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1.
Biomed Opt Express ; 13(5): 2728-2738, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35774323

RESUMO

Clinically, optical coherence tomography (OCT) has been utilized to obtain the images of the kidney's proximal convoluted tubules (PCTs), which can be used to quantify the morphometric parameters such as tubular density and diameter. Such parameters are useful for evaluating the status of the donor kidney for transplant. Quantifying PCTs from OCT images by human readers is a time-consuming and tedious process. Despite the fact that conventional deep learning models such as conventional neural networks (CNNs) have achieved great success in the automatic segmentation of kidney OCT images, gaps remain regarding the segmentation accuracy and reliability. Attention-based deep learning model has benefits over regular CNNs as it is intended to focus on the relevant part of the image and extract features for those regions. This paper aims at developing an Attention-based UNET model for automatic image analysis, pattern recognition, and segmentation of kidney OCT images. We evaluated five methods including the Residual-Attention-UNET, Attention-UNET, standard UNET, Residual UNET, and fully convolutional neural network using 14403 OCT images from 169 transplant kidneys for training and testing. Our results show that Residual-Attention-UNET outperformed the other four methods in segmentation by showing the highest values of all the six metrics including dice score (0.81 ± 0.01), intersection over union (IOU, 0.83 ± 0.02), specificity (0.84 ± 0.02), recall (0.82 ± 0.03), precision (0.81 ± 0.01), and accuracy (0.98 ± 0.08). Our results also show that the performance of the Residual-Attention-UNET is equivalent to the human manual segmentation (dice score = 0.84 ± 0.05). Residual-Attention-UNET and Attention-UNET also demonstrated good performance when trained on a small dataset (3456 images) whereas the performance of the other three methods dropped dramatically. In conclusion, our results suggested that the soft Attention-based models and specifically Residual-Attention-UNET are powerful and reliable methods for tubule lumen identification and segmentation and can help clinical evaluation of transplant kidney viability as fast and accurate as possible.

2.
Res Sq ; 2022 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-35664994

RESUMO

To create a scientific resource of expression quantitative trail loci (eQTL), we conducted a genome-wide association study (GWAS) using genotypes obtained from whole genome sequencing (WGS) of DNA and gene expression levels from RNA sequencing (RNA-seq) of whole blood in 2622 participants in Framingham Heart Study. We identified 6,778,286 cis -eQTL variant-gene transcript (eGene) pairs at p < 5x10 - 8 (2,855,111 unique cis -eQTL variants and 15,982 unique eGenes) and 1,469,754 trans -eQTL variant-eGene pairs at p < 1e-12 (526,056 unique trans -eQTL variants and 7,233 unique eGenes). In addition, 442,379 cis -eQTL variants were associated with expression of 1518 long non-protein coding RNAs (lncRNAs). Gene Ontology (GO) analyses revealed that the top GO terms for cis- eGenes are enriched for immune functions (FDR < 0.05). The cis -eQTL variants are enriched for SNPs reported to be associated with 815 traits in prior GWAS, including cardiovascular disease risk factors. As proof of concept, we used this eQTL resource in conjunction with genetic variants from public GWAS databases in causal inference testing (e.g., COVID-19 severity). After Bonferroni correction, Mendelian randomization analyses identified putative causal associations of 60 eGenes with systolic blood pressure, 13 genes with coronary artery disease, and seven genes with COVID-19 severity. This study created a comprehensive eQTL resource via BioData Catalyst that will be made available to the scientific community. This will advance understanding of the genetic architecture of gene expression underlying a wide range of diseases.

3.
medRxiv ; 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35547845

RESUMO

To create a scientific resource of expression quantitative trail loci (eQTL), we conducted a genome-wide association study (GWAS) using genotypes obtained from whole genome sequencing (WGS) of DNA and gene expression levels from RNA sequencing (RNA-seq) of whole blood in 2622 participants in Framingham Heart Study. We identified 6,778,286 cis -eQTL variant-gene transcript (eGene) pairs at p <5×10 -8 (2,855,111 unique cis -eQTL variants and 15,982 unique eGenes) and 1,469,754 trans -eQTL variant-eGene pairs at p <1e-12 (526,056 unique trans -eQTL variants and 7,233 unique eGenes). In addition, 442,379 cis -eQTL variants were associated with expression of 1518 long non-protein coding RNAs (lncRNAs). Gene Ontology (GO) analyses revealed that the top GO terms for cis- eGenes are enriched for immune functions (FDR <0.05). The cis -eQTL variants are enriched for SNPs reported to be associated with 815 traits in prior GWAS, including cardiovascular disease risk factors. As proof of concept, we used this eQTL resource in conjunction with genetic variants from public GWAS databases in causal inference testing (e.g., COVID-19 severity). After Bonferroni correction, Mendelian randomization analyses identified putative causal associations of 60 eGenes with systolic blood pressure, 13 genes with coronary artery disease, and seven genes with COVID-19 severity. This study created a comprehensive eQTL resource via BioData Catalyst that will be made available to the scientific community. This will advance understanding of the genetic architecture of gene expression underlying a wide range of diseases.

