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INTRODUCTION: Men with African ancestry have the highest incidence and mortality rates of prostate cancer (PCa) worldwide. METHODS: This study aimed to identify differentially methylated genes between tumor vs. adjacent normal and aggressive vs. indolent PCa in 121 African American patients. Epigenome-wide DNA methylation patterns in tumor DNA were assessed using the human Illumina Methylation EPIC V1 array. RESULTS: Around 5,139 differentially methylated CpG-sites (q < 0.01, lΔßl > 0.2) were identified when comparing normal vs. tumor, with an overall trend of hypermethylation in prostate tumors. Multiple representative differentially methylated regions (DMRs), including immune-related genes, such as CD40, Galectin3, OX40L, and STING, were detected in prostate tumors when compared to adjacent normal tissues. Based on an epigenetic clock model, we observed that tumors' total number of stem cell divisions and the stem cell division rate were significantly higher than adjacent normal tissues. Regarding PCa aggressiveness, 2,061 differentially methylated CpG-sites (q < 0.05, lΔßl > .05) were identified when the grade group (GG)1 was compared with GG4/5. Among these 2,061 CpG sites, 155 probes were consistently significant in more than one comparison. Among these genes, several immune system genes, such as COL18A1, S100A2, ITGA4, HLA-C, and ADCYAP1, have previously been linked to tumor progression in PCa. CONCLUSION: Several differentially methylated genes involved in immune-oncologic pathways associated with disease risk or aggressiveness were identified. In addition, 261 African American-specific differentially methylated genes related to the risk of PCa were identified. These results can shedlight on potential mechanisms contributing to PCa disparities in the African American Population.
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Negro o Afroamericano , Metilación de ADN , Estudio de Asociación del Genoma Completo , Neoplasias de la Próstata , Humanos , Masculino , Negro o Afroamericano/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/etnología , Persona de Mediana Edad , Anciano , Epigenoma , Islas de CpG , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Biomarcadores de Tumor/genéticaRESUMEN
Background: Hair products may be a source of harmful chemicals and have been linked to age-related health outcomes. We investigated whether the use of hair products is related to epigenetic age in a sample of Black (both Hispanic and non-Hispanic) and non-Hispanic White women. Methods: In a subset of 4358 participants aged 35-74 years from the Sister Study, we estimated cross-sectional associations between self-reported use of four chemical hair products (permanent dye, semipermanent dye, straighteners/relaxers, and hair permanents/body waves) in the year before enrollment (2003-2009) and three DNA methylation-based measures of epigenetic age (DunedinPACE, GrimAge age acceleration [GrimAgeAccel], and PhenoAge age acceleration [PhenoAgeAccel]) using survey-weighted multivariable linear regressions. Associations were estimated both overall and by self-identified race and ethnicity, adjusting for chronological age, socioeconomic and lifestyle factors, body mass index, menopausal status, and DNA methylation platform. Results: Associations between the use of hair products and the three epigenetic age measures were largely null. Use of hair permanents/body waves was modestly associated with higher DunedinPACE among all participants (ßever-never = 0.010; 95% confidence interval [CI] = 0.001, 0.019) and with lower PhenoAgeAccel among Black women (ßever-never = -1.53; 95% CI = -2.84, -0.21). Conclusion: In this US-based study, we found little evidence of associations between chemical hair product use and epigenetic age in Black and non-Hispanic White women. Observed associations were modest and largely not supported by dose-response relationships or were inconsistent across epigenetic age measures. Previously observed associations between chemical hair product use and aging-related health outcomes may not be explained by the biological aging pathways captured by DunedinPACE, GrimAgeAccel, or PhenoAgeAccel. Alternative biological pathways are worth investigating in racially diverse samples.
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MOTIVATION: DNA methylation-based predictors of various biological metrics have been widely published and are becoming valuable tools in epidemiologic studies of epigenetics and personalized medicine. However, generating these predictors from original source software and web servers is complex and time consuming. Furthermore, different predictors were often derived based on data from different types of arrays, where array differences and batch effects can make predictors difficult to compare across studies. RESULTS: We integrate these published methods into a single R function to produce 158 previously published predictors for chronological age, biological age, exposures, lifestyle traits and serum protein levels using both classical and principal component-based methods. To mitigate batch and array differences, we also provide a modified RCP method (ref-RCP) that normalize input DNA methylation data to reference data prior to estimation. Evaluations in real datasets show that this approach improves estimate precision and comparability across studies. AVAILABILITY AND IMPLEMENTATION: The function was included in software package ENmix, and is freely available from Bioconductor website (https://www.bioconductor.org/packages/release/bioc/html/ENmix.html).
