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1.
Am J Hypertens ; 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31545351

RESUMO

BACKGROUND: Only a handful of genetic discovery efforts in apparent treatment resistant hypertension (aTRH) have been described. METHODS: We conducted a case-control genome-wide association study (GWAS) of aTRH among persons treated for hypertension, using data from 10 cohorts of European ancestry (EA) and 5 cohorts of African ancestry (AA). Cases were treated with 3 different antihypertensive medication classes and had blood pressure (BP) above goal (systolic (SBP)≥140 mm Hg and/or diastolic (DBP)≥90 mm Hg) or 4 or more medication classes regardless of BP control (nEA =931, nAA= 228). Both a normotensive control group and a treatment-responsive control group were considered in separate analyses. Normotensive controls were untreated (nEA = 14210, nAA= 2480) and had SBP/DBP <140/90 mm Hg. Treatment-responsive controls (nEA = 5266, nAA= 1817) had BP at goal (<140/90 mm Hg) while treated with one antihypertensive medication class. Individual cohorts used logistic regression with adjustment for age, sex, study site and principal components for ancestry to examine the association of SNPs with case-control status. Inverse variance-weighted fixed-effects meta-analyses were carried out using METAL. RESULTS: The known hypertension locus, CASZ1, was a top finding among EAs (P=1.1*10-8) and in the race-combined analysis (P=1.5*10-9) using the normotensive control group (rs12046278 OR=0.71[95% CI 0.6-0.8]). SNPs in this locus were robustly replicated in the Million Veterans Program (MVP) study in consideration of a treatment-responsive control group. There were no statistically significant findings for the discovery analyses including treatment-responsive controls. CONCLUSION: This genomic discovery effort for aTRH identified CASZ1 as an aTRH risk locus.

2.
Epigenetics ; : 1-13, 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31506003

RESUMO

DNA methylation (DNAm) has a well-established association with age in many tissues, including peripheral blood mononuclear cells (PBMCs). Compared to DNAm, the closely related epigenetic modification known as DNA hydroxymethylation (DNAhm) was much more recently discovered in mammals. Preliminary investigations have observed a positive correlation between gene body DNAhm and cis-gene expression. While some of these studies have observed an association between age and global DNAhm, none have investigated region-specific age-related DNAhm in human blood samples. In this study, we investigated DNAhm and gene expression in PBMCs of 10 young and 10 old, healthy female volunteers. Thousands of regions were differentially hydroxymethylated in the old vs. young individuals in gene bodies, exonic regions, enhancers, and promoters. Consistent with previous work, we observed directional consistency between age-related differences in DNAhm and gene expression. Further, age-related DNAhm and genes with high levels of DNAhm were enriched for immune system processes which may support a role of age-related DNAhm in immunosenescence.

3.
Environ Int ; 132: 105065, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31382185

RESUMO

BACKGROUND: Evidence of the association between daily variation in air pollution and risk of stroke is inconsistent, potentially due to the heterogeneity in stroke etiology. OBJECTIVES: To estimate the associations between daily variation in ambient air pollution and risk of stroke and its subtypes among participants of the Women's Health Initiative, a large prospective cohort study in the United States. METHODS: We used national-scale, log-normal ordinary kriging models to estimate daily concentrations of fine particulate matter (PM2.5), respirable particulate matter (PM10), nitrogen dioxide (NO2), nitrogen oxides (NOx), sulphur dioxide, and ozone at participant addresses. Stroke was adjudicated by trained neurologists and classified as ischemic or hemorrhagic. Ischemic strokes were further classified according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification. We used a time-stratified case-crossover approach to estimate the odds ratio (OR) of the risk of stroke associated with an interquartile range (IQR) increase in concentrations of each air pollutant. We performed stratified analysis to examine whether associations varied across subgroups defined by age at stroke onset, US census region, smoking status, body mass index, and prior history of diabetes mellitus, hypertension, heart or circulation problems, or arterial fibrillation at enrollment. RESULTS: Among 5417 confirmed strokes between 1993 and 2012, 4300 (79.4%) were classified as ischemic and 924 (17.1%) as hemorrhagic. No association was observed between day-to-day variation in any pollutant and risk of total stroke, ischemic stroke, or specific etiologies of ischemic stroke. We observed a positive association between risk of hemorrhagic stroke and NO2 and NOx in the 3 days prior to stroke with OR of 1.24 (95% CI: 1.01, 1.52) and 1.18 (95% CI: 1.03, 1.34) per IQR increase, respectively. The observed associations with hemorrhagic stroke were more pronounced among non-obese participants. CONCLUSIONS: In this large cohort of post-menopausal US women, daily NO2 and NOx were associated with higher risk of hemorrhagic stroke, but ambient levels of four other air pollutants were not associated with higher risk of total stroke, ischemic stroke, or ischemic stroke subtypes.

