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PURPOSE OF REVIEW: There are no current drug therapies to limit abdominal aortic aneurysm (AAA) growth. This review summarizes evidence suggesting that inhibiting proprotein convertase subtilisin/kexin type 9 (PCSK9) may be a drug target to limit AAA growth. RECENT FINDINGS: Mendelian randomization studies suggest that raised LDL and non-HDL-cholesterol are causal in AAA formation. PCSK9 was reported to be upregulated in human AAA samples compared to aortic samples from organ donors. PCSK9 gain of function viral vectors promoted aortic expansion in C57BL/6 mice infused with angiotensin II. The effect of altering PCSK9 expression in the aortic perfusion elastase model was reported to be inconsistent. Mutations in the gene encoding PCSK9, which increase serum cholesterol, were associated with increased risk of human AAA. Patients with AAA also have a high risk of cardiovascular death, myocardial infarction and stroke. Recent research suggests that PCSK9 inhibition would substantially reduce the risk of these events. SUMMARY: Past research suggests that drugs that inhibit PCSK9 have potential as a novel therapy for AAA to both limit aneurysm growth and reduce risk of cardiovascular events. A large multinational randomized controlled trial is needed to test if PCSK9 inhibition limits AAA growth and cardiovascular events.
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OBJECTIVES: A paucity of point-of-care ultrasound (POCUS) databases limits machine learning (ML). Assess feasibility of training ML algorithms to visually estimate left ventricular ejection fraction (EF) from a subxiphoid (SX) window using only apical 4-chamber (A4C) images. METHODS: Researchers used a long-short-term-memory algorithm for image analysis. Using the Stanford EchoNet-Dynamic database of 10,036 A4C videos with calculated exact EF, researchers tested 3 ML training permeations. First, training on unaltered Stanford A4C videos, then unaltered and 90° clockwise (CW) rotated videos and finally unaltered, 90° rotated and horizontally flipped videos. As a real-world test, we obtained 615 SX videos from Harbor-UCLA (HUCLA) with EF calculations in 5% ranges. Researchers performed 1000 randomizations of EF point estimation within HUCLA EF ranges to compensate for ML and HUCLA EF mismatch, obtaining a mean value for absolute error (MAE) comparison and performed Bland-Altman analyses. RESULTS: The ML algorithm EF mean MAE was estimated at 23.0, with a range of 22.8-23.3 using unaltered A4C video, mean MAE was 16.7, with a range of 16.5-16.9 using unaltered and 90° CW rotated video, mean MAE was 16.6, with a range of 16.3-16.8 using unaltered, 90° CW rotated and horizontally flipped video training. Bland-Altman showed weakest agreement at 40-45% EF. CONCLUSIONS: Researchers successfully adapted unrelated ultrasound window data to train a POCUS ML algorithm with fair MAE using data manipulation to simulate a different ultrasound examination. This may be important for future POCUS algorithm design to help overcome a paucity of POCUS databases.
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Inteligência Artificial , Função Ventricular Esquerda , Algoritmos , Ecocardiografia/métodos , Humanos , Aprendizado de Máquina , Volume SistólicoRESUMO
Methicillin-resistant Staphylococcus aureus (MRSA) poses significant therapeutic challenges related to its frequency in clinical infections, innate virulence properties, and propensity for multiantibiotic resistance. MRSA is among the most common causes of endovascular infections, including infective endocarditis (IE). Our objective was to employ transthoracic echocardiography (TTE) to evaluate the effect of exebacase, a novel direct lytic agent, in experimental aortic valve MRSA IE. TTE was utilized to evaluate the in vivo effect of exebacase on MRSA-infected vegetation progression when combined with daptomycin (versus daptomycin alone). Primary intravegetation outcomes were maximum size, weights at sacrifice, and MRSA counts at infection baseline versus after 4 days of daptomycin treatment (alone or in addition to exebacase administered once on treatment day 1). A single dose of exebacase in addition to daptomycin cleared significantly more intravegetation MRSA than daptomycin alone. This was associated with a statistical trend toward reduced maximum vegetation size in the exebacase plus daptomycin versus the daptomycin alone therapy groups (P = 0.07). Also, mean vegetation weights in the exebacase-treated group were significantly lower than those of the daptomycin alone group (P < 0.0001). Maximum vegetation size by TTE correlated with vegetation weight (P = 0.005). In addition, intravegetation MRSA counts in the combination group were significantly lower than those of untreated controls (P < 0.0001) and the daptomycin alone group (P < 0.0001). This study suggests that exebacase has a salutary impact on MRSA-infected vegetation progression when combined with daptomycin, especially in terms of vegetation MRSA burden, size, and weight. Moreover, TTE appears to be an efficient noninvasive tool to assess therapeutic efficacies in experimental MRSA IE.