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Metilación de ADN , Programas Informáticos , Humanos , Epigénesis Genética , Epigenómica/métodosRESUMEN
BACKGROUND: Women with breast cancer are at higher risk of cardiovascular disease (CVD) compared with women without breast cancer. Whether higher diet quality at breast cancer diagnosis lowers this risk remains unknown. We set out to determine if higher diet quality at breast cancer diagnosis was related to lower risk of CVD and CVD-related death. METHODS: This analysis included 3415 participants from the Pathway Study, a prospective cohort of women diagnosed with invasive breast cancer at Kaiser Permanente Northern California between 2005 and 2013 and followed through December 31, 2021. Scores from 5 diet quality indices consistent with healthy eating were obtained at the time of breast cancer diagnosis. Scores were categorized into ascending quartiles of concordance for each diet quality index, and multivariable adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated. P values were 2-sided. RESULTS: The Dietary Approaches to Stop Hypertension diet quality index was associated with lower risk of heart failure (HR = 0.53, 95% CI = 0.33 to 0.87; Ptrend = .03), arrhythmia (HR = 0.77, 95% CI = 0.62 to 0.94; Ptrend = .008), cardiac arrest (HR = 0.77, 95% CI = 0.61 to 0.96; Ptrend = .02), valvular heart disease (HR = 0.79, 95% CI = 0.64 to 0.98; Ptrend = .046), venous thromboembolic disease (HR = 0.75, 95% CI = 0.60 to 0.93; Ptrend = .01), and CVD-related death (HR = 0.70, 95% CI = 0.50 to 0.99; Ptrend = .04), when comparing the highest with lowest quartiles. Inverse associations were also found between the healthy plant-based dietary index and heart failure (HR = 0.60, 95% CI = 0.39 to 0.94; Ptrend = .02), as well as the alternate Mediterranean dietary index and arrhythmia (HR = 0.74, 95% CI = 0.60 to 0.93; Ptrend = .02). CONCLUSION: Among newly diagnosed breast cancer patients, higher diet quality at diagnosis was associated with lower risk of CVD events and death.
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Neoplasias de la Mama , Supervivientes de Cáncer , Enfermedades Cardiovasculares , Insuficiencia Cardíaca , Humanos , Femenino , Neoplasias de la Mama/epidemiología , Enfermedades Cardiovasculares/epidemiología , Estudios Prospectivos , Dieta/efectos adversos , Arritmias CardíacasRESUMEN
Importance: Changes in leukocyte composition often precede chronic disease onset. Patients with a history of breast cancer (hereinafter referred to as breast cancer survivors) are at increased risk for subsequent chronic diseases, but the long-term changes in peripheral leukocyte composition following a breast cancer diagnosis and treatment remain unknown. Objective: To examine longitudinal changes in peripheral leukocyte composition in women who did and did not develop breast cancer and identify whether differences in breast cancer survivors were associated with specific treatments. Design, Setting, and Participants: In this prospective cohort study, paired blood samples were collected from 2315 women enrolled in The Sister Study, a US-nationwide prospective cohort study of 50â¯884 women, at baseline (July 2003 to March 2009) and follow-up (October 2013 to March 2015) home visits, with a mean (SD) follow-up interval of 7.6 (1.4) years. By design, approximately half of the included women had been diagnosed and treated for breast cancer after enrollment and before the second blood draw. A total of 410 women were included in the present study, including 185 breast cancer survivors and 225 who remained free of breast cancer over a comparable follow-up period. Data were analyzed from April 21 to September 9, 2022. Exposures: Breast cancer status and, among breast cancer survivors, cancer treatment type (chemotherapy, radiotherapy, endocrine therapy, or surgery). Main Outcomes and Measures: Blood DNA methylation data were generated in 2019 using a genome-wide methylation screening tool and deconvolved to estimate percentages of 12 circulating leukocyte subsets. Results: Of the 410 women included in the analysis, the mean (SD) age at enrollment was 56 (9) years. Compared with breast cancer-free women, breast cancer survivors had decreased percentages of circulating eosinophils (-0.45% [95% CI, -0.87% to -0.03%]; P = .03), total CD4+ helper T cells (-1.50% [95% CI, -2.56% to -0.44%]; P = .01), and memory B cells (-0.22% [95% CI, -0.34% to -0.09%]; P = .001) and increased percentages of circulating naive B cells (0.46% [95% CI, 0.17%-0.75%]; P = .002). In breast cancer survivor-only analyses, radiotherapy was associated with decreases in total CD4+ T cell levels, whereas chemotherapy was associated with increases in naive B cell levels. Surgery and endocrine therapy were not meaningfully associated with leukocyte changes. Conclusions and Relevance: In this cohort study of 410 women, breast cancer survivors experienced lasting changes in peripheral leukocyte composition compared with women who remained free of breast cancer. These changes may be related to treatment with chemotherapy or radiotherapy and could influence future chronic disease risk.
