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1.
Sci Rep ; 11(1): 611, 2021 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436758

RESUMO

High blood pressure (BP) is a major risk factor for many noncommunicable diseases. The effect of mitochondrial DNA single-nucleotide polymorphisms (mtSNPs) on BP is less known than that of nuclear SNPs. We investigated the mitochondrial genetic determinants of systolic, diastolic, and mean arterial BP. MtSNPs were determined from peripheral blood by sequencing or with genome-wide association study SNP arrays in two independent Finnish cohorts, the Young Finns Study and the Finnish Cardiovascular Study, respectively. In total, over 4200 individuals were included. The effects of individual common mtSNPs, with an additional focus on sex-specificity, and aggregates of rare mtSNPs grouped by mitochondrial genes were evaluated by meta-analysis of linear regression and a sequence kernel association test, respectively. We accounted for the predicted pathogenicity of the rare variants within protein-encoding and the tRNA regions. In the meta-analysis of 87 common mtSNPs, we did not observe significant associations with any of the BP traits. Sex-specific and rare-variant analyses did not pinpoint any significant associations either. Our results are in agreement with several previous studies suggesting that mtDNA variation does not have a significant role in the regulation of BP. Future studies might need to reconsider the mechanisms thought to link mtDNA with hypertension.

2.
Int J Cardiol Heart Vasc ; 31: 100639, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33015317

RESUMO

Background: Intraventricular conduction delays (IVCDs) are hallmarks of heart failure (HF) and structural heart disease (SHD) but their prognostic value for HF and SHD is unclear. Methods: Relation of eight IVCDs and the incidence of first-time HF or SHD was studied in a nationally representative random sample of 6080 Finnish subjects aged ≥ 30 years (mean age 52.1, SD 14.5 years) who participated in the health examination including 12-lead ECG. Results: During 16.5 years' follow up, half of the subjects with left bundle branch block (LBBB) and one third of the subjects with non-specific IVCD developed HF. After controlling for known clinical risk factors the hazard ratio (HR) for new-onset HF for LBBB was 3.29 (95% confidence interval 1.93-5.63, P < 0.001) and 3.53 for non-specific IVCD (1.65-7.55, P = 0.001). In corresponding analysis, LBBB predicted SHD with HR 2.60 (1.21-5.62, P = 0.015). Excluding subjects with history of heart disease, including coronary heart disease, did not have impact on results. Right bundle branch block and other IVCDs displayed no relation to endpoints. Conclusion: LBBB and non-specific IVCD were associated with more than three-fold risk of new-onset HF. Furthermore, LBBB was associated with novel SHD. Their presence should alert clinician even in subjects free from any known heart disease.

3.
Ann Noninvasive Electrocardiol ; : e12799, 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32975832

RESUMO

BACKGROUND: Inverted T waves in the electrocardiogram (ECG) have been associated with coronary heart disease (CHD) and mortality. The pathophysiology and prognostic significance of T-wave inversion may differ between different anatomical lead groups, but scientific data related to this issue is scarce. METHODS: A representative sample of Finnish subjects (n = 6,354) aged over 30 years underwent a health examination including a 12-lead ECG in the Health 2000 survey. ECGs with T-wave inversions were divided into three anatomical lead groups (anterior, lateral, and inferior) and were compared to ECGs with no pathological T-wave inversions in multivariable-adjusted Fine-Gray and Cox regression hazard models using CHD and mortality as endpoints. RESULTS: The follow-up for both CHD and mortality lasted approximately fifteen years (median value with interquartile ranges between 14.9 and 15.3). In multivariate-adjusted models, anterior and lateral (but not inferior) T-wave inversions associated with increased risk of CHD (HR: 2.37 [95% confidence interval 1.20-4.68] and 1.65 [1.27-2.15], respectively). In multivariable analyses, only lateral T-wave inversions associated with increased risk of mortality in the entire study population (HR 1.51 [1.26-1.81]) as well as among individuals with no CHD at baseline (HR 1.59 [1.29-1.96]). CONCLUSIONS: The prognostic information of inverted T waves differs between anatomical lead groups. T-wave inversion in the anterior and lateral lead groups is independently associated with the risk of CHD, and lateral T-wave inversion is also associated with increased risk of mortality. Inverted T wave in the inferior lead group proved to be a benign phenomenon.

