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1.
Circulation ; 140(8): 645-657, 2019 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-31424985

RESUMO

BACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts. METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts. RESULTS: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts. CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.

2.
Clin Epigenetics ; 11(1): 119, 2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31426852

RESUMO

BACKGROUND: African Americans (AAs) experience premature chronic health outcomes and longevity disparities consistent with an accelerated aging phenotype. DNA methylation (DNAm) levels at specific CpG positions are hallmarks of aging evidenced by the presence of age-associated differentially methylated CpG positions (aDMPs) that are the basis for the epigenetic clock for measuring biological age acceleration. Since DNAm has not been widely studied among non-European populations, we examined the association between DNAm and chronological age in AAs and whites, and the association between race, poverty, sex, and epigenetic age acceleration. RESULTS: We measured genome-wide DNA methylation (866,836 CpGs) using the Illumina MethylationEPIC BeadChip in blood DNA extracted from 487 middle-aged AA (N = 244) and white (N = 243), men (N = 248), and women (N = 239). The mean (sd) age was 48.4 (8.8) in AA and 49.0 (8.7) in whites (p = 0.48). We identified 4930 significantly associated aDMPs in AAs and 469 in whites. Of these, 75.6% and 53.1% were novel, largely driven by the increased number of measured CpGs in the EPIC array, in AA and whites, respectively. AAs had more age-associated DNAm changes than whites in genes implicated in age-related diseases and cellular pathways involved in growth and development. We assessed three epigenetic age acceleration measures (universal, intrinsic, and extrinsic). AAs had a significantly slower extrinsic aging compared to whites. Furthermore, compared to AA women, both AA and white men had faster aging in the universal age acceleration measure (+ 2.04 and + 1.24 years, respectively, p < 0.05). CONCLUSIONS: AAs have more wide-spread methylation changes than whites. Race and sex interact to underlie biological age acceleration suggesting altered DNA methylation patterns may be important in age-associated health disparities.

3.
Psychoneuroendocrinology ; 104: 18-24, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30784901

RESUMO

BACKGROUND: Higher mortality experienced by socially disadvantaged groups and/or racial/ethnic minorities is hypothesized to be, at least in part, due to an acceleration of the aging process. Using a new epigenetic aging measure, Levine DNAmAge, this study aimed to investigate whether epigenetic aging accounts for mortality disparities by race/ethnicity and education in a sample of U.S. postmenopausal women. METHODS: 1834 participants from an ancillary study (BA23) in the Women's Health Initiative, a national study that recruited postmenopausal women (50-79 years) were included. Over the 22 years of follow-up, 551 women died, and 31,946 person-years were observed. Levine DNAmAge (unit in years) was calculated based on an equation that we previously developed in an independent sample, which incorporates methylation levels at 513 CpG sites. RESULTS: As previously reported, non-Hispanic blacks and Hispanics were epigenetically older than non-Hispanic whites of the same chronological age. Similarly, those with less education had older epigenetic ages than expected in the full sample, as well as among non-Hispanic whites and Hispanics, but not among non-Hispanic blacks. Non-Hispanic blacks and those with low education exhibited the greatest risk of mortality. However, this association was partially attenuated when accounting for differences in DNAmAge. Furthermore, formal mediation analysis suggested that DNAmAge partially mediated the mortality increase among non-Hispanic blacks, compared to non-Hispanic whites (proportion mediated, 15.8%, P = 0.002), as well as the mortality increase for those with less than high school education, compared to college educated (proportion mediated, 11.6%, P < 2E-16). CONCLUSIONS: Among a group of postmenopausal women, non-Hispanic blacks and those with less education exhibit higher epigenetic aging, which partially accounts for their shorter life expectancies.

