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1.
Heart ; 2019 Aug 17.
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.

2.
Nat Hum Behav ; 3(9): 950-961, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31358974

RESUMO

Excessive alcohol consumption is one of the main causes of death and disability worldwide. Alcohol consumption is a heritable complex trait. Here we conducted a meta-analysis of genome-wide association studies of alcohol consumption (g d-1) from the UK Biobank, the Alcohol Genome-Wide Consortium and the Cohorts for Heart and Aging Research in Genomic Epidemiology Plus consortia, collecting data from 480,842 people of European descent to decipher the genetic architecture of alcohol intake. We identified 46 new common loci and investigated their potential functional importance using magnetic resonance imaging data and gene expression studies. We identify genetic pathways associated with alcohol consumption and suggest genetic mechanisms that are shared with neuropsychiatric disorders such as schizophrenia.

3.
J Am Coll Cardiol ; 73(24): 3118-3131, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31221261

RESUMO

BACKGROUND: Subclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions. OBJECTIVES: This study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population. METHODS: Summary results collected from 153,014 individuals (54.4% women; mean age 55.1 ± 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs. RESULTS: Lower calcium was associated with longer QT intervals (-11.5 ms; 99.75% confidence interval [CI]: -13.7 to -9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (-2.8 ms; 99.75% CI: -3.5 to -2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals. CONCLUSIONS: The study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to clinically relevant QT prolongation by >5 ms.

4.
Sci Rep ; 9(1): 8887, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31222113

RESUMO

We analyzed the associations between whole blood microRNA profiles and the indices of glucose metabolism and impaired fasting glucose and examined whether the discovered microRNAs correlate with the expression of their mRNA targets. MicroRNA and gene expression profiling were performed for the Young Finns Study participants (n = 871). Glucose, insulin, and glycated hemoglobin (HbA1c) levels were measured, the insulin resistance index (HOMA2-IR) was calculated, and the glycemic status (normoglycemic [n = 534]/impaired fasting glucose [IFG] [n = 252]/type 2 diabetes [T2D] [n = 24]) determined. Levels of hsa-miR-144-5p, -122-5p, -148a-3p, -589-5p, and hsa-let-7a-5p associated with glycemic status. hsa-miR-144-5p and -148a-3p associated with glucose levels, while hsa-miR-144-5p, -122-5p, -184, and -339-3p associated with insulin levels and HOMA2-IR, and hsa-miR-148a-3p, -15b-3p, -93-3p, -146b-5p, -221-3p, -18a-3p, -642a-5p, and -181-2-3p associated with HbA1c levels. The targets of hsa-miR-146b-5p that correlated with its levels were enriched in inflammatory pathways, and the targets of hsa-miR-221-3p were enriched in insulin signaling and T2D pathways. These pathways showed indications of co-regulation by HbA1c-associated miRNAs. There were significant differences in the microRNA profiles associated with glucose, insulin, or HOMA-IR compared to those associated with HbA1c. The HbA1c-associated miRNAs also correlated with the expression of target mRNAs in pathways important to the development of T2D.

5.
Nat Genet ; 51(5): 804-814, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043758

RESUMO

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.


Assuntos
Peso ao Nascer/genética , Adulto , Pressão Sanguínea/genética , Estatura/genética , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Feminino , Desenvolvimento Fetal/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cardiopatias/etiologia , Cardiopatias/genética , Humanos , Recém-Nascido , Masculino , Herança Materna/genética , Troca Materno-Fetal/genética , Doenças Metabólicas/etiologia , Doenças Metabólicas/genética , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Gravidez , Fatores de Risco
6.
Ann Med ; 51(2): 156-163, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31030570