4.
Diabetes ; 69(12): 2806-2818, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32917775

RESUMO

Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.

5.
Ann Noninvasive Electrocardiol ; : e12788, 2020 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-32804416

RESUMO

BACKGROUND: Previous population studies have presented conflicting results regarding the prognostic impact of intraventricular conduction delays (IVCD). METHODS: We studied long-term prognostic impact and the association with comorbidities of eight IVCDs in a random sample of 6,299 Finnish subjects (2,857 men and 3,442 women, mean age 52.8, SD 14.9 years) aged 30 or over who participated in the health examination including 12-lead ECG. For left bundle branch block (LBBB) and non-specific IVCD (NSIVCD), two different definitions were used. RESULTS: During 16.5 years' follow-up, 1,309 of the 6,299 subjects (20.8%) died and of these 655 (10.4%) were cardiovascular (CV) deaths. After controlling for known clinical risk factors, the hazard ratio for CV death, compared with individuals without IVCD, was 1.55 for the Minnesota definition of LBBB (95% confidence interval 1.04-2.31, p = .032) and 1.27 (95% confidence interval 0.80-2.02, p = .308) for the Strauss' definition of LBBB. Subjects with NSIVCD were associated with twofold to threefold increase in CV mortality depending on the definition. While right bundle branch block, left anterior fascicular block and incomplete bundle branch blocks were associated with seemingly higher mortality, this was no longer the case after adjustment for age and sex. The presence of R-R' pattern was not associated with any adverse outcome. CONCLUSIONS: In a population study with long-term follow-up, NSIVCD and Minnesota definition of LBBB were independently associated with CV mortality. Other IVCDs had no significant impact on prognosis. The prognostic impact of LBBB and NSIVCD was affected by the definition of the conduction disorder.

6.
Circulation ; 142(6): 546-555, 2020 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-32654539

RESUMO

BACKGROUND: Studies examining the role of factor V Leiden among patients at higher risk of atherothrombotic events, such as those with established coronary heart disease (CHD), are lacking. Given that coagulation is involved in the thrombus formation stage on atherosclerotic plaque rupture, we hypothesized that factor V Leiden may be a stronger risk factor for atherothrombotic events in patients with established CHD. METHODS: We performed an individual-level meta-analysis including 25 prospective studies (18 cohorts, 3 case-cohorts, 4 randomized trials) from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) consortium involving patients with established CHD at baseline. Participating studies genotyped factor V Leiden status and shared risk estimates for the outcomes of interest using a centrally developed statistical code with harmonized definitions across studies. Cox proportional hazards regression models were used to obtain age- and sex-adjusted estimates. The obtained estimates were pooled using fixed-effect meta-analysis. The primary outcome was composite of myocardial infarction and CHD death. Secondary outcomes included any stroke, ischemic stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality. RESULTS: The studies included 69 681 individuals of whom 3190 (4.6%) were either heterozygous or homozygous (n=47) carriers of factor V Leiden. Median follow-up per study ranged from 1.0 to 10.6 years. A total of 20 studies with 61 147 participants and 6849 events contributed to analyses of the primary outcome. Factor V Leiden was not associated with the combined outcome of myocardial infarction and CHD death (hazard ratio, 1.03 [95% CI, 0.92-1.16]; I2=28%; P-heterogeneity=0.12). Subgroup analysis according to baseline characteristics or strata of traditional cardiovascular risk factors did not show relevant differences. Similarly, risk estimates for the secondary outcomes including stroke, coronary revascularization, cardiovascular mortality, and all-cause mortality were also close to identity. CONCLUSIONS: Factor V Leiden was not associated with increased risk of subsequent atherothrombotic events and mortality in high-risk participants with established and treated CHD. Routine assessment of factor V Leiden status is unlikely to improve atherothrombotic events risk stratification in this population.