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Neoplasias de la Mama , Humanos , Femenino , Persona de Mediana Edad , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/terapia , Estudios de Cohortes , Estudios Prospectivos , Leucocitos , Enfermedad CrónicaRESUMEN
BACKGROUND: DNA methylation-based measures of biological aging have been associated with air pollution and may link pollutant exposures to aging-related health outcomes. However, evidence is inconsistent and there is little information for Black women. OBJECTIVE: We examined associations of ambient particulate matter <2.5 µm and <10 µm in diameter (PM2.5 and PM10) and nitrogen dioxide (NO2) with DNA methylation, including epigenetic aging and individual CpG sites, and evaluated whether associations differ between Black and non-Hispanic White (NHW) women. METHODS: Validated models were used to estimate annual average outdoor residential exposure to PM2.5, PM10, and NO2 in a sample of self-identified Black (n=633) and NHW (n=3493) women residing in the contiguous US. We used sampling-weighted generalized linear regression to examine the effects of pollutants on six epigenetic aging measures (primary: DunedinPACE, GrimAgeAccel, and PhenoAgeAccel; secondary: Horvath intrinsic epigenetic age acceleration [EAA], Hannum extrinsic EAA, and skin & blood EAA) and epigenome-wide associations for individual CpG sites. Wald tests of nested models with and without interaction terms were used to examine effect measure modification by race/ethnicity. RESULTS: Black participants had higher median air pollution exposure than NHW participants. GrimAgeAccel was associated with both PM10 and NO2 among Black participants, (Q4 versus Q1, PM10: ß=1.09, 95% CI: 0.16-2.03; NO2: ß=1.01, 95% CI 0.08-1.94) but not NHW participants (p-for-heterogeneity: PM10=0.10, NO2=0.20). In Black participants, we also observed a monotonic exposure-response relationship between NO2 and DunedinPACE (Q4 versus Q1, NO2: ß=0.029, 95% CI: 0.004-0.055; p-for-trend=0.03), which was not observed in NHW participants (p-for-heterogeneity=0.09). In the EWAS, pollutants were significantly associated with differential methylation at 19 CpG sites in Black women and one in NHW women. CONCLUSIONS: In a US-wide cohort study, our findings suggest that air pollution is associated with DNA methylation alterations consistent with higher epigenetic aging among Black, but not NHW, women.
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Contaminantes Atmosféricos , Contaminación del Aire , Contaminantes Ambientales , Humanos , Femenino , Contaminantes Atmosféricos/efectos adversos , Contaminantes Atmosféricos/análisis , Estudios de Cohortes , Dióxido de Nitrógeno/efectos adversos , Dióxido de Nitrógeno/análisis , Blanco , Contaminación del Aire/efectos adversos , Contaminación del Aire/análisis , Material Particulado/efectos adversos , Material Particulado/análisis , Envejecimiento/genética , Epigénesis Genética , Exposición a Riesgos Ambientales/efectos adversos , Exposición a Riesgos Ambientales/análisisRESUMEN
OBJECTIVE: People with HIV (PWH) are living longer and experiencing higher numbers of non-AIDS-defining cancers (NADC). Epigenetic aging biomarkers have been linked to cancer risk, and cancer is now a leading cause of death in PWH, but these biomarkers have not been investigated in PWH and cancer. DESIGN: In order to compare epigenetic age by HIV status, HIV-uninfected participants were matched to PWH by reported age, tumor site, tumor sequence number, and cancer treatment status. METHODS: DNA from blood was assayed using Illumina MethylationEPIC BeadChip, and we estimated immune cell composition and aging from three epigenetic clocks: Horvath, GrimAge, and epiTOC2. Age acceleration by clock was computed as the residual from the expected value, calculated using linear regression, for each study participant. Comparisons across HIV status used the Wilcoxon rank sum test. Hazard ratios and 95% confidence intervals for the association between age acceleration and survival in PWH were estimated with Cox regression. RESULTS: Among 65 NADC participants with HIV and 64 without, biological age from epiTOC2 ( P â<â0.0001) and GrimAge ( P â=â0.017) was significantly higher in PWH. Biological age acceleration was significantly higher in PWH using epiTOC2 ( P â<â0.01) and GrimAge ( P â<â0.0001), with the difference in GrimAge remaining statistically significant after adjustment for immune cell composition. Among PWH, GrimAge acceleration was significantly associated with increased risk of death (hazard ratio 1.11; 95% confidence interval (CI) 1.04-1.18). CONCLUSION: We observed a higher epigenetic age in PWH with a NADC diagnosis compared with their HIV-uninfected counterparts, as well as a significant association between this accelerated biological aging and survival for patients diagnosed with a NADC.