4.
Clin Epigenetics ; 10(1): 161, 2018 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-30587240

RESUMO

BACKGROUND: Most research into myocardial infarctions (MIs) have focused on preventative efforts. For survivors, the occurrence of an MI represents a major clinical event that can have long-lasting consequences. There has been little to no research into the molecular changes that can occur as a result of an incident MI. Here, we use three cohorts to identify epigenetic changes that are indicative of an incident MI and their association with gene expression and metabolomics. RESULTS: Using paired samples from the KORA cohort, we screened for DNA methylation loci (CpGs) whose change in methylation is potentially indicative of the occurrence of an incident MI between the baseline and follow-up exams. We used paired samples from the NAS cohort to identify 11 CpGs which were predictive in an independent cohort. After removing two CpGs associated with medication usage, we were left with an "epigenetic fingerprint" of MI composed of nine CpGs. We tested this fingerprint in the InCHIANTI cohort where it moderately discriminated incident MI occurrence (AUC = 0.61, P = 6.5 × 10-3). Returning to KORA, we associated the epigenetic fingerprint loci with cis-gene expression and integrated it into a gene expression-metabolomic network, which revealed links between the epigenetic fingerprint CpGs and branched chain amino acid (BCAA) metabolism. CONCLUSIONS: There are significant changes in DNA methylation after an incident MI. Nine of these CpGs show consistent changes in multiple cohorts, significantly discriminate MI in independent cohorts, and were independent of medication usage. Integration with gene expression and metabolomics data indicates a link between MI-associated epigenetic changes and BCAA metabolism.


Assuntos
Metilação de DNA , Perfilação da Expressão Gênica/métodos , Estudo de Associação Genômica Ampla/métodos , Leucócitos/química , Infarto do Miocárdio/genética , Idoso , Ilhas de CpG , Epigênese Genética , Feminino , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Predisposição Genética para Doença , Humanos , Masculino , Metabolômica , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Fatores de Risco
5.
Artigo em Inglês | MEDLINE | ID: mdl-29718110

RESUMO

Background: Epigenetic clocks based on DNA methylation yield high correlations with chronological age in cross-sectional data. Due to a paucity of longitudinal data, it is not known how Δage (epigenetic age - chronological age) changes over time or if it remains constant from childhood to old age. Here, we investigate this using longitudinal DNA methylation data from five datasets, covering most of the human life course. Methods: Two measures of the epigenetic clock (Hannum and Horvath) are used to calculate Δage in the following cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) offspring (n = 986, total age-range 7-19 years, 2 waves), ALSPAC mothers (n = 982, 16-60 years, 2 waves), InCHIANTI (n = 460, 21-100 years, 2 waves), SATSA (n = 373, 48-99 years, 5 waves), Lothian Birth Cohort 1936 (n = 1,054, 70-76 years, 3 waves), and Lothian Birth Cohort 1921 (n = 476, 79-90 years, 3 waves). Linear mixed models were used to track longitudinal change in Δage within each cohort. Results: For both epigenetic age measures, Δage showed a declining trend in almost all of the cohorts. The correlation between Δage across waves ranged from 0.22 to 0.82 for Horvath and 0.25 to 0.71 for Hannum, with stronger associations in samples collected closer in time. Conclusions: Epigenetic age increases at a slower rate than chronological age across the life course, especially in the oldest population. Some of the effect is likely driven by survival bias, where healthy individuals are those maintained within a longitudinal study, although other factors like the age distribution of the underlying training population may also have influenced this trend.

6.
Aging (Albany NY) ; 10(4): 573-591, 2018 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-29676998

RESUMO

Identifying reliable biomarkers of aging is a major goal in geroscience. While the first generation of epigenetic biomarkers of aging were developed using chronological age as a surrogate for biological age, we hypothesized that incorporation of composite clinical measures of phenotypic age that capture differences in lifespan and healthspan may identify novel CpGs and facilitate the development of a more powerful epigenetic biomarker of aging. Using an innovative two-step process, we develop a new epigenetic biomarker of aging, DNAm PhenoAge, that strongly outperforms previous measures in regards to predictions for a variety of aging outcomes, including all-cause mortality, cancers, healthspan, physical functioning, and Alzheimer's disease. While this biomarker was developed using data from whole blood, it correlates strongly with age in every tissue and cell tested. Based on an in-depth transcriptional analysis in sorted cells, we find that increased epigenetic, relative to chronological age, is associated with increased activation of pro-inflammatory and interferon pathways, and decreased activation of transcriptional/translational machinery, DNA damage response, and mitochondrial signatures. Overall, this single epigenetic biomarker of aging is able to capture risks for an array of diverse outcomes across multiple tissues and cells, and provide insight into important pathways in aging.