RESUMO

Objective: Investigation of the clinical potential of extensive phenotype data and machine learning (ML) in the prediction of mortality in acute coronary syndrome (ACS). Methods: The value of ML and extensive clinical data was analyzed in a retrospective registry study of 9066 consecutive ACS patients (January 2007 to October 2017). Main outcome was six-month mortality. Prediction models were developed using two ML methods, logistic regression and extreme gradient boosting (xgboost). The models were fitted in training set of patients treated in 2007-2014 and 2017 (81%, n = 7344) and validated in a separate validation set of patients treated in 2015-2016 with full GRACE score data available for comparison of model accuracy (19%, n = 1722). Results: Overall, six-month mortality was 7.3% (n = 660). Several variables were found to be significantly associated with six-month mortality by both ML methods. The xgboost scored the best performance: AUC 0.890 (0.864-0.916). The AUC values for logistic regression and GRACE score were 0.867(0.837-0.897) and 0.822 (0.785-0.859), respectively. The AUC value of xgboost was better when compared to logistic regression (p = .012) and GRACE score (p < .00001). Conclusions: The use of extensive phenotype data and novel machine learning improves prediction of mortality in ACS over traditional GRACE score. KEY MESSAGES The collection of extensive cardiovascular phenotype data from electronic health records as well as from data recorded by physicians can be used highly effectively in prediction of mortality after acute coronary syndrome. Supervised machine learning methods such as logistic regression and extreme gradient boosting using extensive phenotype data significantly outperform conventional risk assessment by the current golden standard GRACE score. Integration of electronic health records and the use of supervised machine learning methods can be easily applied in a single centre level to model the risk of mortality.

7.
Circ Genom Precis Med ; 12(4): e002470, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30896328

RESUMO

BACKGROUND: The Genetics of Subsequent Coronary Heart Disease (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers for risk of subsequent CHD events, in individuals with established CHD. METHODS: The consortium currently includes 57 studies from 18 countries, recruiting 185 614 participants with either acute coronary syndrome, stable CHD, or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events. RESULTS: Enrollment into the individual studies took place between 1985 to present day with a duration of follow-up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (hazard ratio, 1.15; 95% CI, 1.14-1.16) per 5-year increase, male sex (hazard ratio, 1.17; 95% CI, 1.13-1.21) and smoking (hazard ratio, 1.43; 95% CI, 1.35-1.51) with risk of subsequent CHD death or myocardial infarction and differing associations with other individual and composite cardiovascular endpoints. CONCLUSIONS: GENIUS-CHD is a global collaboration seeking to elucidate genetic and nongenetic determinants of subsequent event risk in individuals with established CHD, to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.

8.
Circ Genom Precis Med ; 12(4): e002471, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30897348

RESUMO

BACKGROUND: Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions about its value for stratification of residual risk. METHODS: A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103 357 Europeans with established CHD at baseline from the GENIUS-CHD (Genetics of Subsequent Coronary Heart Disease) Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/myocardial infarction), occurred in 13 040 of the 93 115 participants with available outcome data. Effect estimates were compared with case/control risk obtained from the CARDIoGRAMplusC4D consortium (Coronary Artery Disease Genome-wide Replication and Meta-analysis [CARDIoGRAM] plus The Coronary Artery Disease [C4D] Genetics) including 47 222 CHD cases and 122 264 controls free of CHD. RESULTS: Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/myocardial infarction among those with established CHD at baseline (GENIUS-CHD odds ratio, 1.02; 95% CI, 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D odds ratio 1.20; 95% CI, 1.18-1.22; P for interaction <0.001 compared with the GENIUS-CHD estimate. Similarly, no clear associations were identified for additional subsequent outcomes, including all-cause death, although we found a modest positive association between chromosome 9p21 and subsequent revascularization (odds ratio, 1.07; 95% CI, 1.04-1.09). CONCLUSIONS: In contrast to studies comparing individuals with CHD to disease-free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

10.
Eur J Hum Genet ; 27(6): 952-962, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30679814

RESUMO

Genome-wide association studies (GWAS) of quantitative electrocardiographic (ECG) traits in large consortia have identified more than 130 loci associated with QT interval, QRS duration, PR interval, and heart rate (RR interval). In the current study, we meta-analyzed genome-wide association results from 30,000 mostly Dutch samples on four ECG traits: PR interval, QRS duration, QT interval, and RR interval. SNP genotype data was imputed using the Genome of the Netherlands reference panel encompassing 19 million SNPs, including millions of rare SNPs (minor allele frequency < 5%). In addition to many known loci, we identified seven novel locus-trait associations: KCND3, NR3C1, and PLN for PR interval, KCNE1, SGIP1, and NFKB1 for QT interval, and ATP2A2 for QRS duration, of which six were successfully replicated. At these seven loci, we performed conditional analyses and annotated significant SNPs (in exons and regulatory regions), demonstrating involvement of cardiac-related pathways and regulation of nearby genes.