4.
Aging Cell ; 21(6): e13608, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35546478

RESUMO

DNA methylation (DNAm) has been reported to be associated with many diseases and with mortality. We hypothesized that the integration of DNAm with clinical risk factors would improve mortality prediction. We performed an epigenome-wide association study of whole blood DNAm in relation to mortality in 15 cohorts (n = 15,013). During a mean follow-up of 10 years, there were 4314 deaths from all causes including 1235 cardiovascular disease (CVD) deaths and 868 cancer deaths. Ancestry-stratified meta-analysis of all-cause mortality identified 163 CpGs in European ancestry (EA) and 17 in African ancestry (AA) participants at p < 1 × 10-7 , of which 41 (EA) and 16 (AA) were also associated with CVD death, and 15 (EA) and 9 (AA) with cancer death. We built DNAm-based prediction models for all-cause mortality that predicted mortality risk after adjusting for clinical risk factors. The mortality prediction model trained by integrating DNAm with clinical risk factors showed an improvement in prediction of cancer death with 5% increase in the C-index in a replication cohort, compared with the model including clinical risk factors alone. Mendelian randomization identified 15 putatively causal CpGs in relation to longevity, CVD, or cancer risk. For example, cg06885782 (in KCNQ4) was positively associated with risk for prostate cancer (Beta = 1.2, PMR  = 4.1 × 10-4 ) and negatively associated with longevity (Beta = -1.9, PMR  = 0.02). Pathway analysis revealed that genes associated with mortality-related CpGs are enriched for immune- and cancer-related pathways. We identified replicable DNAm signatures of mortality and demonstrated the potential utility of CpGs as informative biomarkers for prediction of mortality risk.


Assuntos
Doenças Cardiovasculares , Neoplasias , Biomarcadores , Doenças Cardiovasculares/genética , Metilação de DNA/genética , Epigênese Genética , Epigenômica , Humanos , Masculino , Neoplasias/genética
5.
Am J Respir Crit Care Med ; 206(3): 321-336, 2022 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-35536696

RESUMO

Rationale: Methylation integrates factors present at birth and modifiable across the lifespan that can influence pulmonary function. Studies are limited in scope and replication. Objectives: To conduct large-scale epigenome-wide meta-analyses of blood DNA methylation and pulmonary function. Methods: Twelve cohorts analyzed associations of methylation at cytosine-phosphate-guanine probes (CpGs), using Illumina 450K or EPIC/850K arrays, with FEV1, FVC, and FEV1/FVC. We performed multiancestry epigenome-wide meta-analyses (total of 17,503 individuals; 14,761 European, 2,549 African, and 193 Hispanic/Latino ancestries) and interpreted results using integrative epigenomics. Measurements and Main Results: We identified 1,267 CpGs (1,042 genes) differentially methylated (false discovery rate, <0.025) in relation to FEV1, FVC, or FEV1/FVC, including 1,240 novel and 73 also related to chronic obstructive pulmonary disease (1,787 cases). We found 294 CpGs unique to European or African ancestry and 395 CpGs unique to never or ever smokers. The majority of significant CpGs correlated with nearby gene expression in blood. Findings were enriched in key regulatory elements for gene function, including accessible chromatin elements, in both blood and lung. Sixty-nine implicated genes are targets of investigational or approved drugs. One example novel gene highlighted by integrative epigenomic and druggable target analysis is TNFRSF4. Mendelian randomization and colocalization analyses suggest that epigenome-wide association study signals capture causal regulatory genomic loci. Conclusions: We identified numerous novel loci differentially methylated in relation to pulmonary function; few were detected in large genome-wide association studies. Integrative analyses highlight functional relevance and potential therapeutic targets. This comprehensive discovery of potentially modifiable, novel lung function loci expands knowledge gained from genetic studies, providing insights into lung pathogenesis.


Assuntos
Metilação de DNA , Epigenoma , Ilhas de CpG , Metilação de DNA/genética , Epigênese Genética/genética , Epigenômica , Estudo de Associação Genômica Ampla , Humanos , Recém-Nascido , Pulmão
6.
PLoS One ; 17(4): e0266523, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35390066

RESUMO

RATIONALE: It has been speculated that shared mechanisms underlie respiratory and cardiovascular diseases (CVD) including systemic inflammation or mutual risk factors. In this context, we sought to examine the associations of CVD-related plasma proteins with lung function as measured by spirometry in a large community-based cohort of adults. METHODS: The study included 5777 Framingham Heart Study participants who had spirometry and measurement of 71 CVD-related plasma proteins. The association of plasma proteins with lung function was assessed cross-sectionally and longitudinally using models accounting for familial correlations. Linear mixed models were used for the following measurements: FEV1%predicted, FVC%predicted, and FEV1/FVC ratio with secondary analyses examining obstructive and restrictive physiology at baseline and their new onset during follow up. MEASUREMENTS AND MAIN RESULTS: Among the 71 CVD-related plasma proteins, 13 proteins were associated in cross-sectional analyses with FEV1%predicted, 17 proteins were associated with FVC%predicted, and 1 protein was associated with FEV1/FVC. The proteins with the greatest inverse relations to FEV1%predicted and FVC%predicted included leptin, adrenomedullin, and plasminogen activator inhibitor-1; in contrast there were three proteins with positive relations to FEV1%predicted and FVC%predicted including insulin growth factor binding protein 2, tetranectin, and soluble receptor for advanced glycation end products. In longitudinal analyses, three proteins were associated with longitudinal change in FEV1 (ΔFEV1) and four with ΔFVC; no proteins were associated with ΔFEV1/FVC. CONCLUSION: Our findings highlight CVD-related plasma proteins that are associated with lung function including markers of inflammation, adiposity, and fibrosis, representing proteins that may contribute both to respiratory and CVD risk.