7.
Blood Press ; 29(6): 362-369, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32597238

RESUMO

PURPOSE: To study whether systemic hemodynamics, especially systemic vascular resistance, predicts the development of hypertension and improves the risk prediction of incident hypertension beyond common risk factors in the risk models in young adults. MATERIALS AND METHODS: Typical risk factors for hypertension in the risk prediction models (systolic and diastolic blood pressure, parental history of hypertension, age, sex, body-mass index, smoking), laboratory values (high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, glucose, insulin, C-reactive protein), heart rate (HR), stroke index (SI), and systemic vascular resistance index (SVRI) calculated by whole-body impedance cardiography were evaluated in 2007 and blood pressure in 2011 in 1293 Finnish adults (aged 30-45 years; females 56%; n = 1058 normotensive in 2007). RESULTS: Of hemodynamic variables, SVRI and HR evaluated in 2007 were independently associated with systolic blood pressure (p < 0.001 and p = 0.047, respectively) and SVRI with diastolic blood pressure measured in 2011 (p = 0.014), and SVRI and HR were independent predictors of incident hypertension (p < 0.001 and p = 0.024, respectively). SVRI was the most significant predictor of incident hypertension independently of other risk factors (odds ratio 2.73 per 1 standard deviation increase, 95% confidence interval 1.93-3.94, p < 0.001). The extended prediction model (including SVRI) improved the incident hypertension risk prediction beyond other risk factors, with an area under the receiver operating characteristic curve of 0.846 versus 0.817 (p = 0.042) and a continuous net reclassification improvement of 0.734 (p < 0.001). CONCLUSIONS: These findings suggest that systemic vascular resistance index predicts the incidence of hypertension in young adults and that the evaluation of systemic hemodynamics could provide an additional tool for hypertension risk prediction.

8.
Scand J Clin Lab Invest ; 80(5): 370-374, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32491935

RESUMO

Coronary artery and peripheral artery diseases represent different clinical outcomes of atherosclerosis and despite sharing common risk factors the ultimate reasons determining disease presentation are still unclear. The present study sought to define and compare the serum lipid and apolipoprotein profiles of patients undergoing coronary artery bypass grafting and those treated invasively for symptomatic lower extremity peripheral artery disease. Altogether 218 coronary and 280 peripheral artery disease patients treated between 2013 and 2014 in the Tampere University Hospital, Tampere, Finland, with available lipid measurements within two years prior to the intervention were retrospectively analysed. The Extended Friedewald formula neural network model was used to obtain apolipoprotein and lipoprotein subfraction values. Patients undergoing coronary artery bypass surgery had a clear male predominance (82% versus 53%, p < 0.001), lower median age (69 versus 74 years, p < 0.001) and a lower prevalence of smoking (18% versus 32%, p = 0.001) and pulmonary disease (12% versus 20%, p = 0.023) compared to peripheral artery disease patients. There were some differences in the serum lipid profiles between the study groups in the univariable analyses. When controlling for the statistically significant differences in age, sex, urgency of treatment and comorbidities between the groups in a multivariable logistic regression model, higher serum concentrations of apolipoprotein A-I were significantly and independently associated with coronary artery disease (OR 1.11 for 0.01 g/L increase, p = 0.044). In conclusion, patients undergoing coronary artery bypass grafting appear to have higher apolipoprotein A-I levels when compared to patients treated for peripheral artery disease.

9.
Mol Psychiatry ; 2020 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-32372009

RESUMO

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10-8). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.