11.
Hum Mol Genet ; 28(8): 1381-1391, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30629177

RESUMO

The effect of mitochondrial DNA (mtDNA) variation on peripheral blood transcriptomics in health and disease is not fully known. Sex-specific mitochondrially controlled gene expression patterns have been shown in Drosophila melanogaster but in humans, evidence is lacking. Functional variation in mtDNA may also have a role in the development of type 2 diabetes and its precursor state, i.e. prediabetes. We examined the associations between mitochondrial single-nucleotide polymorphisms (mtSNPs) and peripheral blood transcriptomics with a focus on sex- and prediabetes-specific effects. The genome-wide blood cell expression data of 19 637 probes, 199 deep-sequenced mtSNPs and nine haplogroups of 955 individuals from a population-based Young Finns Study cohort were used. Significant associations were identified with linear regression and analysis of covariance. The effects of sex and prediabetes on the associations between gene expression and mtSNPs were studied using random-effect meta-analysis. Our analysis identified 53 significant expression probe-mtSNP associations after Bonferroni correction, involving 7 genes and 31 mtSNPs. Eight probe-mtSNP signals remained independent after conditional analysis. In addition, five genes showed differential expression between haplogroups. The meta-analysis did not show any significant differences in linear model effect sizes between males and females but identified the association between the OASL gene and mtSNP C16294T to show prediabetes-specific effects. This study pinpoints new independent mtSNPs associated with peripheral blood transcriptomics and replicates six previously reported associations, providing further evidence of the mitochondrial genetic control of blood cell gene expression. In addition, we present evidence that prediabetes might lead to perturbations in mitochondrial control.


Assuntos
DNA Mitocondrial/genética , Regulação da Expressão Gênica/genética , Adulto , Sequência de Bases , Células Sanguíneas/metabolismo , Células Sanguíneas/fisiologia , DNA Mitocondrial/sangue , Diabetes Mellitus Tipo 2/genética , Feminino , Expressão Gênica , Estudos de Associação Genética/métodos , Variação Genética/genética , Genética Populacional/métodos , Estudo de Associação Genômica Ampla/métodos , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias/genética , Polimorfismo de Nucleotídeo Único/genética , Análise de Sequência de DNA , Transcriptoma/genética
12.
Eur J Vasc Endovasc Surg ; 57(3): 331-338, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30583960

RESUMO

OBJECTIVE/BACKGROUND: Sarcopenia is a predictor of mortality in elderly patients. Masseter area (MA) reflects sarcopenia in trauma patients. It was hypothesised that MA and Masseter density (MD) could be evaluated reliably from pre-operative computed tomography angiography (CTA) scans and that they predict post-operative survival in carotid endarterectomy (CEA) patients. METHODS: This was an observational registry study. Patients (n = 242) were operated on for asymptomatic stenosis (n = 32; 13.2%), amaurosis fugax (n = 41; 16.9%), transient ischaemic attack (n = 85; 35.1%), or ischaemic stroke (n = 84; 34.7%). Internal carotid artery stenoses were graded angiographically. Intraclass correlation coefficient (ICC) was used to analyse measurement reliability by three independent observers. Cox regression analysis was used to study the effect of MA and MD on survival (hazard ratio [HR]). RESULTS: Median patient age was 71.0 years (interquartile range [IQR] 13.0) and follow up time was 68.5 months (range 3-163 months); at the end of follow up (1 October 2017), 104 (43.0%) patients had died according to the National Population Register. The average MA (MAavg, the mean of left and right MA [median 394.0 mm2; IQR 110.1 mm2]) and MD (MDavg, the mean of left and right MD [median 53.5 HU; IQR 16.5 HU]) could be measured with excellent reliability (ICC > 0.865, p < .001 for all). In multivariable analyses only body surface area (BSA) (p < .001) and dental status were associated with MAavg (p = .021). Increased MAavg predicted lower mortality (HR 0.76, 95% confidence interval [CI] 0.61-0.96; p = .023) independent of age (HR 1.05, 95% CI 1.02-1.07; p = 0.001), female sex, body mass index, renal insufficiency, ipsilateral stenosis, indication category, and presence of teeth. MDavg was not associated with mortality. After further adjustment, BSA (the most significant determinant of MAavg) did not alter the association between MAavg and mortality (0.75, 95% CI 0.58-0.97; p = .031). CONCLUSION: Average MA but not MD measured from the pre-operative CTA scan provides a reliable estimate of post-operative long-term survival in CEA patients independent of other risk factors, anthropometric measurements, and dental status.