Assuntos
Doenças Cardiovasculares , Adulto , Proteínas Sanguíneas , Estudos Transversais , Volume Expiratório Forçado/fisiologia , Humanos , Inflamação , Pulmão , Espirometria , Capacidade Vital/fisiologia
7.
Am J Clin Nutr ; 115(1): 163-170, 2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-34134146

RESUMO

BACKGROUND: DNA methylation-based epigenetic age measures have been used as biological aging markers and are associated with a healthy lifespan. Few population-based studies have examined the relation between diet and epigenetic age acceleration. OBJECTIVES: We aimed to investigate the relation between diet quality and epigenetic age acceleration. METHODS: We analyzed data from 1995 participants (mean age, 67 years; 55% women) of the Framingham Heart Study Offspring Cohort. Cross-sectional associations between the Dietary Approaches to Stop Hypertension (DASH) score and 3 whole-blood DNA methylation-derived epigenetic age acceleration measures-Dunedin Pace of Aging Methylation (DunedinPoAm), GrimAge acceleration (GrimAA), and PhenoAge acceleration (PhenoAA)-were examined. A mediation analysis was conducted to assess the mediating role of epigenetic age acceleration in relation to DASH and all-cause mortality. RESULTS: A higher DASH score was associated with lower levels of DunedinPoAm (ß = -0.05; SE = 0.02; P = 0.007), GrimAA (ß = -0.09; SE = 0.02; P < 0.001), and PhenoAA (ß = -0.07; SE = 0.02; P = 0.001). All 3 epigenetic measures mediated the association between the DASH score and all-cause mortality, with mean proportions of 22.1% for DunedinPoAm (Pmediation = 0.04), 45.1% for GrimAA (Pmediation = 0.001), and 22.9% for PhenoAA (Pmediation = 0.03). An interaction was observed between the DASH score and smoking status in relation to the epigenetic aging markers. The association between the DASH score and epigenetic aging markers tended to be stronger in "ever-smokers" (former and current smokers) compared to "never-smokers." The proportions of mediation were 31.3% for DunedinPoAm, 46.8% for GrimAA, and 10.3% for PhenoAA in ever-smokers, whereas no significant mediation was observed in never-smokers. CONCLUSIONS: Higher diet quality is associated with slower epigenetic age acceleration, which partially explains the beneficial effect of diet quality on the lifespan. Our findings emphasize that adopting a healthy diet is crucial for maintaining healthy aging.


Assuntos
Envelhecimento , Metilação de DNA , Abordagens Dietéticas para Conter a Hipertensão/mortalidade , Epigênese Genética , Fenômenos Fisiológicos da Nutrição/genética , Idoso , Biomarcadores/análise , Causas de Morte , Estudos Transversais , Feminino , Humanos , Longevidade , Masculino
8.
Epigenetics ; : 1-12, 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34570667

RESUMO

Cigarette smoking is associated with epigenetic changes that may be reversible following smoking cessation. Whole blood DNA methylation was evaluated in Framingham Heart Study Offspring (n = 169) and Third Generation (n = 30) cohort participants at two study visits 6 years apart and in Atherosclerosis Risk in Communities (ARIC) study (n = 222) participants at two study visits 20 years apart. Changes in DNA methylation (delta ß values) at 483,565 cytosine-phosphate-guanine (CpG) sites and differentially methylated regions (DMRs) were compared between participants who were current, former, or never smokers at both visits (current-current, former-former, never-never, respectively), versus those who quit in the interim (current-former). Interim quitters had more hypermethylation at four CpGs annotated to AHRR, one CpG annotated to F2RL3, and one intergenic CpG (cg21566642) compared with current-current smokers (FDR < 0.02 for all), and two significant DMRs were identified. While there were no significant differentially methylated CpGs in the comparison of interim quitters and former-former smokers, 106 DMRs overlapping with small nucleolar RNA were identified. As compared with all non-smokers, current-current smokers additionally had more hypermethylation at two CpG sites annotated to HIVEP3 and TMEM126A, respectively, and another intergenic CpG (cg14339116). Gene transcripts associated with smoking cessation were implicated in immune responses, cell homoeostasis, and apoptosis. Smoking cessation is associated with early reversion of blood DNA methylation changes at CpG sites annotated to AHRR and F2RL3 towards those of never smokers. Associated gene expression suggests a role of longitudinal smoking-related DNA methylation changes in immune response processes.