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Síndrome de Inmunodeficiencia Adquirida , Infecciones por VIH , Neoplasias , Humanos , Infecciones por VIH/complicaciones , Síndrome de Inmunodeficiencia Adquirida/complicaciones , Envejecimiento , Neoplasias/genética , Neoplasias/complicaciones , Epigénesis GenéticaRESUMEN
BACKGROUND: Breast cancer survivors have increased incidence of age-related diseases, suggesting that some survivors may experience faster biological aging. METHODS: Among 417 women enrolled in the prospective Sister Study cohort, DNA methylation data were generated on paired blood samples collected an average of 7.7 years apart and used to calculate 3 epigenetic metrics of biological aging (PhenoAgeAccel, GrimAgeAccel, and Dunedin Pace of Aging Calculated from the Epigenome [DunedinPACE]). Approximately half (n = 190) the women sampled were diagnosed and treated for breast cancer between blood draws, whereas the other half (n = 227) remained breast cancer-free. Breast tumor characteristics and treatment information were abstracted from medical records. RESULTS: Among women who developed breast cancer, diagnoses occurred an average of 3.5 years after the initial blood draw and 4 years before the second draw. After accounting for covariates and biological aging metrics measured at baseline, women diagnosed and treated for breast cancer had higher biological aging at the second blood draw than women who remained cancer-free as measured by PhenoAgeAccel (standardized mean difference [ß] = 0.13, 95% confidence interval [CI) = 0.00 to 0.26), GrimAgeAccel (ß = 0.14, 95% CI = 0.03 to 0.25), and DunedinPACE (ß = 0.37, 95% CI = 0.24 to 0.50). In case-only analyses assessing associations with different breast cancer therapies, radiation had strong positive associations with biological aging (PhenoAgeAccel: ß = 0.39, 95% CI = 0.19 to 0.59; GrimAgeAccel: ß = 0.29, 95% CI = 0.10 to 0.47; DunedinPACE: ß = 0.25, 95% CI = 0.02 to 0.48). CONCLUSIONS: Biological aging is accelerated following a breast cancer diagnosis and treatment. Breast cancer treatment modalities appear to differentially contribute to biological aging.
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Neoplasias de la Mama , Supervivientes de Cáncer , Femenino , Humanos , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/terapia , Estudios Prospectivos , Envejecimiento/genética , Metilación de ADN , Epigénesis GenéticaRESUMEN
BACKGROUND: Hypertension is common in older individuals and is a major risk factor for cardiovascular disease. Blood DNA methylation profiles have been used to derive metrics of biological age that capture age-related physiological change, disease risk, and mortality. The relationships between hypertension and DNA methylation-based biological age metrics have yet to be carefully described. METHODS: Among 4419 women enrolled in the prospective Sister Study cohort, DNA methylation data generated from whole blood samples collected at baseline were used to calculate 3 biological age metrics (PhenoAgeAccel, GrimAgeAccel, DunedinPACE). Women were classified as hypertensive at baseline if they had high blood pressure (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg) or reported current use of antihypertensive medication. New incident cases of hypertension during follow-up were identified via self-report on annual health questionnaires. RESULTS: All 3 DNA methylation metrics of biological age were positively associated with prevalent hypertension at baseline (per 1-SD increase; PhenoAgeAccel, adjusted odds ratio, 1.16 [95% CI, 1.05-1.28]; GrimAgeAccel, adjusted odds ratio, 1.28 [95% CI, 1.14-1.45]; DunedinPACE, adjusted odds ratio, 1.16 [95% CI, 1.03-1.30]). Among 2610 women who were normotensive at baseline, women with higher biological age were more likely to be diagnosed with incident hypertension (per 1-SD increase; PhenoAgeAccel, adjusted hazard ratio, 1.09 [95% CI, 0.97-1.23]; GrimAgeAccel, adjusted hazard ratio, 1.16 [95% CI, 0.99-1.36]; DunedinPACE, adjusted hazard ratio, 1.16 [95% CI, 1.01-1.33]). CONCLUSIONS: Methylation-based biological age metrics increase before a hypertension diagnosis and appear to remain elevated in the years after clinical diagnosis and treatment.