10.
Ann Med ; 52(3-4): 63-73, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32077319

RESUMO

Introduction: Partial and advanced interatrial block (IAB) in the electrocardiographic (ECG) represents inter-atrial conduction delay. IAB is associated with atrial fibrillation (AF) and stroke in the general population.Material and methods: A representative sample of Finnish subjects (n = 6354) aged over 30 years (mean: 52.2 years, standard deviation: 14.6) underwent a health examination including a 12-lead ECG. Five different IAB groups based on automatic measurements were compared to normal P waves using multivariate-adjusted Cox proportional hazard model. Follow-up lasted up to 15 years.Results: The prevalence of advanced and partial IAB was 1.0% and 9.7%, respectively. In the multivariate model, both advanced (hazard ratio (HR): 1.63 (95% confidence interval (CI): 1.00-2.65)) and partial IAB (HR: 1.39 (1.09-1.77)) were associated with increased risk of AF. Advanced IAB was associated with increased risk of stroke or transient ischaemic attack (TIA) independently of associated AF (HR: 2.22 (1.20-4.13)). Partial IAB was also associated with increased risk of being diagnosed with coronary heart disease (HR: 1.26 (1.01-1.58)).Discussion: IAB is a rather frequent finding in the general population. IAB is a risk factor for AF and is associated with an increased risk of stroke or TIA independently of associated AF.Key messagesBoth partial and advanced interatrial block are associated with increased risk of atrial fibrillation in the general population.Advanced interatrial block is an independent risk factor for stroke and transient ischaemic attack.The clinical significance of interatrial block is dependent on the subtype classification.

11.
J Electrocardiol ; 58: 176-183, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31911397

RESUMO

BACKGROUND: Even minor ST depression in the electrocardiogram (ECG) is associated with cardiovascular disease and increased mortality. There is limited data on the prognostic significance of ST-level changes in the general population. SUBJECTS AND METHODS: A random sample of Finnish subjects (n = 6354) aged over 30 years (56.1% women) underwent a health examination including a 12­lead ECG in the Health 2000 survey. The effects of relative ST level as a continuous variable and ST slope (upsloping, horizontal, downsloping) in three different lead groups were analyzed using a multi-adjusted Cox proportional hazard model separately for men and women with total mortality as endpoint. RESULTS: The follow-up lasted for 13.7 (SD 3.3) years for men and 13.9 (SD 3.1) years for women. Lower lateral ST levels were associated with all-cause mortality in multi-adjusted models in both genders (at J + 80 ms hazard ratio [HR] 0.64 for a change of 1.0 mm [95% confidence interval 0.49-0.84, p = 0.002] for men and HR 0.61 [0.48-0.78, p < 0.001] for women). Associated coronary heart disease had no major influence on the results. Exclusion of subjects with ECG signs of left ventricular hypertrophy from the analyses increased the mortality risk of lower lateral ST levels in men but decreased it in women. For the anterior and inferior lead groups, no statistically significant difference was seen after multivariate adjustment. ST slope was not an independent predictor of mortality after multivariate adjustment. CONCLUSION: Lower ST level in the lateral ECG leads is an independent prognostic factor to predict all-cause mortality in the general population.

12.
Mol Psychiatry ; 25(10): 2275-2294, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-30279457

RESUMO

Experimental studies of learning suggest that human temperament may depend on the molecular mechanisms for associative conditioning, which are highly conserved in animals. The main genetic pathways for associative conditioning are known in experimental animals, but have not been identified in prior genome-wide association studies (GWAS) of human temperament. We used a data-driven machine learning method for GWAS to uncover the complex genotypic-phenotypic networks and environmental interactions related to human temperament. In a discovery sample of 2149 healthy Finns, we identified sets of single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (i.e., SNP sets) regardless of phenotype. Second, we identified 3 clusters of people with distinct temperament profiles measured by the Temperament and Character Inventory regardless of genotype. Third, we found 51 SNP sets that identified 736 gene loci and were significantly associated with temperament. The identified genes were enriched in pathways activated by associative conditioning in animals, including the ERK, PI3K, and PKC pathways. 74% of the identified genes were unique to a specific temperament profile. Environmental influences measured in childhood and adulthood had small but significant effects. We confirmed the replicability of the 51 Finnish SNP sets in healthy Korean (90%) and German samples (89%), as well as their associations with temperament. The identified SNPs explained nearly all the heritability expected in each sample (37-53%) despite variable cultures and environments. We conclude that human temperament is strongly influenced by more than 700 genes that modulate associative conditioning by molecular processes for synaptic plasticity and long-term memory.