7.
J Diabetes ; 10(6): 524-533, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29417738

RESUMO

BACKGROUND: Sex hormones are implicated in the development of diabetes. However, whether genetic variations in sex hormone pathways (SHPs) contribute to the risk of type 2 diabetes mellitus (T2DM) remains to be determined. This study investigated associations between genetic variations in all candidate genes in SHPs and T2DM risk among a cohort of women participating in the Women's Health Initiative (WHI). METHODS: Single nucleotide polymorphisms (SNPs) located within 30 kb upstream and downstream of SHP genes were comprehensively examined in 8180 African American, 3498 Hispanic American, and 3147 European American women in the WHI. In addition, whether significant SNPs would be replicated in independent populations was examined. RESULTS: After adjusting for age, region, and ancestry estimates and correcting for multiple testing, seven SNPs were significantly associated with the risk of T2DM among Hispanic American women were identified in the progesterone receptor (PGR) gene, with rs948516 showing the greatest significance (odds ratio 0.67; 95% confidence interval 0.57-0.78; P = 8.8 × 10-7 ; false discovery rate, Q = 7.8 × 10-4 ). These findings were not replicated in other ethnic groups in the WHI or in sex-combined analyses in replication studies. CONCLUSION: Significant signals were identified implicating the PGR gene in T2DM development in Hispanic American women in the WHI, which are consistent with genome-wide association studies findings linking PGR to glucose homeostasis. Nevertheless, the PGR SNPs-T2DM association was not statistically significant in other ethnic populations. Further studies, especially sex-specific analyses, are needed to confirm the findings and clarify the role of SHPs in T2DM.


Assuntos
Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Pós-Menopausa/genética , Afro-Americanos/genética , Idoso , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Seguimentos , Hispano-Americanos/genética , Humanos , Pessoa de Meia-Idade , Pós-Menopausa/etnologia , Prognóstico , Receptores de Progesterona/genética
8.
Nat Commun ; 9(1): 387, 2018 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-29374233

RESUMO

DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9907 individuals, we find gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in three loci associated with extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggests causal influences of menarche and menopause on IEAA and lipoproteins on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) paradoxically confer higher IEAA (P < 2.7 × 10-11). Causal modeling indicates TERT-specific and independent effects on LTL and IEAA. Experimental hTERT-expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the epigenetic clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.

9.
Aging Cell ; 17(1)2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29044988

RESUMO

Recent studies provide evidence of correlations of DNA methylation and expression of protein-coding genes with human aging. The relations of microRNA expression with age and age-related clinical outcomes have not been characterized thoroughly. We explored associations of age with whole-blood microRNA expression in 5221 adults and identified 127 microRNAs that were differentially expressed by age at P < 3.3 × 10-4 (Bonferroni-corrected). Most microRNAs were underexpressed in older individuals. Integrative analysis of microRNA and mRNA expression revealed changes in age-associated mRNA expression possibly driven by age-associated microRNAs in pathways that involve RNA processing, translation, and immune function. We fitted a linear model to predict 'microRNA age' that incorporated expression levels of 80 microRNAs. MicroRNA age correlated modestly with predicted age from DNA methylation (r = 0.3) and mRNA expression (r = 0.2), suggesting that microRNA age may complement mRNA and epigenetic age prediction models. We used the difference between microRNA age and chronological age as a biomarker of accelerated aging (Δage) and found that Δage was associated with all-cause mortality (hazards ratio 1.1 per year difference, P = 4.2 × 10-5 adjusted for sex and chronological age). Additionally, Δage was associated with coronary heart disease, hypertension, blood pressure, and glucose levels. In conclusion, we constructed a microRNA age prediction model based on whole-blood microRNA expression profiling. Age-associated microRNAs and their targets have potential utility to detect accelerated aging and to predict risks for age-related diseases.