4.
Aging (Albany NY) ; 11(16): 5895-5923, 2019 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-31422385

RESUMO

Telomere length (TL) is associated with several aging-related diseases. Here, we present a DNA methylation estimator of TL (DNAmTL) based on 140 CpGs. Leukocyte DNAmTL is applicable across the entire age spectrum and is more strongly associated with age than measured leukocyte TL (LTL) (r ~-0.75 for DNAmTL versus r ~ -0.35 for LTL). Leukocyte DNAmTL outperforms LTL in predicting: i) time-to-death (p=2.5E-20), ii) time-to-coronary heart disease (p=6.6E-5), iii) time-to-congestive heart failure (p=3.5E-6), and iv) association with smoking history (p=1.21E-17). These associations are further validated in large scale methylation data (n=10k samples) from the Framingham Heart Study, Women's Health Initiative, Jackson Heart Study, InChianti, Lothian Birth Cohorts, Twins UK, and Bogalusa Heart Study. Leukocyte DNAmTL is also associated with measures of physical fitness/functioning (p=0.029), age-at-menopause (p=0.039), dietary variables (omega 3, fish, vegetable intake), educational attainment (p=3.3E-8) and income (p=3.1E-5). Experiments in cultured somatic cells show that DNAmTL dynamics reflect in part cell replication rather than TL per se. DNAmTL is not only an epigenetic biomarker of replicative history of cells, but a useful marker of age-related pathologies that are associated with it.

5.
Am Heart J ; 216: 1-8, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31352135

RESUMO

BACKGROUND: A lower prevalence of atrial fibrillation (AF), but paradoxically higher burden of cardiovascular disease risk factors, has been observed among African Americans compared to Whites in studies of AF identified by mostly 12-lead electrocardiograms (ECGs) and clinically. METHODS: We performed 48-hour ambulatory electrocardiography (aECG) in a biracial sample of 1,193 participants in the Atherosclerosis Risk in Communities (ARIC) (mean age = 78 years, 62% African Americans, 64% female). Atrial fibrillation was identified from aECG, study visit ECGs, and discharge codes from cohort hospitalizations. We used covariate-adjusted logistic regression to estimate prevalence odds ratios (ORs) for AF in African Americans versus Whites, with adjustment for sampling and nonresponse. RESULTS: African Americans were more likely than Whites to have hypertension and diabetes but less likely to have coronary heart disease. The prevalence of AF detected by aECG or ARIC study ECG (adjusted for age and coronary heart disease) was lower in African Americans than Whites (2.7% vs 5.0%). White men had a higher (although not significant) AF prevalence of 7.8% compared to the other race and gender groups at 2.3%-2.8%. The adjusted OR for AF was 0.49 (0.24-0.99) comparing African Americans to Whites. Findings were similar when AF was defined to include prior AF hospitalizations (OR = 0.42, 0.25-0.72). There were no significant differences by race for asymptomatic or paroxysmal AF. CONCLUSIONS: Atrial fibrillation was less prevalent in African American than white older adults, regardless of detection method. Although overall detection of new AF cases with aECG was low, future studies should consider longer-term monitoring to characterize AF by race.