13.
Mol Psychiatry ; 25(10): 2295-2312, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-30283034

RESUMO

Human personality is 30-60% heritable according to twin and adoption studies. Hundreds of genetic variants are expected to influence its complex development, but few have been identified. We used a machine learning method for genome-wide association studies (GWAS) to uncover complex genotypic-phenotypic networks and environmental interactions. The Temperament and Character Inventory (TCI) measured the self-regulatory components of personality critical for health (i.e., the character traits of self-directedness, cooperativeness, and self-transcendence). In a discovery sample of 2149 healthy Finns, we identified sets of single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (i.e., SNP sets) regardless of phenotype. Second, we identified five clusters of people with distinct profiles of character traits regardless of genotype. Third, we found 42 SNP sets that identified 727 gene loci and were significantly associated with one or more of the character profiles. Each character profile was related to different SNP sets with distinct molecular processes and neuronal functions. Environmental influences measured in childhood and adulthood had small but significant effects. We confirmed the replicability of 95% of the 42 SNP sets in healthy Korean and German samples, as well as their associations with character. The identified SNPs explained nearly all the heritability expected for character in each sample (50 to 58%). We conclude that self-regulatory personality traits are strongly influenced by organized interactions among more than 700 genes despite variable cultures and environments. These gene sets modulate specific molecular processes in brain for intentional goal-setting, self-reflection, empathy, and episodic learning and memory.

14.
Scand Cardiovasc J ; 54(3): 146-152, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31775530

RESUMO

Objectives. Acute coronary syndrome (ACS) is associated with high mortality. Charlson comorbidity index (CCI) was designed over 30 years ago to measure the impact of pre-existing comorbidities on long-term survival of the patient. We wanted to re-evaluate the performance of CCI and its components in modern setting. Design. This is a retrospective study of 1576 consecutive patients undergoing invasive evaluation and treated for ACS in single tertiary center between 2015-2016. Mortality was analyzed in timeframes of 1, 6 and 24 months. CCI-scores were retrieved from written medical records and complimented with data from electronic sources. The performance of CCI and its components was compared to the GRACE-score measuring patients' status upon hospital admission. Results. Population mean age at baseline was 69.3 (SD 11.8) years and 69.1% of the patients were male (n = 1089). Most of the components of CCI associated significantly with mortality at all timeframes despite adjusting for age but only diabetes and congestive heart failure associated with mortality at all time points after adjusting for GRACE-score. CCI associated with mortality [GRACE adjusted HR-values of single unit increase of CCI after 1, 6 and 24-month follow-up: 1.12(95% CI:1.00-1.25), 1.17(1.07-1.29) and 1.24(1.16-1.33)]. CCI performed modestly with its AUC-values ranging between 0.755 and 0.784, with prognostic performance increasing with longer follow-up. Adding components of CCI did not significantly improve risk prediction over GRACE-score. Conclusions. In conclusion, CCI or its individual components measuring the impact of comorbidities on overall mortality does not provide any significant value compared to GRACE-score during up to 2 years of follow-up.