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Endocardite Bacteriana , Endocardite , Staphylococcus aureus Resistente à Meticilina , Infecções Estafilocócicas , Animais , Antibacterianos/uso terapêutico , Ecocardiografia , Endocardite/tratamento farmacológico , Endocardite Bacteriana/diagnóstico por imagem , Endocardite Bacteriana/tratamento farmacológico , Endopeptidases , Testes de Sensibilidade Microbiana , Coelhos , Infecções Estafilocócicas/tratamento farmacológicoRESUMO
BACKGROUND: Efforts have been made to simplify and reduce technical errors, such as limb leads reversal and inaccurate chest leads placement, for the 12-lead ECG tests. We compared standard ECG using individual electrodes with a novel pre-positioned electrode system to determine equivalency. METHODS: Subjects were recruited from the Emergency Department and cardiac lab of an acute care hospital in Los Angeles. First, subjects underwent a conventional 12-lead ECG using Philips PageWriter (clinical ECG). A second ECG was then performed using a novel system containing pre-positioned electrodes and a compact recorder (study ECG). All ECGs were reviewed by 3 blinded, board-certified adult cardiologists using 14 pre-specified ECG diagnostic categories to determine if the interpretations of clinical ECG and study ECG of the same patient were "equivalent". Majority rule was applied when there were discrepant interpretations among the 3 cardiologists. RESULTS: One hundred subjects, ages 18 to 74 completed the study. With pre-positioned electrodes, the rate of "electrode fit" as judged by the research associates at the time of lead placement was 96.2%. We found that the study ECG system was equivalent (in clinical interpretation) to the clinical ECG system, with equivalency rate of 96% (95% confidence interval 92% to 100%) in "overall interpretation". The equivalence rate for the 14 ECG diagnostic categories ranged from 96% to 100%, with mean 99.2 ± 1.1%. CONCLUSIONS: 12-lead ECGs performed using single-piece, pre-positioned electrodes are clinically equivalent to those performed using 10 individually placed conventional electrodes. With 4 sizes for adults, the single-piece electrodes can fit 96% of the study patients.
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Eletrocardiografia , Adolescente , Adulto , Idoso , Eletrodos , Humanos , Pessoa de Meia-Idade , Adulto JovemRESUMO
We tested whether DNA-methylation profiles account for inter-individual variation in body mass index (BMI) and height and whether they predict these phenotypes over and above genetic factors. Genetic predictors were derived from published summary results from the largest genome-wide association studies on BMI (n â¼ 350,000) and height (n â¼ 250,000) to date. We derived methylation predictors by estimating probe-trait effects in discovery samples and tested them in external samples. Methylation profiles associated with BMI in older individuals from the Lothian Birth Cohorts (LBCs, n = 1,366) explained 4.9% of the variation in BMI in Dutch adults from the LifeLines DEEP study (n = 750) but did not account for any BMI variation in adolescents from the Brisbane Systems Genetic Study (BSGS, n = 403). Methylation profiles based on the Dutch sample explained 4.9% and 3.6% of the variation in BMI in the LBCs and BSGS, respectively. Methylation profiles predicted BMI independently of genetic profiles in an additive manner: 7%, 8%, and 14% of variance of BMI in the LBCs were explained by the methylation predictor, the genetic predictor, and a model containing both, respectively. The corresponding percentages for LifeLines DEEP were 5%, 9%, and 13%, respectively, suggesting that the methylation profiles represent environmental effects. The differential effects of the BMI methylation profiles by age support previous observations of age modulation of genetic contributions. In contrast, methylation profiles accounted for almost no variation in height, consistent with a mainly genetic contribution to inter-individual variation. The BMI results suggest that combining genetic and epigenetic information might have greater utility for complex-trait prediction.