7.
Environ Int ; 132: 104723, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31208937

RESUMO

BACKGROUND: DNA methylation (DNAm) may contribute to processes that underlie associations between air pollution and poor health. Therefore, our objective was to evaluate associations between DNAm and ambient concentrations of particulate matter (PM) ≤2.5, ≤10, and 2.5-10 µm in diameter (PM2.5; PM10; PM2.5-10). METHODS: We conducted a methylome-wide association study among twelve cohort- and race/ethnicity-stratified subpopulations from the Women's Health Initiative and the Atherosclerosis Risk in Communities study (n = 8397; mean age: 61.5 years; 83% female; 45% African American; 9% Hispanic/Latino American). We averaged geocoded address-specific estimates of daily and monthly mean PM concentrations over 2, 7, 28, and 365 days and 1 and 12 months before exams at which we measured leukocyte DNAm in whole blood. We estimated subpopulation-specific, DNAm-PM associations at approximately 485,000 Cytosine-phosphate-Guanine (CpG) sites in multi-level, linear, mixed-effects models. We combined subpopulation- and site-specific estimates in fixed-effects, inverse variance-weighted meta-analyses, then for associations that exceeded methylome-wide significance and were not heterogeneous across subpopulations (P < 1.0 × 10-7; PCochran's Q > 0.10), we characterized associations using publicly accessible genomic databases and attempted replication in the Cooperative Health Research in the Region of Augsburg (KORA) study. RESULTS: Analyses identified significant DNAm-PM associations at three CpG sites. Twenty-eight-day mean PM10 was positively associated with DNAm at cg19004594 (chromosome 20; MATN4; P = 3.33 × 10-8). One-month mean PM10 and PM2.5-10 were positively associated with DNAm at cg24102420 (chromosome 10; ARPP21; P = 5.84 × 10-8) and inversely associated with DNAm at cg12124767 (chromosome 7; CFTR; P = 9.86 × 10-8). The PM-sensitive CpG sites mapped to neurological, pulmonary, endocrine, and cardiovascular disease-related genes, but DNAm at those sites was not associated with gene expression in blood cells and did not replicate in KORA. CONCLUSIONS: Ambient PM concentrations were associated with DNAm at genomic regions potentially related to poor health among racially, ethnically and environmentally diverse populations of U.S. women and men. Further investigation is warranted to uncover mechanisms through which PM-induced epigenomic changes may cause disease.

8.
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
9.
PLoS One ; 14(6): e0217796, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31251759

RESUMO

BACKGROUND: The electrocardiographically quantified QRS duration measures ventricular depolarization and conduction. QRS prolongation has been associated with poor heart failure prognosis and cardiovascular mortality, including sudden death. While previous genome-wide association studies (GWAS) have identified 32 QRS SNPs across 26 loci among European, African, and Asian-descent populations, the genetics of QRS among Hispanics/Latinos has not been previously explored. METHODS: We performed a GWAS of QRS duration among Hispanic/Latino ancestry populations (n = 15,124) from four studies using 1000 Genomes imputed genotype data (adjusted for age, sex, global ancestry, clinical and study-specific covariates). Study-specific results were combined using fixed-effects, inverse variance-weighted meta-analysis. RESULTS: We identified six loci associated with QRS (P<5x10-8), including two novel loci: MYOCD, a nuclear protein expressed in the heart, and SYT1, an integral membrane protein. The top SNP in the MYOCD locus, intronic SNP rs16946539, was found in Hispanics/Latinos with a minor allele frequency (MAF) of 0.04, but is monomorphic in European and African descent populations. The most significant QRS duration association was with intronic SNP rs3922344 (P = 1.19x10-24) in SCN5A/SCN10A. Three other previously identified loci, CDKN1A, VTI1A, and HAND1, also exceeded the GWAS significance threshold among Hispanics/Latinos. A total of 27 of 32 previously identified QRS duration SNPs were shown to generalize in Hispanics/Latinos. CONCLUSIONS: Our QRS duration GWAS, the first in Hispanic/Latino populations, identified two new loci, underscoring the utility of extending large scale genomic studies to currently under-examined populations.

10.
Am J Public Health ; 109(5): 774-780, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30969834

RESUMO

OBJECTIVES: To test whether indicators of despair are rising among US adults as they age toward midlife and whether this rise is concentrated among low-educated Whites and in rural areas. METHODS: We used data from the National Longitudinal Study of Adolescent to Adult Health, a nationally representative study of US adolescents in 1994. Our sample was restricted to individuals who participated in 1 or more of 5 waves (1994-2017) and self-identified as non-Hispanic White, non-Hispanic Black, or Hispanic (n = 18 446). We examined change in indicators of despair from adolescence to adulthood using multilevel regression analysis, testing for differences by race/ethnicity, education, and rurality. RESULTS: We found evidence of rising despair among this cohort over the past decade. This increase was not restricted to low-educated Whites or to rural areas. CONCLUSIONS: Results suggest that generally rising despair among the young adult cohort now reaching midlife that cuts across racial/ethnic, educational, and geographic groups may presage rising midlife mortality for these subgroups in the next decade.