Assuntos
Síndrome Coronariana Aguda/mortalidade , Técnicas de Apoio para a Decisão , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/terapia , Idoso , Idoso de 80 Anos ou mais , Comorbidade , Feminino , Finlândia/epidemiologia , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo
15.
Heart ; 106(6): 434-440, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31422363

RESUMO

OBJECTIVE: To evaluate whether cardiorespiratory fitness (CRF) and heart rate recovery (HRR) associate with the risk of sudden cardiac death (SCD) independently of left ventricular ejection fraction (LVEF). METHODS: The Finnish Cardiovascular Study is a prospective clinical study of patients referred to clinical exercise testing in 2001-2008 and follow-up until December 2013. Patients without pacemakers undergoing first maximal or submaximal exercise testing with cycle ergometer were included (n=3776). CRF in metabolic equivalents (METs) was estimated by achieving maximal work level. HRR was defined as the reduction in heart rate 1 min after maximal exertion. Adjudication of SCD was based on death certificates. LVEF was measured for clinical indications in 71.4% of the patients (n=2697). RESULTS: Population mean age was 55.7 years (SD 13.1; 61% men). 98 SCDs were recorded during a median follow-up of 9.1 years (6.9-10.7). Mean CRF and HRR were 7.7 (SD 2.9) METs and 25 (SD 12) beats/min/min. Both CRF and HRR were associated with the risk of SCD in the entire study population (HRCRF0.47 (0.37-0.59), p<0.001 and HRHRR0.57 (0.48-0.67), p<0.001 with HR estimates corresponding to one SD increase in the exposure variables) and with CRF, HRR and LVEF in the same model (HRCRF0.60 (0.45-0.79), p<0.001, HRHRR0.65 (0.51-0.82), p<0.001) or adjusting additionally for all significant risk factors for SCD (LVEF, sex, creatinine level, history of myocardial infarction and atrial fibrillation, corrected QT interval) (HRCRF0.69 (0.52-0.93), p<0.01, HRHRR0.74 (0.58-0.95) p=0.02). CONCLUSIONS: CRF and HRR are significantly associated with the risk of SCD regardless of LVEF.


Assuntos
Aptidão Cardiorrespiratória , Morte Súbita Cardíaca/epidemiologia , Frequência Cardíaca , Volume Sistólico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Medição de Risco , Fatores de Risco
16.
Bioinformatics ; 36(6): 1772-1778, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31702773

RESUMO

MOTIVATION: Selecting the optimal machine learning (ML) model for a given dataset is often challenging. Automated ML (AutoML) has emerged as a powerful tool for enabling the automatic selection of ML methods and parameter settings for the prediction of biomedical endpoints. Here, we apply the tree-based pipeline optimization tool (TPOT) to predict angiographic diagnoses of coronary artery disease (CAD). With TPOT, ML models are represented as expression trees and optimal pipelines discovered using a stochastic search method called genetic programing. We provide some guidelines for TPOT-based ML pipeline selection and optimization-based on various clinical phenotypes and high-throughput metabolic profiles in the Angiography and Genes Study (ANGES). RESULTS: We analyzed nuclear magnetic resonance-derived lipoprotein and metabolite profiles in the ANGES cohort with a goal to identify the role of non-obstructive CAD patients in CAD diagnostics. We performed a comparative analysis of TPOT-generated ML pipelines with selected ML classifiers, optimized with a grid search approach, applied to two phenotypic CAD profiles. As a result, TPOT-generated ML pipelines that outperformed grid search optimized models across multiple performance metrics including balanced accuracy and area under the precision-recall curve. With the selected models, we demonstrated that the phenotypic profile that distinguishes non-obstructive CAD patients from no CAD patients is associated with higher precision, suggesting a discrepancy in the underlying processes between these phenotypes. AVAILABILITY AND IMPLEMENTATION: TPOT is freely available via http://epistasislab.github.io/tpot/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.