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Hipertensión , Humanos , Femenino , Anciano , Estudios Prospectivos , Metilación , Incidencia , Prevalencia , Hipertensión/epidemiología , Hipertensión/genética , Hipertensión/complicaciones , Presión Sanguínea/genética , Factores de Riesgo , Envejecimiento/genéticaRESUMEN
BACKGROUND: The development and consequences of hypertension involve multiple biological systems that may include changes in immune profiles. Whether hypertension is related to peripheral immune cell composition has not been examined in large human cohorts. METHODS: We estimated circulating proportions of 12 leukocyte subsets from the lymphoid and myeloid lineages by deconvolving cell-type-specific DNA methylation data from 4124 women. Hypertension status at baseline was defined by current use of antihypertensive medication and blood pressure measurements while new incident cases were identified during follow-up via annual health questionnaires. RESULTS: Among hypertension-free women at baseline, higher B cell and lower naïve CD4+ helper T cell proportions were associated with subsequent increased hazard of hypertension incidence (B cells; adjusted HR: 1.17 [95% CI: 1.02-1.35]; P=0.03; naïve CD4+ T cell, adjusted HR: 0.88 [95% CI: 0.78-0.99]; P=0.04). Blood pressure measurements at baseline were similarly positively associated with B cells and inversely associated with naïve CD4+ helper T cells. Compared to normotensive women, women with hypertension had higher circulating proportions of neutrophils (adjusted odds ratio: 1.18 [95% CI: 1.07-1.31]; P=0.001) and lower proportions of CD4+ helper T cells (adjusted odds ratio: 0.90 [95% CI: 0.81-1.00] P=0.05), natural killers (adjusted odds ratio: 0.82 [95% CI: 0.74-0.91]; P<0.001), and B cells (adjusted odds ratio: 0.84 [95% CI: 0.74-0.96]; P=0.01). CONCLUSIONS: These observations suggest that shifts in lymphocyte subsets occur before hypertension development, followed by later changes to neutrophils and additional lymphocytes.
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Humanos , FemeninoRESUMEN
α-Klotho (klotho) is a protein involved in suppressing oxidative stress and inflammation. In animal models, it is reported to underlie numerous aging phenotypes and longevity. Among a nationally representative sample of adults aged 40-79 years in the United States, we investigated whether circulating concentrations of klotho is a marker of mortality risk. Serum klotho was measured by ELISA on 10 069 individuals enrolled in the National Health and Nutrition Examination Survey between 2007 and 2014. Mortality follow-up data based on the National Death Index were available through December 31, 2015. After a mean follow-up of 58 months (range: 1-108), 616 incident deaths occurred. Using survey-weighted Cox regression models adjusted for age, sex, and survey cycle, low serum klotho concentration (<666 pg/mL) was associated with a 31% higher risk of death (compared to klotho concentration > 985 pg/mL, hazard ratio [HR]: 1.31, 95% confidence interval [CI]: 1.00, 1.71, p = .05). Associations were consistent for mortality caused by heart disease or cancer. Associations of klotho with all-cause mortality did not appear to differ by most participant characteristics. However, we observed effect modification by physical activity, such that low levels of serum klotho were more strongly associated with mortality among individuals who did not meet recommendation-based physical activity guidelines. Our findings suggest that, among the general population of American adults, circulating levels of klotho may serve as a marker of mortality risk.
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Envejecimiento , Enfermedades Cardiovasculares , Biomarcadores , Humanos , Longevidad , Encuestas Nutricionales , Modelos de Riesgos Proporcionales , Estados Unidos/epidemiologíaRESUMEN
BACKGROUND: Healthy eating is associated with lower risks of disease and mortality, but the mechanisms underlying these associations are unclear. Age is strongly related to health outcomes, and biological age can be estimated using the blood methylome. OBJECTIVES: To determine whether healthy eating patterns are associated with methylation-based measures of biological age. METHODS: Among women in the Sister Study, we calculated scores on 4 recommendation-based healthy eating indexes [Dietary Approaches to Stop Hypertension diet, Healthy Eating Index-2015, Alternative Healthy Eating Index (aHEI-2010), and the Alternative Mediterranean diet] using a validated 110-item Block FFQ completed at enrollment. Genome-wide DNA methylation data were generated using the HumanMethylation450 BeadChip on whole blood samples collected at enrollment from a case-cohort sample of 2694 women and were used to calculate 4 measures of epigenetic age acceleration (Hannum AgeAccel, Horvath AgeAccel, PhenoAgeAccel, and GrimAgeAccel). Linear regression models, adjusted for covariates and cohort sampling weights, were used to examine cross-sectional associations between eating patterns and measures of biological age. RESULTS: All 4 healthy eating indexes had inverse associations with epigenetic age acceleration, most notably with PhenoAgeAccel and GrimAgeAccel. Of these, the strongest associations were for aHEI-2010 [per 1-SD increase in diet quality, PhenoAgeAccel ß = -0.5 y (95% CI: -0.8 to -0.2 y) and GrimAgeAccel ß = -0.4 y (95% CI: -0.6 to -0.3 y)]. Although effect modification was not observed for most lifestyle factors, in analyses stratified by physical activity, the benefits of a healthy diet on epigenetic age acceleration were more pronounced among women who did not meet physical activity guidelines (reporting <2.5 h/wk of exercise). CONCLUSIONS: Higher diet quality is inversely associated with methylation-based measures of biological age. Improving diet could have the most benefits in lowering biological age among women with lower levels of physical activity. This trial was registered at clinicaltrials.gov as NCT00047970.