9.
J Am Heart Assoc ; 10(18): e021245, 2021 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-34482708

RESUMO

Background Biological mechanisms underlying the association of a healthy diet with chronic diseases remain unclear. Targeted proteomics may facilitate the understanding of mechanisms linking diet to chronic diseases. Methods and Results We examined 6360 participants (mean age 50 years; 54% women) in the Framingham Heart Study. The associations between diet and 71 cardiovascular disease (CVD)-related proteins were examined using 3 diet quality scores: the Alternate Healthy Eating Index, the modified Mediterranean-style Diet Score, and the modified Dietary Approaches to Stop Hypertension diet score. A mediation analysis was conducted to examine which proteins mediated the associations of diet with incident CVD and all-cause mortality. Thirty of the 71 proteins were associated with at least 1 diet quality score (P<0.0007) after adjustment for multiple covariates in all study participants and confirmed by an internal validation analysis. Gene ontology analysis identified inflammation-related pathways such as regulation of cell killing and neuroinflammatory response (Bonferroni corrected P<0.05). During a median follow-up of 13 years, we documented 512 deaths and 488 incident CVD events. Higher diet quality scores were associated with lower risk of CVD (P≤0.03) and mortality (P≤0.004). After adjusting for multiple potential confounders, 4 proteins (B2M [beta-2-microglobulin], GDF15 [growth differentiation factor 15], sICAM1 [soluble intercellular adhesion molecule 1], and UCMGP [uncarboxylated matrix Gla-protein]) mediated the association between at least 1 diet quality score and all-cause mortality (median proportion of mediation ranged from 8.6% to 25.9%). We also observed that GDF15 mediated the association of the Alternate Healthy Eating Index with CVD (median proportion of mediation: 8.6%). Conclusions Diet quality is associated with new-onset CVD and mortality and with circulating CVD-related proteins. Several proteins appear to mediate the association of diet with these outcomes.


Assuntos
Doenças Cardiovasculares , Dieta , Mortalidade , Doenças Cardiovasculares/epidemiologia , Doença Crônica , Dieta Saudável , Dieta Mediterrânea , Abordagens Dietéticas para Conter a Hipertensão , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Proteômica , Fatores de Risco
10.
Cardiovasc Res ; 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34469519

RESUMO

AIMS: Recent studies suggest an association between cardiovascular disease (CVD) and cancer incidence/mortality, but the pathophysiological mechanisms underlying these associations are unclear. We aimed to examine biomarkers previously associated with CVD and study their association with incident cancer and cancer-related death in a prospective cohort study. METHODS AND RESULTS: We used a proteomic platform to measure 71 cardiovascular biomarkers among 5,032 participants in the Framingham Heart Study who were free of cancer at baseline. We used multivariable-adjusted Cox models to examine the association of circulating protein biomarkers with risk of cancer incidence and mortality. To account for multiple testing, we set a 2-sided false discovery rate (FDR Q-value) <0.05.Growth differentiation factor-15 (GDF15; also known as macrophage inhibitory cytokine-1 [MIC1])) was associated with increased risk of incident cancer (hazards ratio [HR] per 1 standard deviation increment 1.31, 95% CI 1.17-1.47), incident gastrointestinal cancer (HR 1.85, 95% CI 1.37-2.50), incident colorectal cancer (HR 1.94, 95% CI 1.29-2.91) and cancer-related death (HR 2.15, 95% CI 1.72-2.70). Stromal cell-derived factor-1 (SFD1) showed an inverse association with cancer-related death (HR 0.75, 95% CI 0.65-0.86). Fibroblast growth factor-23 (FGF23) showed an association with colorectal cancer (HR 1.55, 95% CI 1.20-2.00), and granulin (GRN) was associated with hematologic cancer (HR 1.61, 95% CI 1.30-1.99). Other circulating biomarkers of inflammation, immune activation, metabolism, and fibrosis showed suggestive associations with future cancer diagnosis. CONCLUSION: We observed several significant associations between circulating CVD biomarkers and cancer, supporting the idea that shared biological pathways underlie both diseases. Further investigations of specific mechanisms that lead to both CVD and cancer are warranted. TRANSLATIONAL PERSPECTIVE: In our prospective cohort study, baseline levels of biomarkers previously associated with CVD were found to be associated with future development of cancer. In particular, GDF15 was associated with increased risk of cancer incidence and mortality, including gastrointestinal and colorectal cancers; SDF1 was inversely associated with cancer-related death, and FGF23 and GRN were associated with increased risk of colorectal and hematologic cancers, respectively. Other biomarkers of inflammation, immune activation, metabolism, and fibrosis showed suggestive associations. These results suggest potential shared biological pathways that underlie both development of cancer and CVD.