Assuntos
Doença da Artéria Coronariana , Humanos , Aprendizado de Máquina , Metaboloma , Metabolômica
17.
Hypertension ; 75(2): 365-371, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31865795

RESUMO

We aimed to characterize the genetics of endothelial function and how this influences risk for cardiovascular diseases such as ischemic stroke. We integrated genetic data from a study of ultrasound flow-mediated dilatation of brachial artery in adolescents from ALSPAC (Avon Longitudinal Study of Parents and Children; n=5214) with a study of ischemic stroke (MEGASTROKE: n=60 341 cases and 452 969 controls) to identify variants that confer risk of ischemic stroke through altered endothelial function. We identified a variant in PDE3A (Phosphodiesterase 3A), encoding phosphodiesterase 3A, which was associated with flow-mediated dilatation in adolescents (9-12 years of age; ß[SE], 0.38 [0.070]; P=3.8×10-8) and confers risk of ischemic stroke (odds ratio, 1.04 [95% CI, 1.02-1.06]; P=5.2×10-6). Bayesian colocalization analyses showed the same underlying variation is likely to lead to both associations (posterior probability, 97%). The same variant was associated with flow-mediated dilatation in a second study in young adults (age, 24-27 years; ß[SE], 0.47 [0.23]; P=0.047) but not in older adults (ß[SE], -0.012 [0.13]; P=0.89). We conclude that a genetic variant in PDE3A influences endothelial function in early life and leads to increased risk of ischemic stroke. Subtle, measurable changes to the vasculature that are influenced by genetics also influence risk of ischemic stroke.


Assuntos
Isquemia Encefálica/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/genética , Endotélio Vascular/fisiopatologia , Predisposição Genética para Doença , Hipertensão/genética , Polimorfismo de Nucleotídeo Único , Vasodilatação/fisiologia , Adolescente , Adulto , Isquemia Encefálica/etiologia , Criança , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Feminino , Seguimentos , Variação Genética , Humanos , Hipertensão/complicações , Hipertensão/metabolismo , Masculino , Pessoa de Meia-Idade , Gravidez , Complicações Cardiovasculares na Gravidez/genética , Complicações Cardiovasculares na Gravidez/metabolismo , Complicações Cardiovasculares na Gravidez/fisiopatologia , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
18.
PLoS One ; 14(12): e0225621, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31821324

RESUMO

Markers in monocytes, precursors of macrophages, which are related to CAD, are largely unknown. Therefore, we aimed to identify genes in monocytes predictive of a new ischemic event in patients with CAD and/or discriminate between stable CAD and acute coronary syndrome. We included 66 patients with stable CAD, of which 24 developed a new ischemic event, and 19 patients with ACS. Circulating CD14+ monocytes were isolated with magnetic beads. RNA sequencing analysis in monocytes of patients with (n = 13) versus without (n = 11) ischemic event at follow-up and in patients with ACS (n = 12) was validated with qPCR (n = 85). MT-COI, STRN and COX10 predicted new ischemic events in CAD patients (power for separation at 1% error rate of 0.97, 0.90 and 0.77 respectively). Low MT-COI and high STRN were also related to shorter time between blood sampling and event. COX10 and ZNF484 together with MT-COI, STRN and WNK1 separated ACS completely from stable CAD patients. RNA expressions in monocytes of MT-COI, COX10, STRN, WNK1 and ZNF484 were independent of cholesterol lowering and antiplatelet treatment. They were independent of troponin T, a marker of myocardial injury. But, COX10 and ZNF484 in human plaques correlated to plaque markers of M1 macrophage polarization, reflecting vascular injury. Expression of MT-COI, COX10, STRN and WNK1, but not that of ZNF484, PBMCs paired with that in monocytes. The prospective study of relation of MT-COI, COX10, STRN, WNK1 and ZNF484 with unstable CAD is warranted.