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Envejecimiento/genética , Dieta Saludable/mortalidad , Epigénesis Genética , Fenómenos Fisiológicos de la Nutrición/genética , Adulto , Anciano , Estudios Transversales , Metilación de ADN , Encuestas sobre Dietas , Dieta Mediterránea/estadística & datos numéricos , Epigenoma/genética , Ejercicio Físico , Conducta Alimentaria , Femenino , Humanos , Estilo de Vida , Estudios Longitudinales , Persona de Mediana EdadRESUMEN
Although blood DNA methylation (DNAm) profiles are reported to be associated with breast cancer incidence, they have not been widely used in breast cancer risk assessment. Among a breast cancer case-cohort of 2774 women (1551 cases) in the Sister Study, we used candidate CpGs and DNAm estimators of physiologic characteristics to derive a methylation-based breast cancer risk score, mBCRS. Overall, 19 CpGs and five DNAm estimators were selected using elastic net regularization to comprise mBCRS. In a test set, higher mBCRS was positively associated with breast cancer incidence, showing similar strength to the polygenic risk score (PRS) based on 313 single nucleotide polymorphisms (313 SNPs). Area under the curve for breast cancer prediction was 0.60 for self-reported risk factors (RFs), 0.63 for PRS, and 0.63 for mBCRS. Adding mBCRS to PRS and RFs improved breast cancer prediction from 0.66 to 0.71. mBCRS findings were replicated in a nested case-control study within the EPIC-Italy cohort. These results suggest that mBCRS, a risk score derived using blood DNAm, can be used to enhance breast cancer prediction.
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Neoplasias de la Mama , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , Estudios de Casos y Controles , Metilación de ADN/genética , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , HumanosRESUMEN
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.
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Envejecimiento/genética , Metilación de ADN , Epigénesis Genética , Sitios Genéticos , Herencia Multifactorial , Adiposidad/genética , Adiposidad/inmunología , Envejecimiento/inmunología , Biomarcadores/metabolismo , Proteína C-Reactiva/genética , Proteína C-Reactiva/inmunología , Islas de CpG , Escolaridad , Marcadores Genéticos , Genoma Humano , Estudio de Asociación del Genoma Completo , Granulocitos/citología , Granulocitos/inmunología , Humanos , Inmunidad Innata , Metabolismo de los Lípidos/genética , Metabolismo de los Lípidos/inmunología , Inhibidor 1 de Activador Plasminogénico/genética , Inhibidor 1 de Activador Plasminogénico/inmunologíaRESUMEN
Epigenetic age acceleration is considered a measure of biological aging based on genome-wide patterns of DNA methylation. Although age acceleration has been associated with the incidence of diseases and death, less is known about how it is related to lifestyle behaviors. Among 2316 women, we evaluate associations between self-reported alcohol consumption and various metrics of epigenetic age acceleration. Recent average alcohol consumption was defined as the mean number of drinks consumed per week within the past year; lifetime average consumption was estimated as the mean number of drinks per year drinking. Whole-blood genome-wide DNA methylation was measured with HumanMethylation450 BeadChips and used to assess 4 epigenetic clocks (Hannum, Horvath, PhenoAge, and GrimAge) and their corresponding metrics of epigenetic age acceleration (Hannum AgeAccel, Horvath AgeAccel, PhenoAgeAccel, and GrimAgeAccel). Although alcohol consumption showed little association with most age acceleration metrics, both lifetime and recent average consumption measures were positively associated with GrimAgeAccel (lifetime, per additional 135 drinks/year: ß = 0.30 years, 95% confidence interval [CI]: 0.11, 0.48, p = .002; recent, per additional 5 drinks/week: ß = 0.19 years, 95% CI: 0.01, 0.37, p = .04). In a mutually adjusted model, only average lifetime alcohol consumption remained associated with GrimAgeAccel (lifetime, per additional 135 drinks/year: ß = 0.27 years, 95% CI: 0.04, 0.50, p = .02; recent, per 5 additional drinks/week: ß = 0.05 years, 95% CI: -0.16, 0.26, p = .64). Although alcohol use does not appear to be strongly associated with biological age measured by most epigenetic clocks, lifetime average consumption is associated with higher biological age assessed by the GrimAge epigenetic clock.
