Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Nat Commun ; 10(1): 2581, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197173

RESUMO

Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.


Assuntos
Metilação de DNA/fisiologia , Diabetes Mellitus Tipo 2/genética , Glucose/metabolismo , Insulina/metabolismo , Obesidade/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Simulação por Computador , Ilhas de CpG/genética , Diabetes Mellitus Tipo 2/metabolismo , Epigênese Genética/fisiologia , Epigenômica/métodos , Feminino , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla/métodos , Homeostase/genética , Humanos , Masculino , Redes e Vias Metabólicas/genética , Pessoa de Meia-Idade , Obesidade/metabolismo , Polimorfismo de Nucleotídeo Único/fisiologia , Adulto Jovem
2.
Aging Cell ; 17(5): e12799, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29992704

RESUMO

To characterize the proteomic signature of chronological age, 1,301 proteins were measured in plasma using the SOMAscan assay (SomaLogic, Boulder, CO, USA) in a population of 240 healthy men and women, 22-93 years old, who were disease- and treatment-free and had no physical and cognitive impairment. Using a p ≤ 3.83 × 10-5 significance threshold, 197 proteins were positively associated, and 20 proteins were negatively associated with age. Growth differentiation factor 15 (GDF15) had the strongest, positive association with age (GDF15; 0.018 ± 0.001, p = 7.49 × 10-56 ). In our sample, GDF15 was not associated with other cardiovascular risk factors such as cholesterol or inflammatory markers. The functional pathways enriched in the 217 age-associated proteins included blood coagulation, chemokine and inflammatory pathways, axon guidance, peptidase activity, and apoptosis. Using elastic net regression models, we created a proteomic signature of age based on relative concentrations of 76 proteins that highly correlated with chronological age (r = 0.94). The generalizability of our findings needs replication in an independent cohort.

3.
JAMA Cardiol ; 3(6): 463-472, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29617535

RESUMO

Importance: Tumor necrosis factor α (TNF-α) is a proinflammatory cytokine with manifold consequences for mammalian pathophysiology, including cardiovascular disease. A deeper understanding of TNF-α biology may enhance treatment precision. Objective: To conduct an epigenome-wide analysis of blood-derived DNA methylation and TNF-α levels and to assess the clinical relevance of findings. Design, Setting, and Participants: This meta-analysis assessed epigenome-wide associations in circulating TNF-α concentrations from 5 cohort studies and 1 interventional trial, with replication in 3 additional cohort studies. Follow-up analyses investigated associations of identified methylation loci with gene expression and incident coronary heart disease; this meta-analysis included 11 461 participants who experienced 1895 coronary events. Exposures: Circulating TNF-α concentration. Main Outcomes and Measures: DNA methylation at approximately 450 000 loci, neighboring DNA sequence variation, gene expression, and incident coronary heart disease. Results: The discovery cohort included 4794 participants, and the replication study included 816 participants (overall mean [SD] age, 60.7 [8.5] years). In the discovery stage, circulating TNF-α levels were associated with methylation of 7 cytosine-phosphate-guanine (CpG) sites, 3 of which were located in or near DTX3L-PARP9 at cg00959259 (ß [SE] = -0.01 [0.003]; P = 7.36 × 10-8), cg08122652 (ß [SE] = -0.008 [0.002]; P = 2.24 × 10-7), and cg22930808(ß [SE] = -0.01 [0.002]; P = 6.92 × 10-8); NLRC5 at cg16411857 (ß [SE] = -0.01 [0.002]; P = 2.14 × 10-13) and cg07839457 (ß [SE] = -0.02 [0.003]; P = 6.31 × 10-10); or ABO, at cg13683939 (ß [SE] = 0.04 [0.008]; P = 1.42 × 10-7) and cg24267699 (ß [SE] = -0.009 [0.002]; P = 1.67 × 10-7), after accounting for multiple testing. Of these, negative associations between TNF-α concentration and methylation of 2 loci in NLRC5 and 1 in DTX3L-14 PARP9 were replicated. Replicated TNF-α-linked CpG sites were associated with 9% to 19% decreased risk of incident coronary heart disease per 10% higher methylation per CpG site (cg16411857: hazard ratio [HR], 0.86; 95% CI, 0.78-1.95; P = .003; cg07839457: HR, 0.89; 95% CI, 0.80-0.94; P = 3.1 × 10-5; cg00959259: HR, 0.91; 95% CI, 0.84-0.97; P = .002; cg08122652: HR, 0.81; 95% CI, 0.74-0.89; P = 2.0 × 10-5). Conclusions and Relevance: We identified and replicated novel epigenetic correlates of circulating TNF-α concentration in blood samples and linked these loci to coronary heart disease risk, opening opportunities for validation and therapeutic applications.