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Estatura/genética , Metilação de DNA/genética , Obesidade/genética , Fenótipo , Adolescente , Adulto , Análise de Variância , Índice de Massa Corporal , Estudos de Coortes , Estudo de Associação Genômica Ampla/métodos , Genótipo , Humanos , Pessoa de Meia-Idade , Modelos Genéticos , Países Baixos , EscóciaRESUMO
BACKGROUND: The link between DNA methylation, obesity, and adiposity-related diseases in the general population remains uncertain. METHODS AND FINDINGS: We conducted an association study of body mass index (BMI) and differential methylation for over 400,000 CpGs assayed by microarray in whole-blood-derived DNA from 3,743 participants in the Framingham Heart Study and the Lothian Birth Cohorts, with independent replication in three external cohorts of 4,055 participants. We examined variations in whole blood gene expression and conducted Mendelian randomization analyses to investigate the functional and clinical relevance of the findings. We identified novel and previously reported BMI-related differential methylation at 83 CpGs that replicated across cohorts; BMI-related differential methylation was associated with concurrent changes in the expression of genes in lipid metabolism pathways. Genetic instrumental variable analysis of alterations in methylation at one of the 83 replicated CpGs, cg11024682 (intronic to sterol regulatory element binding transcription factor 1 [SREBF1]), demonstrated links to BMI, adiposity-related traits, and coronary artery disease. Independent genetic instruments for expression of SREBF1 supported the findings linking methylation to adiposity and cardiometabolic disease. Methylation at a substantial proportion (16 of 83) of the identified loci was found to be secondary to differences in BMI. However, the cross-sectional nature of the data limits definitive causal determination. CONCLUSIONS: We present robust associations of BMI with differential DNA methylation at numerous loci in blood cells. BMI-related DNA methylation and gene expression provide mechanistic insights into the relationship between DNA methylation, obesity, and adiposity-related diseases.
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Índice de Massa Corporal , Doença da Artéria Coronariana/genética , Metilação de DNA , Regulação da Expressão Gênica , Leucócitos/metabolismo , Metabolismo dos Lipídeos , Idoso , Doença da Artéria Coronariana/etiologia , Epigênese Genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Metabolismo dos Lipídeos/genética , Masculino , Análise da Randomização Mendeliana , Obesidade/complicações , Análise de Sequência com Séries de OligonucleotídeosRESUMO
Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ~50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.