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Envejecimiento , Consumo de Bebidas Alcohólicas , Metilación de ADN , Epigénesis Genética , Envejecimiento/genética , Consumo de Bebidas Alcohólicas/epidemiología , Consumo de Bebidas Alcohólicas/genética , Epigenómica , Femenino , HumanosRESUMEN
Epigenetic clocks use DNA methylation to estimate biological age. Whether body composition and physical activity are associated with these clocks is not well understood. Using blood samples collected at enrollment (2003-2009) from 2,758 women in the US nationwide Sister Study, we calculated 6 epigenetic age acceleration metrics using 4 epigenetic clocks (Hannum, Horvath, PhenoAge, GrimAge). Recreational physical activity was self-reported, and adiposity measures were assessed by trained medical examiners (body mass index (BMI), waist-to-hip ratio (WtH), waist circumference). In cross-sectional analyses, all adiposity measures were associated with epigenetic age acceleration. The strongest association was for BMI and PhenoAge, a measure of biological age that correlates with chronic disease (BMI of ≥35.0 vs. 18.5-24.9, ß = 3.15 years, 95% confidence interval (CI): 2.41, 3.90; P for trend < 0.001). In a mutual-adjustment model, both were associated with PhenoAge age acceleration (BMI of ≥35.0 vs. 18.5-24.9, ß = 2.69 years, 95% CI: 1.90, 3.48; P for trend < 0.001; quartile 4 vs.1 WtH, ß = 1.00 years, 95% CI: 0.34, 1.65; P for trend < 0.008). After adjustment, physical activity was associated only with GrimAge (quartile 4 vs. 1, ß = -0.42 years, 95% CI: -0.70, -0.14; P for trend = 0.001). Physical activity attenuated the waist circumference associations with PhenoAge and GrimAge. Excess adiposity was associated with epigenetic age acceleration; physical activity might attenuate associations with waist circumference.
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Envejecimiento/genética , Composición Corporal/genética , Epigénesis Genética/fisiología , Ejercicio Físico/fisiología , Adiposidad/genética , Adulto , Anciano , Índice de Masa Corporal , Estudios Transversales , Metilación de ADN/fisiología , Femenino , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Estados Unidos , Circunferencia de la Cintura , Relación Cintura-CaderaRESUMEN
Importance: Neighborhood deprivation is associated with age-related disease, mortality, and reduced life expectancy. However, biological pathways underlying these associations are not well understood. Objective: To evaluate the association between neighborhood deprivation and epigenetic measures of age acceleration and genome-wide methylation. Design, Setting, and Participants: This cross-sectional study used data from the Sister Study, a prospective cohort study comprising 50â¯884 women living in the US and Puerto Rico aged 35 to 74 years at enrollment who had a sister with breast cancer but had not had breast cancer themselves. Cohort enrollment occurred between July 2003 and March 2009. Participants completed a computer-assisted telephone interview on demographic, socioeconomic, lifestyle, and residential factors and provided anthropometric measures and peripheral blood samples at a home examination. DNA methylation data obtained for 2630 non-Hispanic White women selected for a case-cohort study in 2014 were used in this cross-sectional analysis. DNA methylation was measured using the HumanMethylation450 BeadChips in whole blood samples collected at baseline. Data analysis for this study was performed from October 17, 2019, to August 27, 2020. Exposures: Each participants' primary address was linked to an established index of neighborhood deprivation. Main Outcomes and Measures: Epigenetic age was estimated using 4 epigenetic clocks (Horvath, Hannum, PhenoAge, and GrimAge). Age acceleration was determined using residuals from regressing chronologic age on each of the 4 epigenetic age metrics. Linear regression was used to estimate associations between neighborhood deprivation and epigenetic age acceleration as well as DNA methylation at individual cytosine-guanine sites across the genome. Results: Mean (SD) age of the 2630 participants was 56.9 (8.7) years. Those with the greatest (>75th percentile) vs least (≤25th percentile) neighborhood deprivation had higher epigenetic age acceleration estimated by Hannum (ß = 0.23; 95% CI, 0.01-0.45), PhenoAge (ß = 0.28; 95% CI, 0.06-.50), and GrimAge (ß = 0.37; 95% CI, 0.12-0.62). Increasing US quartiles of neighborhood deprivation exhibited a trend with Hannum, PhenoAge, and GrimAge. For example, GrimAge showed a significant dose-response (P test for trend <.001) as follows: level 2 vs level 1 (ß = 0.30; 95% CI, 0.17-0.42), level 3 vs level 1 (ß = 0.35; 95% CI, 0.19-0.50), and level 4 vs level 1 (ß = 0.37; 95% CI, 0.12-0.62). Neighborhood deprivation was found to be associated with 3 cytosine-phosphate-guanine sites, with 1 of these annotated to a known gene MAOB (P = 9.71 × 10-08). Conclusions and Relevance: The findings of this study suggest that residing in a neighborhood with a higher deprivation index appears to be reflected by methylation-based markers of aging.