Assuntos
Estenose das Carótidas/diagnóstico por imagem , Estenose das Carótidas/cirurgia , Angiografia por Tomografia Computadorizada/métodos , Endarterectomia das Carótidas/efeitos adversos , Endarterectomia das Carótidas/métodos , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Músculo Masseter , Pessoa de Meia-Idade , Sistema de Registros , Reprodutibilidade dos Testes , Análise de Sobrevida , Resultado do Tratamento
13.
Circ Genom Precis Med ; 11(11): e002234, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30571186

RESUMO

BACKGROUND: Integration of systems-level biomolecular information with electronic health records has led to recent interest in the glycoprotein acetyls (GlycA) biomarker-a serum- or plasma-derived nuclear magnetic resonance spectroscopy signal that represents the abundance of circulating glycated proteins. GlycA predicts risk of diverse outcomes, including cardiovascular disease, type 2 diabetes mellitus, and all-cause mortality; however, the underlying detailed associations of GlycA's morbidity and mortality risk are currently unknown. METHODS: We used 2 population-based cohorts totaling 11 861 adults from the Finnish general population to test for an association with 468 common incident hospitalization and mortality outcomes during an 8-year follow-up. Further, we utilized 900 angiography patients to test for GlycA association with mortality risk and potential utility for mortality risk discrimination during 12-year follow-up. RESULTS: New associations with GlycA and incident alcoholic liver disease, chronic renal failure, glomerular diseases, chronic obstructive pulmonary disease, inflammatory polyarthropathies, and hypertension were uncovered, and known incident disease associations were replicated. GlycA associations for incident disease outcomes were in general not attenuated when adjusting for hsCRP (high-sensitivity C-reactive protein). Among 900 patients referred to angiography, GlycA had hazard ratios of 4.87 (95% CI, 2.45-9.65) and 5.00 (95% CI, 2.38-10.48) for 12-year risk of mortality in the fourth and fifth quintiles by GlycA levels, demonstrating its prognostic potential for identification of high-risk individuals. When modeled together, both hsCRP and GlycA were attenuated but remained significant. CONCLUSIONS: GlycA was predictive of myriad incident diseases across many major internal organs and stratified mortality risk in angiography patients. Both GlycA and hsCRP had shared and independent contributions to mortality risk, suggesting chronic inflammation as an etiological factor. GlycA may be useful in improving risk prediction in specific disease settings.


Assuntos
Ciências Biocomportamentais , Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Nefropatias , Angiografia por Ressonância Magnética , Adulto , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico por imagem , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Intervalo Livre de Doença , Feminino , Humanos , Nefropatias/sangue , Nefropatias/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Taxa de Sobrevida
14.
Am J Hum Genet ; 103(5): 691-706, 2018 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388399

RESUMO

C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10-8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