11.
Hum Mol Genet ; 31(2): 309-319, 2021 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-34415308

RESUMO

We conducted cohort- and race-specific epigenome-wide association analyses of mitochondrial deoxyribonucleic acid (mtDNA) copy number (mtDNA CN) measured in whole blood from participants of African and European origins in five cohorts (n = 6182, mean age = 57-67 years, 65% women). In the meta-analysis of all the participants, we discovered 21 mtDNA CN-associated DNA methylation sites (CpG) (P < 1 × 10-7), with a 0.7-3.0 standard deviation increase (3 CpGs) or decrease (18 CpGs) in mtDNA CN corresponding to a 1% increase in DNA methylation. Several significant CpGs have been reported to be associated with at least two risk factors (e.g. chronological age or smoking) for cardiovascular disease (CVD). Five genes [PR/SET domain 16, nuclear receptor subfamily 1 group H member 3 (NR1H3), DNA repair protein, DNA polymerase kappa and decaprenyl-diphosphate synthase subunit 2], which harbor nine significant CpGs, are known to be involved in mitochondrial biosynthesis and functions. For example, NR1H3 encodes a transcription factor that is differentially expressed during an adipose tissue transition. The methylation level of cg09548275 in NR1H3 was negatively associated with mtDNA CN (effect size = -1.71, P = 4 × 10-8) and was positively associated with the NR1H3 expression level (effect size = 0.43, P = 0.0003), which indicates that the methylation level in NR1H3 may underlie the relationship between mtDNA CN, the NR1H3 transcription factor and energy expenditure. In summary, the study results suggest that mtDNA CN variation in whole blood is associated with DNA methylation levels in genes that are involved in a wide range of mitochondrial activities. These findings will help reveal molecular mechanisms between mtDNA CN and CVD.


Assuntos
Epigenoma , Genoma Mitocondrial , Idoso , Variações do Número de Cópias de DNA/genética , Metilação de DNA/genética , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Epigenoma/genética , Feminino , Genoma Mitocondrial/genética , Humanos , Masculino , Pessoa de Meia-Idade
12.
J Nutr ; 151(9): 2574-2582, 2021 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-34159370

RESUMO

BACKGROUND: Alcohol consumption and cardiovascular disease (CVD) have a complex relation. OBJECTIVES: We examined the associations between alcohol consumption, fasting plasma proteins, and CVD risk. METHODS: We performed cross-sectional association analyses of alcohol consumption with 71 CVD-related plasma proteins, and also performed prospective association analyses of alcohol consumption and protein concentrations with 3 CVD risk factors (obesity, hypertension, and diabetes) in 6745 Framingham Heart Study (FHS) participants (mean age 49 y; 53% women). RESULTS: A unit increase in log10 transformed alcohol consumption (g/d) was associated with an increased risk of hypertension (HR = 1.14; 95% CI: 1.04, 1.26; P = 0.007), and decreased risks of obesity (HR = 0.80; 95% CI: 0.71, 0.91; P = 4.6 × 10-4) and diabetes (HR: 0.68; 95% CI: 0.58, 0.80; P = 5.1 × 10-6) in a median of 13-y (interquartile = 7, 14) of follow-up. We identified 43 alcohol-associated proteins in a discovery sample (n = 4348, false discovery rate <0.05) and 20 of them were significant (P <0.05/43) in an independent validation sample (n = 2397). Eighteen of the 20 proteins were inversely associated with alcohol consumption. Four of the 20 proteins demonstrated 3-way associations, as expected, with alcohol consumption and CVD risk factors. For example, a greater concentration of APOA1 was associated with higher alcohol consumption (P = 1.2 × 10-65), and it was also associated with a lower risk of diabetes (P = 8.5 × 10-6). However, several others showed unexpected 3-way associations. CONCLUSIONS: We identified 20 alcohol-associated proteins in 6745 FHS samples. These alcohol-associated proteins demonstrated complex relations with the 3 CVD risk factors. Future studies with integration of more proteomic markers and larger sample size are warranted to unravel the complex relation between alcohol consumption and CVD risk.


Assuntos
Doenças Cardiovasculares , Consumo de Bebidas Alcoólicas/efeitos adversos , Biomarcadores , Doenças Cardiovasculares/etiologia , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Proteômica , Fatores de Risco
13.
Clin Epigenetics ; 13(1): 43, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33632303

RESUMO

BACKGROUND: Epigenetic alterations may contribute to early detection of cancer. We evaluated the association of blood DNA methylation with lymphatic-hematopoietic cancers and, for comparison, with solid cancers. We also evaluated the predictive ability of DNA methylation for lymphatic-hematopoietic cancers. METHODS: Blood DNA methylation was measured using the Illumina Infinium methylationEPIC array in 2324 Strong Heart Study participants (41.4% men, mean age 56 years). 788,368 CpG sites were available for differential DNA methylation analysis for lymphatic-hematopoietic, solid and overall cancers using elastic-net and Cox regression models. We conducted replication in an independent population: the Framingham Heart Study. We also analyzed differential variability and conducted bioinformatic analyses to assess for potential biological mechanisms. RESULTS: Over a follow-up of up to 28 years (mean 15), we identified 41 lymphatic-hematopoietic and 394 solid cancer cases. A total of 126 CpGs for lymphatic-hematopoietic cancers, 396 for solid cancers, and 414 for overall cancers were selected as predictors by the elastic-net model. For lymphatic-hematopoietic cancers, the predictive ability (C index) increased from 0.58 to 0.87 when adding these 126 CpGs to the risk factor model in the discovery set. The association was replicated with hazard ratios in the same direction in 28 CpGs in the Framingham Heart Study. When considering the association of variability, rather than mean differences, we found 432 differentially variable regions for lymphatic-hematopoietic cancers. CONCLUSIONS: This study suggests that differential methylation and differential variability in blood DNA methylation are associated with lymphatic-hematopoietic cancer risk. DNA methylation data may contribute to early detection of lymphatic-hematopoietic cancers.