10.
J Diabetes ; 10(6): 502-511, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28609023

RESUMO

BACKGROUND: Sex hormones may play important roles in sex-specific biological aging. In the study, we specifically examined associations between circulating sex hormone concentrations and leukocyte telomere length (TL). METHODS: A cross-sectional study was conducted among 1124 Black, 444 Hispanic, and 289 Asian/Pacific Islander women in the Women's Health Initiative Observational Cohort. Estradiol and testosterone concentrations were measured using electrochemiluminescence immunoassays; TL was measured using quantitative polymerase chain reaction. RESULTS: Women in the study were aged 50-79 years. Estradiol concentrations were not significantly associated with TL in this sample. The associations between total and free testosterone and TL differed by race/ethnicity (Pinteraction = 0.03 and 0.05 for total and free testosterone, respectively). Total and free testosterone concentrations were not associated with TL in Black and Hispanic women, whereas in Asian/Pacific Islander women their concentrations were inversely associated with TL (Ptrend = 0.003 for both). These associations appeared robust in multiple subgroup analyses and multivariable models adjusted for potential confounding factors. In Asian/Pacific Islander women, a doubling of serum free and total testosterone concentrations was associated with a 202-bp shorter TL (95% confidence interval [CI] 51-353 bp) and 203-bp shorter TL (95% CI 50-355 bp), respectively. CONCLUSIONS: Serum estradiol concentrations were not associated with leukocyte TL in this large sample of postmenopausal women. Total and free testosterone concentrations were inversely associated with TL in Asian/Pacific Islander women, but not in Black and Hispanic women, although future studies to replicate our observations are warranted particularly to address potential ethnicity-specific relationships.


Assuntos
Estradiol/sangue , Grupos Étnicos/estatística & dados numéricos , Leucócitos/metabolismo , Pós-Menopausa/sangue , Pós-Menopausa/etnologia , Homeostase do Telômero , Testosterona/sangue , Afro-Americanos/estatística & dados numéricos , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Biomarcadores/análise , Estudos de Coortes , Estudos Transversais , Feminino , Seguimentos , Hispano-Americanos/estatística & dados numéricos , Humanos , Pessoa de Meia-Idade , Grupo com Ancestrais Oceânicos/estatística & dados numéricos , Prognóstico , Globulina de Ligação a Hormônio Sexual/análise
11.
Aging (Albany NY) ; 9(9): 1983-1995, 2017 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-28930701

RESUMO

Both leukocyte telomere length (LTL) and DNA methylation age are strongly associated with chronological age. One measure of DNA methylation age─ the extrinsic epigenetic age acceleration (EEAA)─ is highly predictive of all-cause mortality. We examined the relation between LTL and EEAA. LTL was measured by Southern blots and leukocyte DNA methylation was determined using Illumina Infinium HumanMethylation450 BeadChip in participants in the Women's Health Initiative (WHI; n=804), the Framingham Heart Study (FHS; n=909) and the Bogalusa Heart study (BHS; n=826). EEAA was computed using 71 DNA methylation sites, further weighted by proportions of naïve CD8+ T cells, memory CD8+ T cells, and plasmablasts. Shorter LTL was associated with increased EEAA in participants from the WHI (r=-0.16, p=3.1x10-6). This finding was replicated in the FHS (r=-0.09, p=6.5x10-3) and the BHS (r=-0.07, p=3.8x 10-2). LTL was also inversely related to proportions of memory CD8+ T cells (p=4.04x10-16) and positively related to proportions of naive CD8+ T cells (p=3.57x10-14). These findings suggest that for a given age, an individual whose blood contains comparatively more memory CD8+ T cells and less naive CD8+ T cells would display a relatively shorter LTL and an older DNA methylation age, which jointly explain the striking ability of EEAA to predict mortality.


Assuntos
Envelhecimento/fisiologia , Linfócitos T CD8-Positivos/citologia , Metilação de DNA/fisiologia , Telômero , Adulto , Idoso , Feminino , Humanos , Leucócitos , Masculino , Pessoa de Meia-Idade
12.
Cell ; 170(1): 199-212.e20, 2017 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-28666119