15.
Arterioscler Thromb Vasc Biol ; 38(11): 2562-2575, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30354245

RESUMO

Objective- Palmitoylethanolamide is an endogenous fatty acid mediator that is synthetized from membrane phospholipids by N-acyl phosphatidylethanolamine phospholipase D. Its biological actions are primarily mediated by PPAR-α (peroxisome proliferator-activated receptors α) and the orphan receptor GPR55. Palmitoylethanolamide exerts potent anti-inflammatory actions but its physiological role and promise as a therapeutic agent in chronic arterial inflammation, such as atherosclerosis remain unexplored. Approach and Results- First, the polarization of mouse primary macrophages towards a proinflammatory phenotype was found to reduce N-acyl phosphatidylethanolamine phospholipase D expression and palmitoylethanolamide bioavailability. N-acyl phosphatidylethanolamine phospholipase D expression was progressively downregulated in the aorta of apolipoprotein E deficient (ApoE-/-) mice during atherogenesis. N-acyl phosphatidylethanolamine phospholipase D mRNA levels were also downregulated in unstable human plaques and they positively associated with smooth muscle cell markers and negatively with macrophage markers. Second, ApoE-/- mice were fed a high-fat diet for 4 or 16 weeks and treated with either vehicle or palmitoylethanolamide (3 mg/kg per day, 4 weeks) to study the effects of palmitoylethanolamide on early established and pre-established atherosclerosis. Palmitoylethanolamide treatment reduced plaque size in early atherosclerosis, whereas in pre-established atherosclerosis, palmitoylethanolamide promoted signs of plaque stability as evidenced by reduced macrophage accumulation and necrotic core size, increased collagen deposition and downregulation of M1-type macrophage markers. Mechanistically, we found that palmitoylethanolamide, by activating GPR55, increases the expression of the phagocytosis receptor MerTK (proto-oncogene tyrosine-protein kinase MER) and enhances macrophage efferocytosis, indicative of proresolving properties. Conclusions- The present study demonstrates that palmitoylethanolamide protects against atherosclerosis by promoting an anti-inflammatory and proresolving phenotype of lesional macrophages, representing a new therapeutic approach to resolve arterial inflammation.

16.
Sci Rep ; 8(1): 15078, 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30305673

RESUMO

α-melanocyte-stimulating hormone (α-MSH) is processed from pro-opiomelanocortin (POMC) and mediates anti-inflammatory actions in leukocytes. α-MSH also promotes macrophage reverse cholesterol transport by inducing ATP-binding cassette transporters ABCA1 and ABCG1. Here we investigated the regulation of POMC and α-MSH expression in atherosclerosis. First, transcript levels of POMC and its processing enzymes were analyzed in human arterial plaques (n = 68) and non-atherosclerotic controls (n = 24) as well as in whole blood samples from coronary artery disease patients (n = 55) and controls (n = 45) by microarray. POMC expression was increased in femoral plaques compared to control samples as well as in unstable advanced plaques. α-MSH-producing enzyme, carboxypeptidase E, was down-regulated, whereas prolylcarboxypeptidase, an enzyme inactivating α-MSH, was up-regulated in unstable plaques compared to stable plaques, suggesting a possible reduction in intraplaque α-MSH levels. Second, immunohistochemical analyses revealed the presence of α-MSH in atherosclerotic plaques and its localization in macrophages and other cell types. Lastly, supporting the role of α-MSH in reverse cholesterol transport, POMC expression correlated with ABCA1 and ABCG1 in human plaque and whole blood samples. In conclusion, α-MSH is expressed in atherosclerotic plaques and its processing enzymes associate with plaque stability, suggesting that measures to enhance the local bioavailability of α-MSH might protect against atherosclerosis.

17.
Mol Psychiatry ; 2018 Oct 02.
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.

18.
Mol Psychiatry ; 2018 Oct 03.
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.

19.
Wellcome Open Res ; 3: 4, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30175238

RESUMO

Background: Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease. Methods: We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV 1), forced vital capacity (FVC) and the ratio of FEV 1 to FVC (FEV 1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. Results: We identified significant (P<2·8x10 -7) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs ( SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including TYRO3 and PLAU. Conclusions: Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

20.
Genome Biol ; 19(1): 87, 2018 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-30012220

RESUMO

BACKGROUND: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear. RESULTS: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction. CONCLUSIONS: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.


Assuntos
Proteínas ADAMTS/genética , Conexina 43/genética , Exoma , Loci Gênicos , Sistema de Condução Cardíaco/metabolismo , Miocárdio/metabolismo , Grupo com Ancestrais do Continente Africano , Animais , Eletrocardiografia , Grupo com Ancestrais do Continente Europeu , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Sistema de Condução Cardíaco/fisiopatologia , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Miocárdio/patologia , Fases de Leitura Aberta , Polimorfismo de Nucleotídeo Único , Sequenciamento Completo do Exoma
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