Assuntos
Detecção Precoce de Câncer/métodos , Neoplasias Hematológicas/genética , Sistema Linfático/patologia , Neoplasias/sangue , Neoplasias/genética , /etnologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etnologia , Biologia Computacional/métodos , Ilhas de CpG , Metilação de DNA , Epigenômica , Feminino , Seguimentos , Neoplasias Hematológicas/patologia , Humanos , Incidência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Valor Preditivo dos Testes , Estudos Prospectivos , Mapas de Interação de Proteínas/genética , Fatores de Risco
14.
Circ Res ; 128(1): e1-e23, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33092465

RESUMO

RATIONALE: Previous translational studies implicate plasma extracellular microRNA-30d (miR-30d) as a biomarker in left ventricular remodeling and clinical outcome in heart failure (HF) patients, although precise mechanisms remain obscure. OBJECTIVE: To investigate the mechanism of miR-30d-mediated cardioprotection in HF. METHODS AND RESULTS: In rat and mouse models of ischemic HF, we show that miR-30d gain of function (genetic, lentivirus, or agomiR-mediated) improves cardiac function, decreases myocardial fibrosis, and attenuates cardiomyocyte (CM) apoptosis. Genetic or locked nucleic acid-based knock-down of miR-30d expression potentiates pathological left ventricular remodeling, with increased dysfunction, fibrosis, and cardiomyocyte death. RNA sequencing of in vitro miR-30d gain and loss of function, together with bioinformatic prediction and experimental validation in cardiac myocytes and fibroblasts, were used to identify and validate direct targets of miR-30d. miR-30d expression is selectively enriched in cardiomyocytes, induced by hypoxic stress and is acutely protective, targeting MAP4K4 (mitogen-associate protein kinase 4) to ameliorate apoptosis. Moreover, miR-30d is secreted primarily in extracellular vesicles by cardiomyocytes and inhibits fibroblast proliferation and activation by directly targeting integrin α5 in the acute phase via paracrine signaling to cardiac fibroblasts. In the chronic phase of ischemic remodeling, lower expression of miR-30d in the heart and plasma extracellular vesicles is associated with adverse remodeling in rodent models and human subjects and is linked to whole-blood expression of genes implicated in fibrosis and inflammation, consistent with observations in model systems. CONCLUSIONS: These findings provide the mechanistic underpinning for the cardioprotective association of miR-30d in human HF. More broadly, our findings support an emerging paradigm involving intercellular communication of extracellular vesicle-contained miRNAs (microRNAs) to transregulate distinct signaling pathways across cell types. Functionally validated RNA biomarkers and their signaling networks may warrant further investigation as novel therapeutic targets in HF.


Assuntos
MicroRNAs/metabolismo , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Comunicação Parácrina , Função Ventricular Esquerda , Remodelação Ventricular , Animais , Apoptose , Células Cultivadas , Modelos Animais de Doenças , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Regulação da Expressão Gênica , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , MicroRNAs/genética , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , /metabolismo , Ratos Sprague-Dawley , Ratos Transgênicos , Transdução de Sinais
15.
Genet Epidemiol ; 45(3): 280-292, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33038041

RESUMO

Multiple methods have been proposed to aggregate genetic variants in a gene or a region and jointly test their association with a trait of interest. However, these joint tests do not provide estimates of the individual effect of each variant. Moreover, few methods have evaluated the joint association of multiple variants with DNA methylation. We propose a method based on linear mixed models to estimate the joint and individual effect of multiple genetic variants on DNA methylation leveraging genomic annotations. Our approach is flexible, can incorporate covariates and annotation features, and takes into account relatedness and linkage disequilibrium (LD). Our method had correct Type-I error and overall high power for different simulated scenarios where we varied the number and specificity of functional annotations, number of causal and total genetic variants, frequency of genetic variants, LD, and genetic variant effect. Our method outperformed the family Sequence Kernel Association Test and had more stable estimations of effects than a classical single-variant linear mixed-effect model. Applied genome-wide to the Framingham Heart Study data, our method identified 921 DNA methylation sites influenced by at least one rare or low-frequency genetic variant located within 50 kilobases (kb) of the DNA methylation site.