RESUMO

Type 2 diabetes (T2D) affects Latinos at twice the rate seen in populations of European descent. We recently identified a risk haplotype spanning SLC16A11 that explains ∼20% of the increased T2D prevalence in Mexico. Here, through genetic fine-mapping, we define a set of tightly linked variants likely to contain the causal allele(s). We show that variants on the T2D-associated haplotype have two distinct effects: (1) decreasing SLC16A11 expression in liver and (2) disrupting a key interaction with basigin, thereby reducing cell-surface localization. Both independent mechanisms reduce SLC16A11 function and suggest SLC16A11 is the causal gene at this locus. To gain insight into how SLC16A11 disruption impacts T2D risk, we demonstrate that SLC16A11 is a proton-coupled monocarboxylate transporter and that genetic perturbation of SLC16A11 induces changes in fatty acid and lipid metabolism that are associated with increased T2D risk. Our findings suggest that increasing SLC16A11 function could be therapeutically beneficial for T2D. VIDEO ABSTRACT.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Basigina/metabolismo , Membrana Celular/metabolismo , Cromossomos Humanos Par 17/metabolismo , Técnicas de Silenciamento de Genes , Haplótipos , Hepatócitos/metabolismo , Heterozigoto , Código das Histonas , Humanos , Fígado/metabolismo , Modelos Moleculares , Transportadores de Ácidos Monocarboxílicos/química
13.
Aging (Albany NY) ; 9(2): 419-446, 2017 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-28198702

RESUMO

Behavioral and lifestyle factors have been shown to relate to a number of health-related outcomes, yet there is a need for studies that examine their relationship to molecular aging rates. Toward this end, we use recent epigenetic biomarkers of age that have previously been shown to predict all-cause mortality, chronic conditions, and age-related functional decline. We analyze cross-sectional data from 4,173 postmenopausal female participants from the Women's Health Initiative, as well as 402 male and female participants from the Italian cohort study, Invecchiare nel Chianti.Extrinsic epigenetic age acceleration (EEAA) exhibits significant associations with fish intake (p=0.02), moderate alcohol consumption (p=0.01), education (p=3x10-5), BMI (p=0.01), and blood carotenoid levels (p=1x10-5)-an indicator of fruit and vegetable consumption, whereas intrinsic epigenetic age acceleration (IEAA) is associated with poultry intake (p=0.03) and BMI (p=0.05). Both EEAA and IEAA were also found to relate to indicators of metabolic syndrome, which appear to mediate their associations with BMI. Metformin-the first-line medication for the treatment of type 2 diabetes-does not delay epigenetic aging in this observational study. Finally, longitudinal data suggests that an increase in BMI is associated with increase in both EEAA and IEAA.Overall, the epigenetic age analysis of blood confirms the conventional wisdom regarding the benefits of eating a high plant diet with lean meats, moderate alcohol consumption, physical activity, and education, as well as the health risks of obesity and metabolic syndrome.


Assuntos
Envelhecimento/metabolismo , Dieta , Epigênese Genética , Exercício , Estilo de Vida , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Estudos de Coortes , Estudos Transversais , Escolaridade , Feminino , Humanos , Pessoa de Meia-Idade
14.
Genome Biol ; 17(1): 255, 2016 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-27955697

RESUMO

BACKGROUND: Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation. RESULTS: We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10-7) in the discovery panel of European ancestry and replicated (P < 2.29 × 10-4) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10-5), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10-3), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10-5). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants. CONCLUSION: We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.


Assuntos
Proteína C-Reativa/genética , Epigênese Genética , Inflamação/genética , Locos de Características Quantitativas/genética , Afro-Americanos , Ilhas de CpG/genética , Metilação de DNA/genética , Grupo com Ancestrais do Continente Europeu , Feminino , Expressão Gênica , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Inflamação/sangue , Masculino , Motivos de Nucleotídeos/genética
15.
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
16.
Diabetes ; 65(12): 3794-3804, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27625022

RESUMO

Genome-wide association studies (GWAS) have successfully identified genetic loci associated with glycemic traits. However, characterizing the functional significance of these loci has proven challenging. We sought to gain insights into the regulation of fasting insulin and fasting glucose through the use of gene expression microarray data from peripheral blood samples of participants without diabetes in the Framingham Heart Study (FHS) (n = 5,056), the Rotterdam Study (RS) (n = 723), and the InCHIANTI Study (Invecchiare in Chianti) (n = 595). Using a false discovery rate q <0.05, we identified three transcripts associated with fasting glucose and 433 transcripts associated with fasting insulin levels after adjusting for age, sex, technical covariates, and complete blood cell counts. Among the findings, circulating IGF2BP2 transcript levels were positively associated with fasting insulin in both the FHS and RS. Using 1000 Genomes-imputed genotype data, we identified 47,587 cis-expression quantitative trait loci (eQTL) and 6,695 trans-eQTL associated with the 433 significant insulin-associated transcripts. Of note, we identified a trans-eQTL (rs592423), where the A allele was associated with higher IGF2BP2 levels and with fasting insulin in an independent genetic meta-analysis comprised of 50,823 individuals. We conclude that integration of genomic and transcriptomic data implicate circulating IGF2BP2 mRNA levels associated with glucose and insulin homeostasis.