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Pressão Sanguínea , Diástole , Genética Populacional , Sístole , População Branca/genética , Pressão Arterial , Biologia Computacional/métodos , Europa (Continente) , Loci Gênicos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único , Controle de Qualidade , Locos de Características Quantitativas , Fatores de RiscoRESUMO
Epigenetic mechanisms such as DNA methylation (DNAm) are essential for regulation of gene expression. DNAm is dynamic, influenced by both environmental and genetic factors. Epigenetic drift is the divergence of the epigenome as a function of age due to stochastic changes in methylation. Here we show that epigenetic drift may be constrained at many CpGs across the human genome by DNA sequence variation and by lifetime environmental exposures. We estimate repeatability of DNAm at 234,811 autosomal CpGs in whole blood using longitudinal data (2-3 repeated measurements) on 478 older people from two Scottish birth cohorts--the Lothian Birth Cohorts of 1921 and 1936. Median age was 79 yr and 70 yr, and the follow-up period was â¼10 yr and â¼6 yr, respectively. We compare this to methylation heritability estimated in the Brisbane Systems Genomics Study, a cross-sectional study of 117 families (offspring median age 13 yr; parent median age 46 yr). CpG repeatability in older people was highly correlated (0.68) with heritability estimated in younger people. Highly heritable sites had strong underlying cis-genetic effects. Thirty-seven and 1687 autosomal CpGs were associated with smoking and sex, respectively. Both sets were strongly enriched for high repeatability. Sex-associated CpGs were also strongly enriched for high heritability. Our results show that a large number of CpGs across the genome, as a result of environmental and/or genetic constraints, have stable DNAm variation over the human lifetime. Moreover, at a number of CpGs, most variation in the population is due to genetic factors, despite some sites being highly modifiable by the environment.
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Ilhas de CpG/genética , Metilação de DNA , Genética Populacional/métodos , Genoma Humano/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Criança , Estudos de Coortes , Estudos Transversais , Saúde da Família , Feminino , Interação Gene-Ambiente , Humanos , Padrões de Herança/genética , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Polimorfismo de Nucleotídeo Único , Fatores Sexuais , Fumar , Adulto JovemRESUMO
OBJECTIVES: Cannabis use motives are differentially related to cannabis-related impairment and coping motives appear to have the strongest relation to use-related impairment. However, it is currently unknown whether African-American individuals differ from White persons in reasons for using cannabis. It is also unknown whether motives' relations to cannabis use and related impairment vary as a function of race. The present study examined the role of race on cannabis use motives and tested whether motives' relations with cannabis use and related impairment differed by race. DESIGN: The sample consisted of 111 (67.6% non-Hispanic White, 32.4% African-American) current cannabis-using adults. RESULTS: African-American participants did not significantly differ from White participants on cannabis use frequency or use-related impairment. African-American participants endorsed more social motives than White participants. Race interacted with social, coping, and conformity motives to predict cannabis-related impairment such that these motives were positively related to cannabis impairment among African-American, but not White, participants. CONCLUSION: Although African-American and White participants do not differ in their cannabis use frequency or cannabis-related impairment, they appear to use cannabis for different reasons. Further, conformity, coping, and social motives were differentially associated with cannabis-related impairment as a function of race. Findings suggest motives for cannabis use should be contexualised in the context of race.
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Negro ou Afro-Americano/psicologia , Fumar Maconha/etnologia , Motivação , População Branca/psicologia , Adaptação Psicológica , Adolescente , Adulto , Cannabis , Feminino , Humanos , Louisiana/epidemiologia , Masculino , Fumar Maconha/efeitos adversos , Fumar Maconha/psicologia , Pessoa de Meia-Idade , Inquéritos e Questionários , Adulto JovemRESUMO
AIMS: To investigate the causal role of high-density lipoprotein cholesterol (HDL-C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization. METHODS AND RESULTS: We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 × 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P ≤ 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75). CONCLUSION: The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain.
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HDL-Colesterol/genética , Doença da Artéria Coronariana/genética , Polimorfismo de Nucleotídeo Único/genética , Triglicerídeos/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Técnicas de Genotipagem , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Medição de RiscoRESUMO
Cannabis use disorders (CUDs) co-occur with anxiety disorders at high rates, presumably because some individuals with anxiety disorders may rely on cannabis to manage anxiety. Motivation enhancement therapy (MET) combined with cognitive-behavioral therapy (CBT) is an efficacious intervention for CUD, yet outcomes are worse for patients with elevated anxiety. The integration of MET-CBT with False Safety Behavior Elimination Treatment (FSET) may be useful with anxious CUD patients, as the use of cannabis to manage anxiety can be targeted as a false safety behavior. Here, we describe the integrated treatment and the successful use of it among two patients-one with CUD and comorbid social anxiety disorder (SAD) and one with CUD and comorbid SAD and generalized anxiety disorder. Data support the feasibility of this integrated treatment as a viable approach to the treatment of CUD and comorbid anxiety disorders. Future controlled trials are now warranted to further evaluate the intervention.