Assuntos
Metilação de DNA , Modelos Genéticos , Humanos , Modelos Lineares , Desequilíbrio de Ligação , Fenótipo
16.
Aging (Albany NY) ; 12(14): 14092-14124, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32697766

RESUMO

DNA methylation has fundamental roles in gene programming and aging that may help predict mortality. However, no large-scale study has investigated whether site-specific DNA methylation predicts all-cause mortality. We used the Illumina-HumanMethylation450-BeadChip to identify blood DNA methylation sites associated with all-cause mortality for 12, 300 participants in 12 Cohorts of the Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium. Over an average 10-year follow-up, there were 2,561 deaths across the cohorts. Nine sites mapping to three intergenic and six gene-specific regions were associated with mortality (P < 9.3x10-7) independently of age and other mortality predictors. Six sites (cg14866069, cg23666362, cg20045320, cg07839457, cg07677157, cg09615688)-mapping respectively to BMPR1B, MIR1973, IFITM3, NLRC5, and two intergenic regions-were associated with reduced mortality risk. The remaining three sites (cg17086398, cg12619262, cg18424841)-mapping respectively to SERINC2, CHST12, and an intergenic region-were associated with increased mortality risk. DNA methylation at each site predicted 5%-15% of all deaths. We also assessed the causal association of those sites to age-related chronic diseases by using Mendelian randomization, identifying weak causal relationship between cg18424841 and cg09615688 with coronary heart disease. Of the nine sites, three (cg20045320, cg07839457, cg07677157) were associated with lower incidence of heart disease risk and two (cg20045320, cg07839457) with smoking and inflammation in prior CHARGE analyses. Methylation of cg20045320, cg07839457, and cg17086398 was associated with decreased expression of nearby genes (IFITM3, IRF, NLRC5, MT1, MT2, MARCKSL1) linked to immune responses and cardiometabolic diseases. These sites may serve as useful clinical tools for mortality risk assessment and preventative care.


Assuntos
Metilação de DNA/genética , Valor Preditivo dos Testes , Adulto , Idoso , Envelhecimento , Causas de Morte , Mapeamento Cromossômico , Doença Crônica/epidemiologia , Estudos de Coortes , Epigênese Genética , Feminino , Seguimentos , Estudo de Associação Genômica Ampla , Humanos , Estudos Longitudinais , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Locos de Características Quantitativas , Medição de Risco
17.
Circ Genom Precis Med ; 13(4): e002766, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32525743

RESUMO

BACKGROUND: DNA methylation patterns associated with habitual diet have not been well studied. METHODS: Diet quality was characterized using a Mediterranean-style diet score and the Alternative Healthy Eating Index score. We conducted ethnicity-specific and trans-ethnic epigenome-wide association analyses for diet quality and leukocyte-derived DNA methylation at over 400 000 CpGs (cytosine-guanine dinucleotides) in 5 population-based cohorts including 6662 European ancestry, 2702 African ancestry, and 360 Hispanic ancestry participants. For diet-associated CpGs identified in epigenome-wide analyses, we conducted Mendelian randomization (MR) analysis to examine their relations to cardiovascular disease risk factors and examined their longitudinal associations with all-cause mortality. RESULTS: We identified 30 CpGs associated with either Mediterranean-style diet score or Alternative Healthy Eating Index, or both, in European ancestry participants. Among these CpGs, 12 CpGs were significantly associated with all-cause mortality (Bonferroni corrected P<1.6×10-3). Hypermethylation of cg18181703 (SOCS3) was associated with higher scores of both Mediterranean-style diet score and Alternative Healthy Eating Index and lower risk for all-cause mortality (P=5.7×10-15). Ten additional diet-associated CpGs were nominally associated with all-cause mortality (P<0.05). MR analysis revealed 8 putatively causal associations for 6 CpGs with 4 cardiovascular disease risk factors (body mass index, triglycerides, high-density lipoprotein cholesterol concentrations, and type 2 diabetes mellitus; Bonferroni corrected MR P<4.5×10-4). For example, hypermethylation of cg11250194 (FADS2) was associated with lower triglyceride concentrations (MR, P=1.5×10-14).and hypermethylation of cg02079413 (SNORA54; NAP1L4) was associated with body mass index (corrected MR, P=1×10-6). CONCLUSIONS: Habitual diet quality was associated with differential peripheral leukocyte DNA methylation levels of 30 CpGs, most of which were also associated with multiple health outcomes, in European ancestry individuals. These findings demonstrate that integrative genomic analysis of dietary information may reveal molecular targets for disease prevention and treatment.


Assuntos
Doenças Cardiovasculares/genética , Metilação de DNA , Dieta Mediterrânea , Leucócitos/metabolismo , Índice de Massa Corporal , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/patologia , Ilhas de CpG , Ácidos Graxos Dessaturases/genética , Estudo de Associação Genômica Ampla , Humanos , Proteínas Nucleares/genética , Fatores de Risco , Proteína 3 Supressora da Sinalização de Citocinas/genética , Triglicerídeos/sangue , /genética
18.
Epigenetics ; 15(1-2): 183-198, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31282290

RESUMO

DNA methylation (DNAm) and microRNAs (miRNAs) have been implicated in a wide-range of human diseases. While often studied in isolation, DNAm and miRNAs are not independent. We analyzed associations of expression of 283 miRNAs with DNAm at >400K CpG sites in whole blood obtained from 3565 individuals and identified 227 CpGs at which differential methylation was associated with the expression of 40 nearby miRNAs (cis-miR-eQTMs) at FDR<0.01, including 91 independent CpG sites at r2 < 0.2. cis-miR-eQTMs were enriched for CpGs in promoter and polycomb-repressed state regions, and 60% were inversely associated with miRNA expression. Bidirectional Mendelian randomization (MR) analysis further identified 58 cis-miR-eQTMCpG-miRNA pairs where DNAm changes appeared to drive miRNA expression changes and opposite directional effects were unlikely. Integration of genetic variants in joint analyses revealed an average partial between cis-miR-eQTM CpGs and miRNAs of 2% after conditioning on site-specific genetic variation, suggesting that DNAm is an important epigenetic regulator of miRNA expression. Finally, two-step MR analysis was performed to identify putatively causal CpGs driving miRNA expression in relation to human complex traits. We found that an imprinted region on 14q32 that was previously identified in relation to age at menarche is enriched with cis-miR-eQTMs. Nine CpGs and three miRNAs at this locus tested causal for age at menarche, reflecting novel epigenetic-driven molecular pathways underlying this complex trait. Our study sheds light on the joint genetic and epigenetic regulation of miRNA expression and provides insights into the relations of miRNAs to their targets and to complex phenotypes.


Assuntos
Metilação de DNA , Epigenoma , MicroRNAs/genética , Herança Multifatorial , Cromossomos Humanos Par 14/genética , Ilhas de CpG , Epigenômica/métodos , Estudo de Associação Genômica Ampla/métodos , Impressão Genômica , Humanos , Menarca/genética , Análise da Randomização Mendeliana/métodos , MicroRNAs/metabolismo , Locos de Características Quantitativas , Transcriptoma
19.
Clin Epigenetics ; 11(1): 160, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31730017

RESUMO

BACKGROUND: The metabolic syndrome (MetS) is a collection of metabolic disturbances that can lead to various cardiovascular diseases. Previous studies have shown a more adverse metabolic risk profile is associated with more advanced biological aging. The associations between epigenetic biomarkers of age with MetS, however, are not well understood. We therefore investigated the associations between epigenetic age acceleration and MetS severity score and incident MetS. RESULTS: A subset of study participants with available whole blood at examination years 15 and 20 from the Coronary Artery Risk Development in Young Adults Study underwent epigenomic profiling using the Illumina MethylationEPIC Beadchip (~ 850,000 sites). Intrinsic and extrinsic epigenetic age acceleration (IEAA and EEAA) were calculated from DNA methylation levels. The MetS severity score was positively associated with IEAA at years 15 (P = 0.016) and 20 (P = 0.016) and EEAA at year 20 (P = 0.040) in cross-sectional analysis. IEAA at year 20 was significantly associated with incident MetS at year 30 (OR = 1.05 [95% CI 1.01, 1.10], P = 0.028). CONCLUSIONS: To our knowledge, this is the first report of the longitudinal association between epigenetic age acceleration and MetS. These findings suggest that a higher MetS severity score is associated with accelerated epigenetic aging and such aging may play a role in the development of metabolic disorders, potentially serving as a useful biomarker of and early detection tool for future MetS.


Assuntos
Envelhecimento/genética , Doenças Cardiovasculares/etiologia , Metilação de DNA , Síndrome Metabólica/genética , Adolescente , Adulto , Doenças Cardiovasculares/genética , Estudos Transversais , Epigênese Genética , Epigenômica/métodos , Feminino , Humanos , Estudos Longitudinais , Masculino , Síndrome Metabólica/complicações , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Adulto Jovem
20.
Nat Commun ; 10(1): 4267, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31537805

RESUMO

Identifying methylation quantitative trait loci (meQTLs) and integrating them with disease-associated variants from genome-wide association studies (GWAS) may illuminate functional mechanisms underlying genetic variant-disease associations. Here, we perform GWAS of >415 thousand CpG methylation sites in whole blood from 4170 individuals and map 4.7 million cis- and 630 thousand trans-meQTL variants targeting >120 thousand CpGs. Independent replication is performed in 1347 participants from two studies. By linking cis-meQTL variants with GWAS results for cardiovascular disease (CVD) traits, we identify 92 putatively causal CpGs for CVD traits by Mendelian randomization analysis. Further integrating gene expression data reveals evidence of cis CpG-transcript pairs causally linked to CVD. In addition, we identify 22 trans-meQTL hotspots each targeting more than 30 CpGs and find that trans-meQTL hotspots appear to act in cis on expression of nearby transcriptional regulatory genes. Our findings provide a powerful meQTL resource and shed light on DNA methylation involvement in human diseases.


Assuntos
Doenças Cardiovasculares/genética , Metilação de DNA/genética , Predisposição Genética para Doença/genética , Locos de Características Quantitativas/genética , Idoso , Ilhas de CpG/genética , Feminino , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética
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