Asunto(s)
Envejecimiento/genética , Metilación de ADN/genética , Epigénesis Genética/genética , Características de la Residencia/estadística & datos numéricos , Adulto , Anciano , Antropometría/métodos , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/etnología , Estudios Transversales , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Modelos Lineales , Persona de Mediana Edad , Estudios Prospectivos , Puerto Rico/epidemiología , Factores SocioeconómicosRESUMEN
Importance: Higher overall leukocyte counts in women may be associated with increased risk of breast cancer, but the association of specific leukocyte subtypes with breast cancer risk remains unknown. Objective: To determine associations between circulating leukocyte subtypes and risk of breast cancer. Design, Setting, and Participants: Between 2003 and 2009, the Sister Study enrolled 50â¯884 women who had a sister previously diagnosed with breast cancer but were themselves breast cancer free. A case-cohort subsample was selected in July 2014 from the full Sister Study cohort. Blood samples were obtained at baseline, and women were followed up through October 2016. Data analysis was performed in April 2019. Main Outcomes and Measures: The main outcome was the development of breast cancer in women. Whole-blood DNA methylation was measured, and methylation values were deconvoluted using the Houseman method to estimate proportions of 6 leukocyte subtypes (B cells, natural killer cells, CD8+ and CD4+ T cells, monocytes, and granulocytes). Leukocyte subtype proportions were dichotomized at their population median value, and Cox proportional hazard models were used to estimate associations with breast cancer. Results: Among 2774 non-Hispanic white women included in the analysis (mean [SD] age at enrollment, 56.6 [8.8] years), 1295 women were randomly selected from the full cohort (of whom 91 developed breast cancer) along with an additional 1479 women who developed breast cancer during follow-up (mean [SD] time to diagnosis, 3.9 [2.2] years). Circulating proportions of B cells were positively associated with later breast cancer (hazard ratio [HR], 1.17; 95% CI, 1.01-1.36; P = .04). Among women who were premenopausal at blood collection, the association between B cells and breast cancer was significant (HR, 1.38; 95% CI, 1.05-1.82; P = .02), and an inverse association for circulating proportions of monocytes was found (HR, 0.75; 95% CI, 0.57-0.99; P = .05). Among all women, associations between leukocyte subtypes and breast cancer were time dependent: higher monocyte proportions were associated with decreased near-term risk (within 1 year of blood collection, HR, 0.62; 95% CI, 0.43-0.89; P = .01), whereas higher B cell proportions were associated with increased risk 4 or more years after blood collection (HR, 1.38; 95% CI, 1.15-1.67; P = .001). Conclusions and Relevance: Circulating leukocyte profiles may be altered before clinical diagnoses of breast cancer and may be time-dependent markers for breast cancer risk, particularly among premenopausal women.
Asunto(s)
Biomarcadores de Tumor/sangre , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/fisiopatología , Predisposición Genética a la Enfermedad , Inmunidad Celular , Leucocitos/inmunología , Factores de Edad , Anciano , Estudios de Cohortes , Femenino , Humanos , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Factores de RiesgoRESUMEN
Measures derived using blood DNA methylation are increasingly under investigation as indicators of disease and mortality risk. Three existing epigenetic age measures or "epigenetic clocks" appear associated with breast cancer. Two newly-developed epigenetic mortality predictors may be related to all-cancer incidence, but associations with specific cancers have not been examined in large studies. Using HumanMethylation450 BeadChips to measure blood DNA methylation in 2,773 cancer-free women enrolled in the Sister Study, we calculated two epigenetic mortality predictors: 'GrimAgeAccel' and the 'mortality score' (MS). Using Cox proportional hazard models, neither GrimAgeAccel nor the MS were associated with overall breast cancer incidence (GrimAgeAccel hazard ratio [HR]: 1.06, 95% confidence interval [CI]: 0.98-1.14, P=0.17; MS HR: 0.99, 95% CI: 0.92-1.07, P=0.85); however, a weak, positive association was observed for GrimAgeAccel and invasive breast cancer (HR: 1.08, 95% CI: 0.99-1.17, P=0.08). Stratification of invasive cancers by menopause status at diagnoses revealed the association was predominantly observed for postmenopausal breast cancer (HR: 1.10, 95% CI: 1.01, 1.20, P=0.04). Although the MS was unrelated to breast cancer risk, we find evidence that GrimAgeAccel may be weakly associated with invasive breast cancer, particularly for women diagnosed after menopause.