Assuntos
Síndrome Coronariana Aguda/diagnóstico , Proteínas de Ligação a Calmodulina/metabolismo , Doença da Artéria Coronariana/diagnóstico , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Placa Aterosclerótica/patologia , Proteína Quinase 1 Deficiente de Lisina WNK/metabolismo , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/patologia , Idoso , Alquil e Aril Transferases/sangue , Alquil e Aril Transferases/metabolismo , Biomarcadores/sangue , Biomarcadores/metabolismo , Proteínas de Ligação a Calmodulina/sangue , Colesterol/sangue , Angiografia Coronária , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/patologia , Diagnóstico Diferencial , Complexo IV da Cadeia de Transporte de Elétrons/sangue , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Feminino , Seguimentos , Humanos , Masculino , Proteínas de Membrana/sangue , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Monócitos/citologia , Monócitos/metabolismo , Proteínas do Tecido Nervoso/sangue , Placa Aterosclerótica/sangue , Estudos Prospectivos , RNA-Seq , Proteína Quinase 1 Deficiente de Lisina WNK/sangue
19.
Mol Psychiatry ; 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31748689

RESUMO

Phylogenetic, developmental, and brain-imaging studies suggest that human personality is the integrated expression of three major systems of learning and memory that regulate (1) associative conditioning, (2) intentionality, and (3) self-awareness. We have uncovered largely disjoint sets of genes regulating these dissociable learning processes in different clusters of people with (1) unregulated temperament profiles (i.e., associatively conditioned habits and emotional reactivity), (2) organized character profiles (i.e., intentional self-control of emotional conflicts and goals), and (3) creative character profiles (i.e., self-aware appraisal of values and theories), respectively. However, little is known about how these temperament and character components of personality are jointly organized and develop in an integrated manner. In three large independent genome-wide association studies from Finland, Germany, and Korea, we used a data-driven machine learning method to uncover joint phenotypic networks of temperament and character and also the genetic networks with which they are associated. We found three clusters of similar numbers of people with distinct combinations of temperament and character profiles. Their associated genetic and environmental networks were largely disjoint, and differentially related to distinct forms of learning and memory. Of the 972 genes that mapped to the three phenotypic networks, 72% were unique to a single network. The findings in the Finnish discovery sample were blindly and independently replicated in samples of Germans and Koreans. We conclude that temperament and character are integrated within three disjoint networks that regulate healthy longevity and dissociable systems of learning and memory by nearly disjoint sets of genetic and environmental influences.

20.
Am J Hum Genet ; 105(6): 1076-1090, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31679650

RESUMO

Cytokines are essential regulatory components of the immune system, and their aberrant levels have been linked to many disease states. Despite increasing evidence that cytokines operate in concert, many of the physiological interactions between cytokines, and the shared genetic architecture that underlies them, remain unknown. Here, we aimed to identify and characterize genetic variants with pleiotropic effects on cytokines. Using three population-based cohorts (n = 9,263), we performed multivariate genome-wide association studies (GWAS) for a correlation network of 11 circulating cytokines, then combined our results in meta-analysis. We identified a total of eight loci significantly associated with the cytokine network, of which two (PDGFRB and ABO) had not been detected previously. In addition, conditional analyses revealed a further four secondary signals at three known cytokine loci. Integration, through the use of Bayesian colocalization analysis, of publicly available GWAS summary statistics with the cytokine network associations revealed shared causal variants between the eight cytokine loci and other traits; in particular, cytokine network variants at the ABO, SERPINE2, and ZFPM2 loci showed pleiotropic effects on the production of immune-related proteins, on metabolic traits such as lipoprotein and lipid levels, on blood-cell-related traits such as platelet count, and on disease traits such as coronary artery disease and type 2 diabetes.


Assuntos
Biomarcadores/análise , Doenças Cardiovasculares/genética , Citocinas/genética , Pleiotropia Genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Adolescente , Adulto , Idoso , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/imunologia , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/patologia , Criança , Citocinas/imunologia , Feminino , Seguimentos , Redes Reguladoras de Genes , Predisposição Genética para Doença , Genoma Humano , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Adulto Jovem
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