCA7(L), andNLRC5, and for several examples, we suggest plausible mechanisms underlying their effect on DNA methylation. Conclusion We report hundreds of genes that affect DNA methylation and provide key insights in the principles underlying epigenetic regulation.Development and application of statistical models for medical scientific researc

Sex differences in the association of prediabetes and type 2 diabetes with microvascular complications and function: the Maastricht Study

Background Women with type 2 diabetes are disproportionally affected by macrovascular complications; we here investigated whether this is also the case for microvascular complications and retinal microvascular measures. Methods In a population-based cohort study of individuals aged 40-75 years (n = 3410; 49% women, 29% type 2 diabetes (oversampled by design)), we estimated sex-specific associations, and differences therein, of (pre)diabetes (reference: normal glucose metabolism), and of continuous measures of glycemia with microvascular complications and retinal measures (nephropathy, sensory neuropathy, and retinal arteriolar and venular diameters and dilatation). Sex differences were analyzed using regression models with interaction terms (i.e. sex-by- (pre)diabetes and sex-by-glycemia) and were adjusted for potential confounders. Results Men with type 2 diabetes (but not those with prediabetes) compared to men with normal glucose metabolism, (and men with higher levels of glycemia), had significantly higher prevalences of nephropathy (odds ratio: 1.58 95% CI (1.01;2.46)) and sensory neuropathy (odds ratio: 2.46 (1.67;3.63)), larger retinal arteriolar diameters (difference: 4.29 mu m (1.22;7.36)) and less retinal arteriolar dilatation (difference: - 0.74% (- 1.22; - 0.25)). In women, these associations were numerically in the same direction, but generally not statistically significant (odds ratios: 1.71 (0.90;3.25) and 1.22 (0.75;1.98); differences: 0.29 mu m (- 3.50;4.07) and: - 0.52% (- 1.11;0.08), respectively). Interaction analyses revealed no consistent pattern of sex differences in the associations of either prediabetes or type 2 diabetes or glycemia with microvascular complications or retinal measures. The prevalence of advanced-stage complications was too low for evaluation. Conclusions Our findings show that women with type 2 diabetes are not disproportionately affected by early microvascular complications.Prevention, Population and Disease management (PrePoD)Public Health and primary car

Plasma Metabolomics Identifies Markers of Impaired Renal Function: A Meta-analysis of 3089 Persons with Type 2 Diabetes

CONTEXT: There is a need for novel biomarkers and better understanding of the pathophysiology of diabetic kidney disease. OBJECTIVE: To investigate associations between plasma metabolites and kidney function in people with type 2 diabetes (T2D). DESIGN: 3089 samples from individuals with T2D, collected between 1999 and 2015, from 5 independent Dutch cohort studies were included. Up to 7 years follow-up was available in 1100 individuals from 2 of the cohorts. MAIN OUTCOME MEASURES: Plasma metabolites (n = 149) were measured by nuclear magnetic resonance spectroscopy. Associations between metabolites and estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and eGFR slopes were investigated in each study followed by random effect meta-analysis. Adjustments included traditional cardiovascular risk factors and correction for multiple testing. RESULTS: In total, 125 metabolites were significantly associated (PFDR = 1.5×10-32 - 0.046; β = -11.98-2.17) with eGFR. Inverse associations with eGFR were demonstrated for branched-chain and aromatic amino acids (AAAs), glycoprotein acetyls, triglycerides (TGs), lipids in very low-density lipoproteins (VLDL) subclasses, and fatty acids (PFDR < 0.03). We observed positive associations with cholesterol and phospholipids in high-density lipoproteins (HDL) and apolipoprotein A1 (PFDR < 0.05). Albeit some metabolites were associated with UACR levels (P < 0.05), significance was lost after correction for multiple testing. Tyrosine and HDL-related metabolites were positively associated with eGFR slopes before adjustment for multiple testing (PTyr = 0.003; PHDLrelated < 0.05), but not after. CONCLUSIONS: This study identified metabolites associated with impaired kidney function in T2D, implying involvement of lipid and amino acid metabolism in the pathogenesis. Whether these processes precede or are consequences of renal impairment needs further investigation

Heritability estimates for 361 blood metabolites across 40 genome-wide association studies

Metabolomics examines the small molecules involved in cellular metabolism. Approximately 50% of total phenotypic differences in metabolite levels is due to genetic variance, but heritability estimates differ across metabolite classes. We perform a review of all genome-wide association and (exome-) sequencing studies published between November 2008 and October 2018, and identify >800 class-specific metabolite loci associated with metabolite levels. In a twin-family cohort (N = 5117), these metabolite loci are leveraged to simultaneously estimate total heritability (h2 total), and the proportion of heritability captured by known metabolite loci (h2 Metabolite-hits) for 309 lipids and