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Blood pressure (BP) is a heritable determinant of risk for cardiovascular disease (CVD). To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP), we genotyped â¼50 000 single-nucleotide polymorphisms (SNPs) that capture variation in â¼2100 candidate genes for cardiovascular phenotypes in 61 619 individuals of European ancestry from cohort studies in the USA and Europe. We identified novel associations between rs347591 and SBP (chromosome 3p25.3, in an intron of HRH1) and between rs2169137 and DBP (chromosome1q32.1 in an intron of MDM4) and between rs2014408 and SBP (chromosome 11p15 in an intron of SOX6), previously reported to be associated with MAP. We also confirmed 10 previously known loci associated with SBP, DBP, MAP or PP (ADRB1, ATP2B1, SH2B3/ATXN2, CSK, CYP17A1, FURIN, HFE, LSP1, MTHFR, SOX6) at array-wide significance (P < 2.4 × 10(-6)). We then replicated these associations in an independent set of 65 886 individuals of European ancestry. The findings from expression QTL (eQTL) analysis showed associations of SNPs in the MDM4 region with MDM4 expression. We did not find any evidence of association of the two novel SNPs in MDM4 and HRH1 with sequelae of high BP including coronary artery disease (CAD), left ventricular hypertrophy (LVH) or stroke. In summary, we identified two novel loci associated with BP and confirmed multiple previously reported associations. Our findings extend our understanding of genes involved in BP regulation, some of which may eventually provide new targets for therapeutic intervention.
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Pressão Sanguínea/genética , Doenças Cardiovasculares/genética , Mapeamento Cromossômico , Estudo de Associação Genômica Ampla , Adulto , Idoso , Doenças Cardiovasculares/fisiopatologia , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , População Branca/genéticaRESUMO
BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal-dominant disorder caused by mutations in 1 of 3 genes. In the 60% of patients who are mutation negative, we have recently shown that the clinical phenotype can be associated with an accumulation of common small-effect LDL cholesterol (LDL-C)-raising alleles by use of a 12-single nucleotide polymorphism (12-SNP) score. The aims of the study were to improve the selection of SNPs and replicate the results in additional samples. METHODS: We used ROC curves to determine the optimum number of LDL-C SNPs. For replication analysis, we genotyped patients with a clinical diagnosis of FH from 6 countries for 6 LDL-C-associated alleles. We compared the weighted SNP score among patients with no confirmed mutation (FH/M-), those with a mutation (FH/M+), and controls from a UK population sample (WHII). RESULTS: Increasing the number of SNPs to 33 did not improve the ability of the score to discriminate between FH/M- and controls, whereas sequential removal of SNPs with smaller effects/lower frequency showed that a weighted score of 6 SNPs performed as well as the 12-SNP score. Metaanalysis of the weighted 6-SNP score, on the basis of polymorphisms in CELSR2 (cadherin, EGF LAG 7-pass G-type receptor 2), APOB (apolipoprotein B), ABCG5/8 [ATP-binding cassette, sub-family G (WHITE), member 5/8], LDLR (low density lipoprotein receptor), and APOE (apolipoprotein E) loci, in the independent FH/M- cohorts showed a consistently higher score in comparison to the WHII population (P < 2.2 × 10(-16)). Modeling in individuals with a 6-SNP score in the top three-fourths of the score distribution indicated a >95% likelihood of a polygenic explanation of their increased LDL-C. CONCLUSIONS: A 6-SNP LDL-C score consistently distinguishes FH/M- patients from healthy individuals. The hypercholesterolemia in 88% of mutation-negative patients is likely to have a polygenic basis.