Assuntos
Glicemia/metabolismo , Jejum/sangue , Insulina/sangue , Transcriptoma/genética , Adulto , Idoso , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Locos de Características Quantitativas/genética , RNA Mensageiro/genética , Proteínas de Ligação a RNA/genética
17.
Proc Natl Acad Sci U S A ; 113(33): 9327-32, 2016 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-27457926

RESUMO

Although epigenetic processes have been linked to aging and disease in other systems, it is not yet known whether they relate to reproductive aging. Recently, we developed a highly accurate epigenetic biomarker of age (known as the "epigenetic clock"), which is based on DNA methylation levels. Here we carry out an epigenetic clock analysis of blood, saliva, and buccal epithelium using data from four large studies: the Women's Health Initiative (n = 1,864); Invecchiare nel Chianti (n = 200); Parkinson's disease, Environment, and Genes (n = 256); and the United Kingdom Medical Research Council National Survey of Health and Development (n = 790). We find that increased epigenetic age acceleration in blood is significantly associated with earlier menopause (P = 0.00091), bilateral oophorectomy (P = 0.0018), and a longer time since menopause (P = 0.017). Conversely, epigenetic age acceleration in buccal epithelium and saliva do not relate to age at menopause; however, a higher epigenetic age in saliva is exhibited in women who undergo bilateral oophorectomy (P = 0.0079), while a lower epigenetic age in buccal epithelium was found for women who underwent menopausal hormone therapy (P = 0.00078). Using genetic data, we find evidence of coheritability between age at menopause and epigenetic age acceleration in blood. Using Mendelian randomization analysis, we find that two SNPs that are highly associated with age at menopause exhibit a significant association with epigenetic age acceleration. Overall, our Mendelian randomization approach and other lines of evidence suggest that menopause accelerates epigenetic aging of blood, but mechanistic studies will be needed to dissect cause-and-effect relationships further.


Assuntos
Envelhecimento/fisiologia , Menopausa/fisiologia , Adulto , Epigênese Genética , Feminino , Humanos , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Ovariectomia , Polimorfismo de Nucleotídeo Único
18.
J Clin Endocrinol Metab ; 101(4): 1779-89, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-26908103

RESUMO

CONTEXT: Metabolic dysregulation underlies key metabolic risk factors­obesity, dyslipidemia, and dysglycemia. OBJECTIVE: To uncover mechanistic links between metabolomic dysregulation and metabolic risk by testing metabolite associations with risk factors cross-sectionally and with risk factor changes over time. DESIGN: Cross-sectional­discovery samples (n = 650; age, 36­69 years) from the Framingham Heart Study (FHS) and replication samples (n = 670; age, 61­76 years) from the BioImage Study, both following a factorial design sampled from high vs low strata of body mass index, lipids, and glucose. Longitudinal­FHS participants (n = 554) with 5­7 years of follow-up for risk factor changes. SETTING: Observational studies. PARTICIPANTS: Cross-sectional samples with or without obesity, dysglycemia, and dyslipidemia, excluding prevalent cardiovascular disease and diabetes or dyslipidemia treatment. Age- and sex-matched by group. INTERVENTIONS: None. MAIN OUTCOME MEASURE(S): Gas chromatography-mass spectrometry detected 119 plasma metabolites. Cross-sectional associations with obesity, dyslipidemia, and dysglycemia were tested in discovery, with external replication of 37 metabolites. Single- and multi-metabolite markers were tested for association with longitudinal changes in risk factors. RESULTS: Cross-sectional metabolite associations were identified with obesity (n = 26), dyslipidemia (n = 21), and dysglycemia (n = 11) in discovery. Glutamic acid, lactic acid, and sitosterol associated with all three risk factors in meta-analysis (P < 4.5 × 10−4). Metabolites associated with longitudinal risk factor changes were enriched for bioactive lipids. Multi-metabolite panels explained 2.5­15.3% of longitudinal changes in metabolic traits. CONCLUSIONS: Cross-sectional results implicated dysregulated glutamate cycling and amino acid metabolism in metabolic risk. Certain bioactive lipids were associated with risk factors cross-sectionally and over time, suggesting their upstream role in risk factor progression. Functional studies are needed to validate findings and facilitate translation into treatments or preventive measures.