11.
Sci Rep ; 9(1): 2079, 2019 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-30765773

RESUMO

Childhood obesity remains an epidemic in the U.S. and worldwide. However, little is understood regarding the epigenetic basis of obesity in adolescents. To investigate the cross-sectional association between DNA methylation level in obesity-related genes and body mass index (BMI) percentile, data from 263 adolescents in the population-based Penn State Child Cohort follow-up exam was analysed. Using DNA extracted from peripheral leukocytes, epigenome-wide single nucleotide resolution of DNA methylation in cytosine-phosphate-guanine (CpG) sites and surrounding regions was obtained. We used multivariable-adjusted linear regression models to assess the association between site-specific methylation level and age- and sex-specific BMI percentile. Hypergeometric and permutation tests were used to determine if obesity-related genes were significantly enriched among all intragenic sites that achieved a p < 0.05 throughout the epigenome. Among the 5,669 sites related to BMI percentile with p < 0.05, 28 were identified within obesity-related genes. Obesity-related genes were significantly enriched among 103,466 intragenic sites (Phypergeometric = 0.006; Ppermutation = 0.006). Moreover, increased methylation on one site within SIM1 was significantly related to higher BMI percentile (P = 4.2E-05). If externally validated, our data would suggest that DNA methylation in obesity-related genes may relate to obesity risk in adolescents.

12.
Am J Public Health ; 109(3): 451-453, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30676799

RESUMO

OBJECTIVES: To use dynamic visualizations of mortality risk functions over both calendar year and age as a way to estimate and visualize patterns in US life spans. METHODS: We built 49 synthetic cohorts, 1 per year 1968 to 2016, using National Center for Health Statistics (NCHS) mortality and population data. Within each cohort, we estimated age-specific probabilities of dying from any cause (all-cause analysis) or from a particular cause (cause-specific analysis). We then used Kaplan-Meier (all-cause) or Aalen-Johansen (cause-specific) estimators to obtain risk functions. We illustrated risk functions using time-lapse animations. RESULTS: Median age at death increased from 75 years in 1970 to 83 years in 2015. Risk by age 100 years of cardiovascular mortality decreased (from a risk of 55% in 1970 to 32% in 2015), whereas risk attributable to other (i.e., nonrespiratory and noncardiovascular) causes increased in compensation. CONCLUSIONS: Our findings were consistent with the trends published in the NCHS 2015 mortality report, and our dynamic animations added an efficient, interpretable tool for visualizing US mortality trends over age and calendar time.

13.
Aging (Albany NY) ; 11(2): 303-327, 2019 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-30669119

RESUMO

It was unknown whether plasma protein levels can be estimated based on DNA methylation (DNAm) levels, and if so, how the resulting surrogates can be consolidated into a powerful predictor of lifespan. We present here, seven DNAm-based estimators of plasma proteins including those of plasminogen activator inhibitor 1 (PAI-1) and growth differentiation factor 15. The resulting predictor of lifespan, DNAm GrimAge (in units of years), is a composite biomarker based on the seven DNAm surrogates and a DNAm-based estimator of smoking pack-years. Adjusting DNAm GrimAge for chronological age generated novel measure of epigenetic age acceleration, AgeAccelGrim.Using large scale validation data from thousands of individuals, we demonstrate that DNAm GrimAge stands out among existing epigenetic clocks in terms of its predictive ability for time-to-death (Cox regression P=2.0E-75), time-to-coronary heart disease (Cox P=6.2E-24), time-to-cancer (P= 1.3E-12), its strong relationship with computed tomography data for fatty liver/excess visceral fat, and age-at-menopause (P=1.6E-12). AgeAccelGrim is strongly associated with a host of age-related conditions including comorbidity count (P=3.45E-17). Similarly, age-adjusted DNAm PAI-1 levels are associated with lifespan (P=5.4E-28), comorbidity count (P= 7.3E-56) and type 2 diabetes (P=2.0E-26). These DNAm-based biomarkers show the expected relationship with lifestyle factors including healthy diet and educational attainment.Overall, these epigenetic biomarkers are expected to find many applications including human anti-aging studies.