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LDL-Colesterol/sangue , Hiperlipoproteinemia Tipo II/genética , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Alelos , Apolipoproteínas B/genética , Canadá , Estudos de Casos e Controles , Criança , LDL-Colesterol/genética , Estudos de Coortes , Europa (Continente) , Feminino , Humanos , Hiperlipoproteinemia Tipo II/sangue , Israel , Masculino , Pessoa de Meia-Idade , Mutação , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/genética , Curva ROC , Receptores de LDL/genética , Fatores de Risco , Serina Endopeptidases/genética , Adulto JovemRESUMO
Monozygotic (MZ) twins provide a natural system for investigating developmental plasticity and the potential epigenetic origins of disease. A major difference in the intrauterine environment between MZ pairs is whether they share a common placenta or have separate placentas. Using DNA methylation measured at >400,000 points in the genome on the Illumina HumanMethylation450 array, we demonstrate that the co-twins of MZ pairs (average age of 14) that shared a common placenta (n = 18 pairs) have more similar DNA methylation levels in blood throughout the genome relative to those with separate placentas (n = 16 pairs). Functional annotation of the genomic regions that show significantly different correlation between monochorionic (MC) and dichorionic (DC) MZ pairs found an over-representation of genes involved in the regulation of transcription, neuronal development, and cellular differentiation. These results support the idea that prenatal environmental exposures may have a lasting effect on an individual's epigenetic landscape, and the potential for these changes to have functional consequences.
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Metilação de DNA , Placenta , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Adolescente , Córion , Feminino , Testes Hematológicos , Humanos , GravidezRESUMO
Following the widespread use of genome-wide association studies (GWAS), focus is turning towards identification of causal variants rather than simply genetic markers of diseases and traits. As a step towards a high-throughput method to identify genome-wide, non-coding, functional regulatory variants, we describe the technique of allele-specific FAIRE, utilising large-scale genotyping technology (FAIRE-gen) to determine allelic effects on chromatin accessibility and regulatory potential. FAIRE-gen was explored using lymphoblastoid cells and the 50,000 SNP Illumina CVD BeadChip. The technique identified an allele-specific regulatory polymorphism within NR1H3 (coding for LXR-α), rs7120118, coinciding with a previously GWAS-identified SNP for HDL-C levels. This finding was confirmed using FAIRE-gen with the 200,000 SNP Illumina Metabochip and verified with the established method of TaqMan allelic discrimination. Examination of this SNP in two prospective Caucasian cohorts comprising 15,000 individuals confirmed the association with HDL-C levels (combined betaâ=â0.016; pâ=â0.0006), and analysis of gene expression identified an allelic association with LXR-α expression in heart tissue. Using increasingly comprehensive genotyping chips and distinct tissues for examination, FAIRE-gen has the potential to aid the identification of many causal SNPs associated with disease from GWAS.
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Alelos , Doenças Cardiovasculares/genética , HDL-Colesterol/genética , Técnicas de Genotipagem , Receptores Nucleares Órfãos/genética , População Branca/genética , Doenças Cardiovasculares/metabolismo , Linhagem Celular , HDL-Colesterol/metabolismo , Cromatina/genética , Mapeamento Cromossômico/métodos , Estudos de Coortes , Genoma Humano , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Receptores X do Fígado , Linfócitos/citologia , Linfócitos/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Receptores Nucleares Órfãos/metabolismo , Fenótipo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Emerging data suggest that dysphoria is one facet of depression that is especially related to various aspects of cigarette smoking. However, it is presently unknown what emotional processes may account for these relations. OBJECTIVES: In the current cross-sectional study, the impact of avoidance and inflexibility to smoking (AIS), a smoking-specific form of experiential avoidance, was tested on the relationship of dysphoria to four specific smoking processes that are key factors in cessation: perceived barriers to cessation, severity of problems during prior quit attempts, negative reinforcement smoking expectancies, and motivation to quit smoking. METHODS: Participants (n = 465) were treatment-seeking adult daily smokers. Relative indirect effects were subjected to bootstrap analyses to test direct and indirect effects of dysphoria on smoking processes. RESULTS: After controlling for gender, nicotine dependence severity, drinking problems, cannabis use, negative affectivity, tobacco-related medical problems, and AIS, dysphoria remained directly, positively related to perceived barriers and cessation problems. Additionally, dysphoria was indirectly, positively related to perceived barriers, cessation problems, negative reinforcement smoking expectancies, and motivation to quit indirectly through higher levels of AIS. CONCLUSION: In the context of dysphoria, AIS may explain a wide range of clinically-relevant smoking processes.
