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1.
Epigenetics ; : 1-23, 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34227900

RESUMO

Epigenetic clocks have been widely used to predict disease risk in multiple tissues or cells. Their success as a measure of biological ageing has prompted research on the connection between epigenetic pathways of ageing and the socioeconomic gradient in health and mortality. However, studies examining social correlates of epigenetic ageing have yielded inconsistent results. We conducted a comprehensive, comparative analysis of associations between various dimensions of socioeconomic status (SES) (education, income, wealth, occupation, neighbourhood environment, and childhood SES) and eight epigenetic clocks in two well-powered US ageing studies: The Multi-Ethnic Study of Atherosclerosis (MESA) (n = 1,211) and the Health and Retirement Study (HRS) (n = 4,018). In both studies, we found robust associations between SES measures in adulthood and the GrimAge and DunedinPoAm clocks (Bonferroni-corrected p-value < 0.01). In the HRS, significant associations with the Levine and Yang clocks were also evident. These associations were only partially mediated by smoking, alcohol consumption, and obesity, which suggests that differences in health behaviours alone cannot explain the SES gradient in epigenetic ageing in older adults. Further analyses revealed concurrent associations between polygenic risk for accelerated intrinsic epigenetic ageing, SES, and the Levine clock, indicating that genetic risk and social disadvantage may contribute additively to faster biological aging.

2.
Genome Biol ; 22(1): 194, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34187551

RESUMO

BACKGROUND: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. RESULTS: Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. CONCLUSION: This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.

3.
Aging (Albany NY) ; 13(11): 14604-14629, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083497

RESUMO

DNA methylation age acceleration, the discrepancy between epigenetic age and chronological age, is associated with mortality and chronic diseases, including diabetes, hypertension, and hyperlipidemia. In this study, we investigate whether medications commonly used to treat these diseases in 15 drug categories are associated with four epigenetic age acceleration measures: HorvathAge acceleration (HorvathAA), HannumAge acceleration (HannumAA), PhenoAge acceleration, and GrimAge acceleration (GrimAA) using cross-sectional (Phase 1, N=1,100) and longitudinal (Phases 1 and 2, N=266) data from African Americans in the Genetic Epidemiology Network of Arteriopathy (GENOA) study. In cross-sectional analyses, the use of calcium channel blockers was associated with 1.27 years lower HannumAA after adjusting for covariates including hypertension (p=0.001). Longitudinal analyses showed that, compared to those who never used antihypertensives, those who started to take antihypertensives after Phase 1 had a 0.97-year decrease in GrimAA (p=0.007). In addition, compared to those who never used NSAID analgesics, those who started to take them after Phase 1 had a 2.61-year increase in HorvathAA (p=0.0005). Our study demonstrates that three commonly used medications are associated with DNAm age acceleration in African Americans and sheds light on the potential epigenetic effects of pharmaceuticals on aging at the cellular level.


Assuntos
Afro-Americanos/genética , Envelhecimento/genética , Metilação de DNA/genética , Preparações Farmacêuticas , Adulto , Anti-Inflamatórios não Esteroides/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Caracteres Sexuais
4.
Clin Epigenetics ; 13(1): 55, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33726838

RESUMO

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of mortality among US adults. African Americans have higher burden of CVD morbidity and mortality compared to any other racial group. Identifying biomarkers for clinical risk prediction of CVD offers an opportunity for precision prevention and earlier intervention. RESULTS: Using linear mixed models, we investigated the cross-sectional association between four measures of epigenetic age acceleration (intrinsic (IEAA), extrinsic (EEAA), PhenoAge (PhenoAA), and GrimAge (GrimAA)) and ten cardiometabolic markers of hypertension, insulin resistance, and dyslipidemia in 1,100 primarily hypertensive African Americans from sibships in the Genetic Epidemiology Network of Arteriopathy (GENOA). We then assessed the association between epigenetic age acceleration and time to self-reported incident CVD using frailty hazard models and investigated CVD risk prediction improvement compared to models with clinical risk scores (Framingham risk score (FRS) and the atherosclerotic cardiovascular disease (ASCVD) risk equation). After adjusting for sex and chronological age, increased epigenetic age acceleration was associated with higher systolic blood pressure (IEAA), higher pulse pressure (EEAA and GrimAA), higher fasting glucose (PhenoAA and GrimAA), higher fasting insulin (EEAA), lower low density cholesterol (GrimAA), and higher triglycerides (GrimAA). A five-year increase in GrimAA was associated with CVD incidence with a hazard ratio of 1.54 (95% CI 1.22-2.01) and remained significant after adjusting for CVD risk factors. The addition of GrimAA to risk score models improved model fit using likelihood ratio tests (P = 0.013 for FRS and P = 0.008 for ASCVD), but did not improve C statistics (P > 0.05). Net reclassification index (NRI) showed small but significant improvement in reassignment of risk categories with the addition of GrimAA to FRS (NRI: 0.055, 95% CI 0.040-0.071) and the ASCVD equation (NRI: 0.029, 95% CI 0.006-0.064). CONCLUSIONS: Epigenetic age acceleration measures are associated with traditional CVD risk factors in an African-American cohort with a high prevalence of hypertension. GrimAA was associated with CVD incidence and slightly improved prediction of CVD events over clinical risk scores.

5.
Epigenetics ; 16(8): 862-875, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33100131

RESUMO

Target organ damage (TOD) manifests as vascular injuries in the body organ systems associated with long-standing hypertension. DNA methylation in peripheral blood leukocytes can capture inflammatory processes and gene expression changes underlying TOD. We investigated the association between epigenome-wide DNA methylation and five measures of TOD (estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (UACR), left ventricular mass index (LVMI), relative wall thickness (RWT), and white matter hyperintensity (WMH)) in 961 African Americans from hypertensive sibships. A multivariate (multi-trait) model of eGFR, UACR, LVMI, and RWT identified seven CpGs associated with at least one of the traits (cg21134922, cg04816311 near C7orf50, cg09155024, cg10254690 near OAT, cg07660512, cg12661888 near IFT43, and cg02264946 near CATSPERD) at FDR q < 0.1. Adjusting for blood pressure, body mass index, and type 2 diabetes attenuated the association for four CpGs. DNA methylation was associated with cis-gene expression for some CpGs, but no significant mediation by gene expression was detected. Mendelian randomization analyses suggested causality between three CpGs and eGFR (cg04816311, cg10254690, and cg07660512). We also assessed whether the identified CpGs were associated with TOD in 614 African Americans in the Hypertension Genetic Epidemiology Network (HyperGEN) study. Out of three CpGs available for replication, cg04816311 was significantly associated with eGFR (p = 0.0003), LVMI (p = 0.0003), and RWT (p = 0.002). This study found evidence of an association between DNA methylation and TOD in African Americans and highlights the utility of using a multivariate-based model that leverages information across related traits in epigenome-wide association studies.

6.
BMC Med Genomics ; 13(1): 131, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917208

RESUMO

BACKGROUND: Hypertension is a major modifiable risk factor for arteriosclerosis that can lead to target organ damage (TOD) of heart, kidneys, and peripheral arteries. A recent epigenome-wide association study for blood pressure (BP) identified 13 CpG sites, but it is not known whether DNA methylation at these sites is also associated with TOD. METHODS: In 1218 African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study, a cohort of hypertensive sibships, we evaluated the associations between methylation at these 13 CpG sites measured in peripheral blood leukocytes and five TOD traits assessed approximately 5 years later. RESULTS: Ten significant associations were found after adjustment for age, sex, blood cell counts, time difference between CpG and TOD measurement, and 10 genetic principal components (FDR q < 0.1): two with estimated glomerular filtration rate (eGFR, cg06690548, cg10601624), six with urinary albumin-to-creatinine ratio (UACR, cg16246545, cg14476101, cg19693031, cg06690548, cg00574958, cg22304262), and two with left ventricular mass indexed to height (LVMI, cg19693031, cg00574958). All associations with eGFR and four associations with UACR remained significant after further adjustment for body mass index (BMI), smoking status, and diabetes. We also found significant interactions between cg06690548 and BMI on UACR, and between 3 CpG sites (cg19693031, cg14476101, and cg06690548) and diabetes on UACR (FDR q < 0.1). Mediation analysis showed that 4.7% to 38.1% of the relationship between two CpG sites (cg19693031 and cg00574958) and two TOD measures (UACR and LVMI) was mediated by blood pressure (Bonferroni-corrected P < 0.05). Mendelian randomization analysis suggests that methylation at two sites (cg16246545 and cg14476101) in PHGDH may causally influence UACR. CONCLUSIONS: In conclusion, we found compelling evidence for associations between arteriosclerotic traits of kidney and heart and previously identified blood pressure-associated DNA methylation sites. This study may lend insight into the role of DNA methylation in pathological mechanisms underlying target organ damage from hypertension.


Assuntos
Afro-Americanos/estatística & dados numéricos , Arteriosclerose/fisiopatologia , Doenças Cardiovasculares/patologia , Metilação de DNA , Epigênese Genética , Hipertensão/complicações , Nefropatias/patologia , Pressão Sanguínea , Doenças Cardiovasculares/etiologia , Estudos de Coortes , Feminino , Taxa de Filtração Glomerular , Humanos , Hipertensão/epidemiologia , Hipertensão/genética , Nefropatias/etiologia , Masculino , Pessoa de Meia-Idade , Epidemiologia Molecular , Fatores de Risco
7.
Transl Psychiatry ; 10(1): 245, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32699239

RESUMO

Cognitive function such as reasoning, attention, memory, and language is strongly correlated with brain aging. Compared to non-Hispanic whites, Hispanics/Latinos have a higher risk of cognitive impairment and dementia. The genetic determinants of cognitive function have not been widely explored in this diverse and admixed population. We conducted a genome-wide association analysis of cognitive function in up to 7600 middle aged and older Hispanics/Latinos (mean = 55 years) from the Hispanic Community Health Study / Study of Latinos (HCHS/SOL). Four cognitive measures were examined: the Brief Spanish English Verbal Learning Test (B-SEVLT), the Word Fluency Test (WFT), the Digit Symbol Substitution Test (DSST), the Six-Item Screener (SIS). Four novel loci were identified: one for B-SEVLT at 4p14, two for WFT at 3p14.1 and 6p21.32, and one for DSST at 10p13. These loci implicate genes highly expressed in brain and previously connected to neurological diseases (UBE2K, FRMD4B, the HLA gene complex). By applying tissue-specific gene expression prediction models to our genotype data, additional genes highly expressed in brain showed suggestive associations with cognitive measures possibly indicating novel biological mechanisms, including IFT122 in the hippocampus for SIS, SNX31 in the basal ganglia for B-SEVLT, RPS6KB2 in the frontal cortex for WFT, and CSPG5 in the hypothalamus for DSST. These findings provide new information about the genetic determinants of cognitive function in this unique population. In addition, we derived a measure of general cognitive function based on these cognitive tests and generated genome-wide association summary results, providing a resource to the research community for comparison, replication, and meta-analysis in future genetic studies in Hispanics/Latinos.


Assuntos
Estudo de Associação Genômica Ampla , Saúde Pública , Idoso , Cognição , Hispano-Americanos/genética , Humanos , Pessoa de Meia-Idade , Testes Neuropsicológicos , Enzimas de Conjugação de Ubiquitina
8.
BMC Med Genomics ; 12(1): 141, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640709

RESUMO

BACKGROUND: Epigenetic age acceleration, a measure of biological aging based on DNA methylation, is associated with cardiovascular mortality. However, little is known about its relationship with hypertensive target organ damage to the heart, kidneys, brain, and peripheral arteries. METHODS: We investigated associations between intrinsic (IEAA) or extrinsic (EEAA) epigenetic age acceleration, blood pressure, and six types of organ damage in a primarily hypertensive cohort of 1390 African Americans from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. DNA methylation from peripheral blood leukocytes was collected at baseline (1996-2000), and measures of target organ damage were assessed in a follow-up visit (2000-2004). Linear regression with generalized estimating equations was used to test for associations between epigenetic age acceleration and target organ damage, as well as effect modification of epigenetic age by blood pressure or sex. Sequential Oligogenic Linkage Analysis Routines (SOLAR) was used to test for evidence of shared genetic and/or environmental effects between epigenetic age acceleration and organ damage pairs that were significantly associated. RESULTS: After adjustment for sex, chronological age, and time between methylation and organ damage measures, higher IEAA was associated with higher urine albumin to creatinine ratio (UACR, p = 0.004), relative wall thickness (RWT, p = 0.022), and left ventricular mass index (LVMI, p = 0.007), and with lower ankle-brachial index (ABI, p = 0.014). EEAA was associated with higher LVMI (p = 0.005). Target organ damage associations for all but IEAA with LVMI remained significant after further adjustment for blood pressure and antihypertensive use (p < 0.05). Further adjustment for diabetes attenuated the IEAA associations with UACR and RWT, and adjustment for smoking attenuated the IEAA association with ABI. No effect modification by age or sex was observed. CONCLUSIONS: Measures of epigenetic age acceleration may help to better characterize the functional mechanisms underlying organ damage from cellular aging and/or hypertension. These measures may act as subclinical biomarkers for damage to the kidney, heart, and peripheral vasculature; however more research is needed to determine whether these relationships remain independent of lifestyle factors and comorbidities.


Assuntos
Afro-Americanos/genética , Epigênese Genética , Hipertensão/patologia , Fatores Etários , Idoso , Índice Tornozelo-Braço , Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea , Creatinina/urina , Metilação de DNA , Feminino , Taxa de Filtração Glomerular , Ventrículos do Coração/química , Humanos , Hipertensão/tratamento farmacológico , Leucócitos Mononucleares/metabolismo , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Albumina Sérica Humana/urina
9.
Nat Hum Behav ; 3(9): 950-961, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31358974

RESUMO

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


Assuntos
Consumo de Bebidas Alcoólicas/genética , Genes/genética , Predisposição Genética para Doença/genética , Transtornos Mentais/genética , Adulto , Idoso , Alcoolismo/genética , Encéfalo/fisiopatologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Genes/fisiologia , Estudo de Associação Genômica Ampla , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Esquizofrenia/genética
10.
Am J Manag Care ; 24(11): e352-e357, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30452203

RESUMO

OBJECTIVES: We describe online portal account adoption and feature access among subgroups of patients who traditionally have been disadvantaged or represent those with high healthcare needs. STUDY DESIGN: Retrospective cohort study of insured primary care patients 18 years and older (N = 20,282) receiving care from an integrated health system. METHODS: Using data from an electronic health record repository, portal adoption was defined by 1 or more online sessions. Feature access (ie, messaging, appointment management, visit/admission summaries, and medical record access and management) was defined by user-initiated "clicks." Multivariable regression methods were used to identify patient factors associated with portal adoption and feature access among adopters. RESULTS: One-third of patients were portal adopters, with African Americans (odds ratio [OR], 0.50; 95% CI, 0.46-0.56), Hispanics (OR, 0.63; 95% CI, 0.47-0.84), those 70 years and older (OR, 0.48; 95% CI, 0.44-0.52), and those preferring a language other than English (OR, 0.43; 95% CI, 0.31-0.59) less likely to be adopters. On the other hand, the likelihood of portal adoption increased with a higher number of comorbidities (OR, 1.04; 95% CI, 1.02-1.07). Among adopters, record access and management features (95.9%) were accessed most commonly. The majority of adopters also accessed appointment management (76.6%) and messaging (59.1%) features. Similar race and age disparities were found in feature access among adopters. CONCLUSIONS: The diversity of portal features accessed may bode well for the ability of portals to engage some patients, but without purposeful intervention, reliance on portals alone for patient engagement may exacerbate known social disparities-even among those with an activated portal account.


Assuntos
Grupos de Populações Continentais/estatística & dados numéricos , Portais do Paciente/estatística & dados numéricos , Atenção Primária à Saúde/estatística & dados numéricos , Adulto , Fatores Etários , Idoso , Agendamento de Consultas , Comorbidade , Registros Eletrônicos de Saúde/estatística & dados numéricos , Correio Eletrônico/estatística & dados numéricos , Feminino , Humanos , Masculino , Michigan , Pessoa de Meia-Idade , Acesso dos Pacientes aos Registros/estatística & dados numéricos , Análise de Regressão , Estudos Retrospectivos , Fatores Sexuais
11.
Artigo em Inglês | MEDLINE | ID: mdl-29258278

RESUMO

Inter-individual variability in blood pressure (BP) is influenced by both genetic and non-genetic factors including socioeconomic and psychosocial stressors. A deeper understanding of the gene-by-socioeconomic/psychosocial factor interactions on BP may help to identify individuals that are genetically susceptible to high BP in specific social contexts. In this study, we used a genomic region-based method for longitudinal analysis, Longitudinal Gene-Environment-Wide Interaction Studies (LGEWIS), to evaluate the effects of interactions between known socioeconomic/psychosocial and genetic risk factors on systolic and diastolic BP in four large epidemiologic cohorts of European and/or African ancestry. After correction for multiple testing, two interactions were significantly associated with diastolic BP. In European ancestry participants, outward/trait anger score had a significant interaction with the C10orf107 genomic region (p = 0.0019). In African ancestry participants, depressive symptom score had a significant interaction with the HFE genomic region (p = 0.0048). This study provides a foundation for using genomic region-based longitudinal analysis to identify subgroups of the population that may be at greater risk of elevated BP due to the combined influence of genetic and socioeconomic/psychosocial risk factors.


Assuntos
Pressão Sanguínea/fisiologia , Interação Gene-Ambiente , Fatores Socioeconômicos , Afro-Americanos , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu , Humanos , Psicologia , Fatores de Risco , Estados Unidos
12.
Epigenetics ; 12(8): 662-673, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28678593

RESUMO

Living in a disadvantaged neighborhood is associated with poor health outcomes even after accounting for individual-level socioeconomic factors. The chronic stress of unfavorable neighborhood conditions may lead to dysregulation of the stress reactivity and inflammatory pathways, potentially mediated through epigenetic mechanisms such as DNA methylation. We used multi-level models to examine the relationship between 2 neighborhood conditions and methylation levels of 18 genes related to stress reactivity and inflammation in purified monocytes from 1,226 participants of the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based sample of US adults. Neighborhood socioeconomic disadvantage, a summary of 16 census-based metrics, was associated with DNA methylation [False discovery rate (FDR) q-value ≤ 0.1] in 2 out of 7 stress-related genes evaluated (CRF, SLC6A4) and 2 out of 11 inflammation-related genes (F8, TLR1). Neighborhood social environment, a summary measure of aesthetic quality, safety, and social cohesion, was associated with methylation in 4 of the 7 stress-related genes (AVP, BDNF, FKBP5, SLC6A4) and 7 of the 11 inflammation-related genes (CCL1, CD1D, F8, KLRG1, NLRP12, SLAMF7, TLR1). High socioeconomic disadvantage and worse social environment were primarily associated with increased methylation. In 5 genes with significant associations between neighborhood and methylation (FKBP5, CD1D, F8, KLRG1, NLRP12), methylation was associated with gene expression of at least one transcript. These results demonstrate that multiple dimensions of neighborhood context may influence methylation levels and subsequent gene expression of stress- and inflammation-related genes, even after accounting for individual socioeconomic factors. Further elucidating the molecular mechanisms underlying these relationships will be important for understanding the etiology of health disparities.


Assuntos
Aterosclerose/genética , Metilação de DNA , Características de Residência , Estresse Psicológico/genética , Idoso , Idoso de 80 Anos ou mais , Aterosclerose/epidemiologia , Aterosclerose/etnologia , Grupos de Populações Continentais , Feminino , Loci Gênicos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Socioeconômicos
13.
Biomed Res Int ; 2017: 5146378, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28459060

RESUMO

Falls are an important health concern among older adults due to age-related changes in the body. Having a medical history of chronic health condition may pose even higher risk of falling. Only few studies have assessed a number of chronic health conditions as risk factor for falls over a large nationally representative sample of US older adults. In this study, Behavioral Risk Factor Surveillance System (BRFSS) 2014 participants aged 65 years and older (n = 159,336) were evaluated. It was found that 29.7% (n = 44,550) of the sample experienced at least one fall and 16.3% (n = 20,444) experienced more than one fall in the past 12 months. According to the study findings, having a medical history of stroke, CKD, arthritis, depression, and diabetes independently predict the risk of first-time falling as well as the risk of recurrent falling in older adult population while controlling for other factors. On the other hand, having a medical history of the heart attack, angina, asthma, and COPD did not predict the risk of first-time falling, but did predict the risk of recurrent falling after experiencing the first fall in this population.


Assuntos
Acidentes por Quedas/estatística & dados numéricos , Doença Crônica/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Depressão , Feminino , Humanos , Vida Independente , Masculino , Fatores de Risco , Acidente Vascular Cerebral
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