Assuntos
Dislipidemias/metabolismo , Metaboloma , Obesidade/metabolismo , Adulto , Idoso , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Masculino , Metabolômica , Pessoa de Meia-Idade , Fatores de Risco
19.
J Glaucoma ; 25(1): e50-2, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25350819

RESUMO

PURPOSE: To report a case of worsening normal-tension glaucoma immediately following ventriculoperitoneal (VP) shunt placement to lower cerebrospinal fluid pressure (CSFP). METHODS: The clinical records of the patient were reviewed retrospectively. Observations were made and collated as the case progressed. RESULTS: A 93-year-old white woman previously diagnosed with normal-tension glaucoma underwent placement of a VP shunt with a Codman-Hakim programmable valve for normal pressure hydrocephalus. Shortly after the procedure, progressive visual field loss was noted in both eyes and new optic disc hemorrhages were seen in the patient's right eye. The hemorrhages resolved, but the patient had recurrent complaints of poor gait, memory, and mentation. The CSFP was lowered by reprogramming the Codman-Hakim valve. The patient's visual fields again worsened in both eyes and a new disc hemorrhage was seen in the right eye. A year later, a new disc hemorrhage was seen in the patient's left eye. The CSFP was raised by reprogramming the VP shunt. Before the placement of the VP shunt, no optic disc hemorrhages had been observed. CONCLUSION: This case suggests that relatively low CSFP is a contributor to worsening normal-tension glaucoma, probably by increasing translaminar pressure gradient of the optic nerve.


Assuntos
Pressão do Líquido Cefalorraquidiano/fisiologia , Hidrocefalia de Pressão Normal/cirurgia , Glaucoma de Baixa Tensão/fisiopatologia , Derivação Ventriculoperitoneal/efeitos adversos , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Hidrocefalia de Pressão Normal/fisiopatologia , Glaucoma de Baixa Tensão/diagnóstico , Glaucoma de Baixa Tensão/etiologia , Hemorragia Retiniana/diagnóstico , Hemorragia Retiniana/fisiopatologia , Estudos Retrospectivos , Punção Espinal , Campos Visuais/fisiologia
20.
Mol Syst Biol ; 11(1): 799, 2015 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-25882670

RESUMO

Genome-wide association studies (GWAS) have identified numerous loci associated with blood pressure (BP). The molecular mechanisms underlying BP regulation, however, remain unclear. We investigated BP-associated molecular mechanisms by integrating BP GWAS with whole blood mRNA expression profiles in 3,679 individuals, using network approaches. BP transcriptomic signatures at the single-gene and the coexpression network module levels were identified. Four coexpression modules were identified as potentially causal based on genetic inference because expression-related SNPs for their corresponding genes demonstrated enrichment for BP GWAS signals. Genes from the four modules were further projected onto predefined molecular interaction networks, revealing key drivers. Gene subnetworks entailing molecular interactions between key drivers and BP-related genes were uncovered. As proof-of-concept, we validated SH2B3, one of the top key drivers, using Sh2b3(-/-) mice. We found that a significant number of genes predicted to be regulated by SH2B3 in gene networks are perturbed in Sh2b3(-/-) mice, which demonstrate an exaggerated pressor response to angiotensin II infusion. Our findings may help to identify novel targets for the prevention or treatment of hypertension.


Assuntos
Pressão Sanguínea/genética , Hipertensão/genética , Adulto , Idoso , Angiotensina II/metabolismo , Animais , Índice de Massa Corporal , Estudos de Coortes , Modelos Animais de Doenças , Feminino , Redes Reguladoras de Genes , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Modelos Lineares , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Domínios e Motivos de Interação entre Proteínas , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de Sequência de RNA , Biologia de Sistemas , Transcriptoma , Adulto Jovem
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