4.
Aging Cell ; 17(1)2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29047204

RESUMO

Mitochondrial DNA copy number (mtDNA-CN) estimated in whole blood is a novel marker of mitochondrial mass and function that can be used in large population-based studies. Analyses that attempt to relate mtDNA-CN to specific aging phenotypes may be confounded by differences in the distribution of blood cell types across samples. Also, low or high mtDNA-CN may have a different meaning given the presence of diseases associated with mitochondrial damage. We evaluated the impact of blood cell type distribution and diabetes status on the association between mtDNA-CN and aging phenotypes, namely chronologic age, interleukin-6, hemoglobin, and all-cause mortality, among 672 participants of the InCHIANTI study. After accounting for white blood cell count, platelet count, and white blood cell proportions in multivariate models, associations of mtDNA-CN with age and interleukin-6 were no longer statistically significant. Evaluation of a statistical interaction by diabetes status suggested heterogeneity of effects in the analysis of mortality (P < 0.01). The magnitude and direction of associations between mtDNA-CN estimated from blood samples and aging phenotypes are influenced by the sample cell type distribution and disease status. Therefore, accounting for these factors may aid understanding of the relevance of mitochondrial DNA copy number to health and aging.

5.
Aging (Albany NY) ; 8(9): 1844-1865, 2016 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-27690265

RESUMO

Estimates of biological age based on DNA methylation patterns, often referred to as "epigenetic age", "DNAm age", have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were predictive of mortality (p≤8.2x10-9), independent of chronological age, even after adjusting for additional risk factors (p<5.4x10-4), and within the racial/ethnic groups that we examined (non-Hispanic whites, Hispanics, African Americans). Epigenetic age estimates that incorporated information on blood cell composition led to the smallest p-values for time to death (p=7.5x10-43). Overall, this study a) strengthens the evidence that epigenetic age predicts all-cause mortality above and beyond chronological age and traditional risk factors, and b) demonstrates that epigenetic age estimates that incorporate information on blood cell counts lead to highly significant associations with all-cause mortality.


Assuntos
Envelhecimento/fisiologia , Metilação de DNA/fisiologia , Envelhecimento/genética , Grupos de Populações Continentais , Epigênese Genética , Feminino , Humanos , Modelos Logísticos , Masculino , Mortalidade , Fatores de Risco , Análise de Sobrevida , Subpopulações de Linfócitos T
6.
J Gerontol A Biol Sci Med Sci ; 71(8): 1029-35, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26355017

RESUMO

Patterns of DNA methylation (DNAm) that track with aging have been identified. However, the relevance of these patterns for aging outcomes remains unclear. Longitudinal epigenome-wide DNAm information was obtained from the InCHIANTI study, a large representative European population. DNAm was evaluated using the Illumina HumanMethylation450 array on blood samples collected at baseline and 9-year follow-up: observations from 499 participants with paired longitudinal blood sample and information on differential blood count were included in analyses. A total of 56,579 markers were significantly associated with age in cross-sectional analysis of DNAm at year 9, 31,252 markers were changed significantly over the 9-year follow-up, and 16,987 markers were both cross-sectionally associated with age and significantly changed over time. Rates of change at 76 markers and year 9 level of DNAm at 88 markers were identified as strongly associated with mortality in Cox proportional hazard models adjusted for age and relevant covariates (mean follow-up time 4.4 years). Less than 0.05% of markers associated with age or that changed over time were also associated with mortality after adjusting for chronological age. Although the influence of DNAm on health and longevity remains unclear, these findings confirm that aging is associated cross-sectionally and longitudinally with robust and consistent patterns of methylation change.