14.
Artigo em Inglês | MEDLINE | ID: mdl-30230942

RESUMO

BACKGROUND: Although social exposures have complex and dynamic relationships and interactions, the existing literature on the impact of rural-urban residence on stage at breast cancer diagnosis does not examine heterogeneity of effect. We examined the joint effect of social support, social relationship strain, and rural-urban residence on stage at breast cancer diagnosis. METHODS: Using data from the Women's Health Initiative (WHI) (n = 161,808), we describe the distribution of social, behavioral, and clinical factors by rural-urban residence among postmenopausal women with incident breast cancer (n = 7,120). We used rural-urban commuting area (RUCA) codes to categorize baseline residential addresses as urban, large rural city/town, or small rural town, and the surveillance, epidemiology, and end results staging system to categorize breast cancer stage at diagnosis (dichotomized as early or late). We then used univariable and multivariable logistic regression to estimate odds ratios (ORs) and associated 95% confidence intervals (95% CI) for the relationship between rural-urban residence and stage at breast cancer diagnosis. We included separate interaction terms between rural-urban residence and social strain and social support to test for statistical interaction. RESULTS: Of the social, behavioral, and clinical factors we examined, only younger age at WHI enrollment screening was significantly associated with late stage at breast cancer diagnosis (p = 0.003). Contrary to our hypothesis, rural-urban residence was not significantly associated with stage at breast cancer diagnosis among postmenopausal women ([adjusted OR, 95% CI] for urban compared with small town: 1.08 [0.76-1.53]; large town compared with small town: 1.16 [0.74-1.84]; and urban compared with large town: 0.93 [0.68-1.26]).The associations did not vary by social support or social strain (p for interaction between RUCA and social strain and social support, respectively: 0.99 and 0.17). CONCLUSIONS: Future studies should examine other potential effect modifiers to identify novel factors predictive or protective for late stage at breast cancer diagnosis associated with rural-urban residence.

15.
J Clin Med ; 7(8)2018 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-30072610

RESUMO

Pancreatic cancer is the fourth leading cause of cancer death. Soluble receptor for glycation end products (sRAGE), which is modulated by anti-hypertensive (HT) medications, has been inversely associated with pancreatic cancer. However, the association between commonly used anti-HT medications and risk of pancreatic cancer is unknown. A total of 145,551 postmenopausal women from the Women Health Initiative (WHI) Study were included in analysis. Use of angiotensin converting enzyme inhibitors (ACEi), ß-blockers, calcium channel blockers (CCBs) and diuretics was ascertained at baseline (1993⁻1998). Baseline sRAGE levels were measured among a subset of 2104 participants using an immunoassay. Multivariable Cox proportional hazard regression model was performed to estimate hazard ratios (HRs) and its 95% confidence intervals (CIs) for pancreatic cancer in association with anti-HT medications. Increased risk of pancreatic cancer was found among users of short-acting CCB (HR = 1.66, 95% CI: 1.20⁻2.28) and long-term (≥3 years) users of short-acting CCB (HR = 2.07, 95% CI: 1.42⁻3.02) compared to users of other anti-HT medications. Average sRAGE levels were lower in short-acting CCB users than users of other anti-HT medications (1173 versus 1454 pg/mL, p = 0.038). Non-statistically significant reduced risk of pancreatic cancer was found among users of ß-blockers (HR = 0.80, 95% CI: 0.60⁻1.07). Average sRAGE levels were higher in ß-blockers users than users of other anti-HT medications (1692 versus 1454 pg/mL, p > 0.05). Future studies are warranted to confirm these findings and elucidate potential mechanisms by which anti-HT medications influence development of pancreatic cancer.

16.
Aging (Albany NY) ; 10(7): 1758-1775, 2018 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-30048243

RESUMO

DNA methylation (DNAm)-based biomarkers of aging have been developed for many tissues and organs. However, these biomarkers have sub-optimal accuracy in fibroblasts and other cell types used in ex vivo studies. To address this challenge, we developed a novel and highly robust DNAm age estimator (based on 391 CpGs) for human fibroblasts, keratinocytes, buccal cells, endothelial cells, lymphoblastoid cells, skin, blood, and saliva samples. High age correlations can also be observed in sorted neurons, glia, brain, liver, and even bone samples. Gestational age correlates with DNAm age in cord blood. When used on fibroblasts from Hutchinson Gilford Progeria Syndrome patients, this age estimator (referred to as the skin & blood clock) uncovered an epigenetic age acceleration with a magnitude that is below the sensitivity levels of other DNAm-based biomarkers. Furthermore, this highly sensitive age estimator accurately tracked the dynamic aging of cells cultured ex vivo and revealed that their proliferation is accompanied by a steady increase in epigenetic age. The skin & blood clock predicts lifespan and it relates to many age-related conditions. Overall, this biomarker is expected to become useful for forensic applications (e.g. blood or buccal swabs) and for a quantitative ex vivo human cell aging assay.

17.
JAMA Psychiatry ; 75(9): 949-959, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-29998287

RESUMO

Importance: Depressive disorders arise from a combination of genetic and environmental risk factors. Epigenetic disruption provides a plausible mechanism through which gene-environment interactions lead to depression. Large-scale, epigenome-wide studies on depression are missing, hampering the identification of potentially modifiable biomarkers. Objective: To identify epigenetic mechanisms underlying depression in middle-aged and elderly persons, using DNA methylation in blood. Design, Setting, and Participants: To date, the first cross-ethnic meta-analysis of epigenome-wide association studies (EWAS) within the framework of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium was conducted. The discovery EWAS included 7948 individuals of European origin from 9 population-based cohorts. Participants who were assessed for both depressive symptoms and whole-blood DNA methylation were included in the study. Results of EWAS were pooled using sample-size weighted meta-analysis. Replication of the top epigenetic sites was performed in 3308 individuals of African American and European origin from 2 population-based cohorts. Main Outcomes and Measures: Whole-blood DNA methylation levels were assayed with Illumina-Infinium Human Methylation 450K BeadChip and depressive symptoms were assessed by questionnaire. Results: The discovery cohorts consisted of 7948 individuals (4104 [51.6%] women) with a mean (SD) age of 65.4 (5.8) years. The replication cohort consisted of 3308 individuals (2456 [74.2%] women) with a mean (SD) age of 60.3 (6.4) years. The EWAS identified methylation of 3 CpG sites to be significantly associated with increased depressive symptoms: cg04987734 (P = 1.57 × 10-08; n = 11 256; CDC42BPB gene), cg12325605 (P = 5.24 × 10-09; n = 11 256; ARHGEF3 gene), and an intergenic CpG site cg14023999 (P = 5.99 × 10-08; n = 11 256; chromosome = 15q26.1). The predicted expression of the CDC42BPB gene in the brain (basal ganglia) (effect, 0.14; P = 2.7 × 10-03) and of ARHGEF3 in fibroblasts (effect, -0.48; P = 9.8 × 10-04) was associated with major depression. Conclusions and Relevance: This study identifies 3 methylated sites associated with depressive symptoms. All 3 findings point toward axon guidance as the common disrupted pathway in depression. The findings provide new insights into the molecular mechanisms underlying the complex pathophysiology of depression. Further research is warranted to determine the utility of these findings as biomarkers of depression and evaluate any potential role in the pathophysiology of depression and their downstream clinical effects.

18.
Pharmacogenomics J ; 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29855607

RESUMO

We evaluated interactions of SNP-by-ACE-I/ARB and SNP-by-TD on serum potassium (K+) among users of antihypertensive treatments (anti-HTN). Our study included seven European-ancestry (EA) (N = 4835) and four African-ancestry (AA) cohorts (N = 2016). We performed race-stratified, fixed-effect, inverse-variance-weighted meta-analyses of 2.5 million SNP-by-drug interaction estimates; race-combined meta-analysis; and trans-ethnic fine-mapping. Among EAs, we identified 11 significant SNPs (P < 5 × 10-8) for SNP-ACE-I/ARB interactions on serum K+ that were located between NR2F1-AS1 and ARRDC3-AS1 on chromosome 5 (top SNP rs6878413 P = 1.7 × 10-8; ratio of serum K+ in ACE-I/ARB exposed compared to unexposed is 1.0476, 1.0280, 1.0088 for the TT, AT, and AA genotypes, respectively). Trans-ethnic fine mapping identified the same group of SNPs on chromosome 5 as genome-wide significant for the ACE-I/ARB analysis. In conclusion, SNP-by-ACE-I /ARB interaction analyses uncovered loci that, if replicated, could have future implications for the prevention of arrhythmias due to anti-HTN treatment-related hyperkalemia. Before these loci can be identified as clinically relevant, future validation studies of equal or greater size in comparison to our discovery effort are needed.

19.
Sci Rep ; 8(1): 5675, 2018 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-29618737

RESUMO

The genetic basis of supraventricular and ventricular ectopy (SVE, VE) remains largely uncharacterized, despite established genetic mechanisms of arrhythmogenesis. To identify novel genetic variants associated with SVE/VE in ancestrally diverse human populations, we conducted a genome-wide association study of electrocardiographically identified SVE and VE in five cohorts including approximately 43,000 participants of African, European and Hispanic/Latino ancestry. In thirteen ancestry-stratified subgroups, we tested multivariable-adjusted associations of SVE and VE with single nucleotide polymorphism (SNP) dosage. We combined subgroup-specific association estimates in inverse variance-weighted, fixed-effects and Bayesian meta-analyses. We also combined fixed-effects meta-analytic t-test statistics for SVE and VE in multi-trait SNP association analyses. No loci reached genome-wide significance in trans-ethnic meta-analyses. However, we found genome-wide significant SNPs intronic to an apoptosis-enhancing gene previously associated with QRS interval duration (FAF1; lead SNP rs7545860; effect allele frequency = 0.02; P = 2.0 × 10-8) in multi-trait analysis among European ancestry participants and near a locus encoding calcium-dependent glycoproteins (DSC3; lead SNP rs8086068; effect allele frequency = 0.17) in meta-analysis of SVE (P = 4.0 × 10-8) and multi-trait analysis (P = 2.9 × 10-9) among African ancestry participants. The novel findings suggest several mechanisms by which genetic variation may predispose to ectopy in humans and highlight the potential value of leveraging pleiotropy in future studies of ectopy-related phenotypes.

20.
Breast ; 39: 63-69, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29614476

RESUMO

OBJECTIVES: Previous research has reported associations between social relationships and carcinogenesis. Inflammation is a potential mediator of these associations. To clarify these links for one tumor site, we examined associations between social relationships, circulating inflammation markers, and breast cancer incidence. MATERIALS AND METHODS: Among 132,262 participants from the prospective Women's Health Initiative, we used linear and logistic regression to evaluate associations between social relationship characteristics (social support, social strain, social network size) and inflammation markers of C-reactive protein (CRP) and white blood cell count (WBC). Cox regression was used to evaluate associations between inflammation markers and breast cancer incidence, as well as associations between social relationship characteristics and breast cancer incidence with and without adjustment for inflammation markers. RESULTS: Larger social networks were associated with lower continuous CRP (beta = -0.22, 95% CI -0.36, -0.08) and WBC (beta = -0.23, 95% CI -0.31, -0.16). Greater social strain was associated with higher continuous CRP (beta = 0.24, 95% CI 0.14, 0.33) and WBC (beta = 0.09, 95% CI 0.04, 0.14). When WBC was dichotomized at 10,000 cells/uL, high WBC was associated with greater hazards of in situ breast cancer (HR = 1.65, 95% CI 1.17, 2.33) but not invasive breast cancer. Social relationship characteristics were not associated with incidence of invasive or in situ breast cancer. CONCLUSION: Larger social networks were associated with lower inflammation and greater social strain was associated with higher inflammation. Higher inflammation might be associated with development of in situ breast cancer, but this appeared to be due to factors other than social relationships.


Assuntos
Neoplasias da Mama/epidemiologia , Proteína C-Reativa/análise , Relações Interpessoais , Contagem de Leucócitos , Apoio Social , Idoso , Biomarcadores/sangue , Carcinoma de Mama in situ/sangue , Carcinoma de Mama in situ/epidemiologia , Carcinoma de Mama in situ/psicologia , Neoplasias da Mama/sangue , Neoplasias da Mama/psicologia , Feminino , Humanos , Incidência , Modelos Lineares , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Estados Unidos/epidemiologia , Saúde da Mulher
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