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Transtornos de Ansiedade , Aprendizagem da Esquiva , Abandono do Hábito de Fumar/psicologia , Fumar/psicologia , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Aceitação pelo Paciente de Cuidados de Saúde , Psicometria , Fumar/terapiaRESUMO
BACKGROUND: Some previously identified predictors of 30-day stroke readmission, including age and stroke severity, are nonmodifiable. We assessed the hypothesis that in-hospital medical complications, which are potentially modifiable, after ischemic stroke (IS) and transient ischemic attack (TIA) predict 30-day readmission. METHODS: In a single-center prospective cohort study of IS and TIA patients admitted from August 1, 2012, to July 31, 2013, we identified those who survived to 30-day follow-up or died during a readmission within 30 days. Patients readmitted within 30 days of discharge were identified by telephone assessment and review of hospital records. We evaluated the association between 12 prespecified and prospectively collected poststroke medical complications and 30-day readmission adjusting for baseline characteristics, in-hospital course and treatments, and discharge status using univariable and multivariable Cox proportional hazards models. RESULTS: Among 505 patients, 107 (21.2%) patients had at least 1 medical complication during hospitalization. The most common complications were urinary tract infection (8.7%), venous thromboembolism (6.1%), and pneumonia (4.6%). Seventy-eight (15.4%) patients were readmitted within 30 days. On multivariable Cox proportional hazards analysis, cardioembolic or large-artery atherosclerotic subtype (adjusted hazard ratio [HR], 1.82; 95% confidence interval [CI], 1.17-2.83) and any medical complication (adjusted HR, 1.68; 95% CI, 1.04-2.73) increased the risk of 30-day readmission. Among the 24 readmitted patients who experienced an initial medical complication, 10 (41.6%) were considered potentially preventable. CONCLUSIONS: The occurrence of medical complications after IS or TIA increased the risk of 30-day all-cause readmission. Stroke patients with medical complications may be suitable for targeted interventions to prevent readmissions.
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Hospitalização/estatística & dados numéricos , Readmissão do Paciente/estatística & dados numéricos , Acidente Vascular Cerebral/complicações , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/complicações , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Alta do Paciente , Modelos de Riscos Proporcionais , Fatores de Risco , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/terapiaRESUMO
Social anxiety nearly quintuples the risk of developing an alcohol use disorder. Although accumulating data suggest that socially anxious persons drink to manage negative effect, socially anxious persons suffer from elevations in both anxiety and depression. Thus, the present study sought to determine whether social anxiety was related to drinking to cope with anxiety or depression and whether drinking motives accounted for the relation of social anxiety to drinking problems among 461 (74% female, 48% with clinically elevated social anxiety) undergraduate drinkers. Compared to women with more normative levels of social anxiety, women with clinically elevated social anxiety endorsed more drinking to cope with anxiety and conformity motives. Drinking to cope with anxiety uniquely mediated the relation of social anxiety and drinking problems among women. Among men, social anxiety was uniquely related to conformity motives, which mediated the social anxiety-drinking problems relationship. Findings support prior work indicating that socially anxious men and women may use alcohol differently and provide unique data on the importance of drinking to cope with anxiety specifically among socially anxious women.
RESUMO
Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.