Assuntos
Envelhecimento/genética , Metilação de DNA/genética , Epigenômica , Mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Contagem de Células Sanguíneas , Índice de Massa Corporal , Estudos Transversais , Feminino , Seguimentos , Humanos , Longevidade , Masculino , Pessoa de Meia-Idade
7.
Am J Hum Genet ; 94(4): 485-95, 2014 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-24656863

RESUMO

Epigenetic marks such as DNA methylation have generated great interest in the study of human disease. However, studies of DNA methylation have not established population-epigenetics principles to guide design, efficient statistics, or interpretation. Here, we show that the clustering of correlated DNA methylation at CpGs was similar to that of linkage-disequilibrium (LD) correlation in genetic SNP variation but for much shorter distances. Some clustering of methylated CpGs appeared to be genetically driven. Further, a set of correlated methylated CpGs related to a single SNP-based LD block was not always physically contiguous-segments of uncorrelated methylation as long as 300 kb could be interspersed in the cluster. Thus, we denoted these sets of correlated CpGs as GeMes, defined as potentially noncontiguous methylation clusters under the control of one or more methylation quantitative trait loci. This type of correlated methylation structure has implications for both biological functions of DNA methylation and for the design, analysis, and interpretation of epigenome-wide association studies.


Assuntos
Metilação de DNA , Epigênese Genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Desequilíbrio de Ligação , Polimorfismo de Nucleotídeo Único , Fumar/genética
8.
J Am Geriatr Soc ; 62(2): 230-6, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24438020

RESUMO

OBJECTIVES: To examine differences in a proxy measure of muscle quality across the adult life span and explore potential mechanisms of muscle quality change through identification of cross-sectional correlates of muscle quality. DESIGN: Cross-sectional study. SETTING: Baltimore Longitudinal Study of Aging. PARTICIPANTS: Seven hundred eighty-six individuals with a mean age of 66.3 (range 26-96) (N = 786). A sensitivity analysis was conducted in a subset of participants matched according to sex, muscle mass, and body size. MEASUREMENTS: Muscle quality was operationalized as the ratio of knee-extension strength (isokinetic dynamometry) to thigh muscle cross-sectional area (computed tomography). Differences in muscle strength, muscle area, and muscle quality ratio with age were evaluated, and the association between the muscle quality ratio and measures reflecting domains of cognitive function, motor control, peripheral nerve function, adiposity, glucose homeostasis, and inflammation were assessed through multivariate regression analyses. RESULTS: A linear relationship between age and muscle quality ratio was observed, suggesting a gradual decline in muscle quality over the adult life course. Associations were observed between muscle quality ratio and measures of adiposity, as well as peroneal nerve motor conduction velocity, finger tapping speed, and memory performance (P < .01). The association between muscle quality ratio and nerve conduction velocity was maintained after adjustment for anthropometric measurements (P < .05). CONCLUSION: Muscle quality declines progressively with age over the adult life span and is affected by obesity and neurological factors. Studies are needed to clarify the mechanisms of these associations and their implications for functional outcomes.


Assuntos
Envelhecimento/fisiologia , Avaliação Geriátrica/métodos , Força Muscular/fisiologia , Músculo Quadríceps/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Baltimore , Índice de Massa Corporal , Estudos Transversais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/fisiopatologia , Músculo Quadríceps/diagnóstico por imagem , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA