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  • Bixler, Edward O  (6)
  • 1
    Online Resource
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    Abstract P129: Association Between Blood Pressure and DNA Methylation in Blood Pressure-related Genes in Adolescents
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Circulation Vol. 137, No. suppl_1 ( 2018-03-20)
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    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 137, No. suppl_1 ( 2018-03-20)
    Abstract: Introduction: Pediatric hypertension is a significant public health burden. Although the association between genetic variants and blood pressure (BP) has been extensively investigated, the relationship between DNA methylation and BP, especially in adolescents, has not been characterized. Hypothesis: DNA methylation of previously reported BP-related genes is associated with BP levels in adolescents. Methods: We examined this relationship in 263 adolescents from the Penn State Child Cohort follow-up exam. We extracted peripheral leukocytes DNA and subjected it to enhanced, reduced representation bisulfite sequencing. A high-throughput assay provided single nucleotide resolution of DNA methylation in cytosine-phosphate-guanine (CpG) sites and surrounding regions. Bases with less than 10x coverage or available from less than 50% of the participants were excluded, resulting in a total of 165,297 analyzable sites. For each participant, 3 seated-BP measurements were taken and the average of 2 nd and 3 rd measurements was used to represent the participant’s BP. We used robust linear regression to associate site-specific methylation level with systolic BP (SBP) and diastolic BP (DBP). All regression models were adjusted for age, race, sex, and body mass index percentile. All intragenic sites were then mapped to the hg19 assembly and subjected to enrichment analyses. Significance of the enrichment analyses was assessed by hypergeometric and permutation tests. False discovery rate (FDR)-corrected p values were used to determine the significance between site-specific methylation and BP measures. Results: The mean (SD) age of the participants was 16.7 (2.2) years. It consisted of 55% male, 79% white and 16% obese. Among the 5,551 and 5,890 sites related to SBP and DBP at p 〈 0.05 level, 35 and 38 were intragenic to BP genes. BP genes were significantly enriched among intragenic sites for both SBP (P (hypergeometric)c =0.015; P (permutation) =0.019) and DBP (P (hypergeometric)c =0.008; P (permutation) =0.012). At individual site level, two sites within MECOM were significantly related to SBP (FDR-corrected P=0.02 and 0.03). Conclusion: Despite the need of external validation from other independent cohorts, data from this exploratory study suggests that DNA methylation of BP-related genes is associated with BP regulation in adolescents and, consequently, with the pathogenesis of hypertension in early developmental periods.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.137.suppl_1.p129
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
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  • 2
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    Abstract MP70: Habitual Sleep Variability, Mediated by Energy Intake, is Associated with Abdominal Obesity in Adolescents
    Ovid Technologies (Wolters Kluwer Health) ; 2015
    In:  Circulation Vol. 131, No. suppl_1 ( 2015-03-10)
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    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 131, No. suppl_1 ( 2015-03-10)
    Abstract: Introduction: Although self-reported sleep duration has been associated with obesity, study of the association between objectively-measured habitual sleep pattern and the more metabolically relevant abdominal obesity, and the mediation factors for such an association, is limited. Hypothesis: We assessed the hypothesis that objectively-measured variability, mediated by excessive energy intake, is associated with abdominal obesity in adolescents. Methods: We used data from 421 adolescents in the Penn State Child Cohort follow-up examination. Actigraphy was used for 7 consecutive nights to calculate each participant’s mean sleep duration as habitual sleep duration (HSD) and the standard deviation of the mean as habitual sleep variability (HSV). Abdominal obesity was assessed by dual-energy x-ray absorptiometry as Android/Gynoid Fat Ratio and visceral fat area . Youth/Adolescents Food Frequency Questionnaire was used to obtain daily caloric, fat, carbohydrate, and protein intakes one year prior to the study. The R-based Mediation Effect Models were used to assess the association between sleep pattern and abdominal obesity, and quantitatively estimate the mediation effects of caloric intake and of other factors not analyzed in this report. Results: As shown in the table, after controlling for major confounders and BMI percentile, HSV was significantly and consistently associated with both abdominal obesity measures. The Mediation analysis consistently indicated a significant mediation effect of caloric intake, especially carbohydrate intake. For example, 20% of the association between HSV and visceral fat could be attributed to carbohydrate intake, while 80% by other factors not analyzed. HSD was not associated with abdominal obesity. Conclusions: Higher HSV, not HSD, is associated with abdominal obesity, which can be partially explained by increased caloric intake, especially from carbohydrate, in adolescents. More studies are needed to identify other mediation factors in the association.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.131.suppl_1.mp70
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2015
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  • 3
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    Abstract P305: Obesity is Associated with Differentiated Methylation in Glucose Tolerance-related Genes in Adolescents
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Circulation Vol. 133, No. suppl_1 ( 2016-03)
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    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 133, No. suppl_1 ( 2016-03)
    Abstract: Background: Childhood obesity is related to increased cardiometabolic risk in adulthood. Insulin resistance is an established underlying mechanism between obesity and CVD risk. However, the role of epigenetic profiles in this mechanistic link is less investigated, especially in adolescents. Hypothesis: We assessed the hypothesis that obesity is associated with differentiated methylation profiles in genes related to glucose tolerance and its downstream functions in adolescents. Methods: We used data from a sample of 116 adolescents from the population-based Penn State Child Cohort follow-up exam (N=421). Among which, 22 were obese (BMI percentile ≥ 95) and 94 were normal weight (BMI percentile 〈 85). Peripheral leukocytes DNA was extracted and subject to enhanced reduced representation bisulfite sequencing. The high-throughput assay provided single nucleotide resolution of DNA methylation in CpG sites and surrounding regions. The R package methylKit was used in the post-processing and analysis. Bases with 〈 10x coverage were excluded in the assay, resulting in a total of 634,418 methylation sites with a minimum of 10 samples per group. Logistic regression was used in the differential methylation calculation. We decided a priori to choose the sites with ≥ 25% difference in methylation with a q value 〈 0.01 for the enrichment analysis. We used Ingenuity Pathway Analysis (IPA) to perform gene-set enrichment analysis for downstream function and effects on the differentially methylated genes. Results: The mean (SD) age of the study sample was 16.3 (2.2) years. The sample consisted of 52% male and 79% white. No significant difference was observed between obese and normal weight groups with respect to demographic characteristics. We identified a total of 2349 bases with statistically significant (q 〈 0.01) differentiated methylation with a difference of 25% or more. IPA revealed 38 sites related to glucose tolerance function, and this function is significantly enriched (p=1.51E-4). Highlighting some individual genes, obese adolescents showed 26.4% higher methylation at a site on the insulin (INS) gene compared to normal weight adolescents, and a site on the gastric inhibitory polypeptide receptor (GIPR) gene had 47.3% differential methylation. Other major significantly differentially methylated glucose tolerance-related genes included interleukin 6 (IL6), and tumor necrosis factor (TNF), and low density lipoprotein receptor (LDLR) genes. Conclusion: Obesity in adolescents is significantly associated with substantially differentiated methylation in glucose tolerance-related genes. It indicated that obesity is related to alternations in the epigenetic profiles related to impaired glucose tolerance, and potentially through which associated with elevated risk of its downstream diseases, such as diabetes and CVD.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.133.suppl_1.p305
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
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  • 4
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    Abstract P135: Abdominal Obesity is Associated With DNA Methylation in Cardiovascular Health Related Genes Among Adolescents
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Circulation Vol. 135, No. suppl_1 ( 2017-03-07)
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    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 135, No. suppl_1 ( 2017-03-07)
    Abstract: Background: Obesity, especially abdominal obesity, is a risk factor for coronary artery disease (CAD) in various populations. Little is known regarding the role of epigenetics in the association between abdominal obesity and cardiovascular health in adolescents. Hypothesis: Abdominal and especially visceral obesity is associated with DNA methylation in genes related to cardiovascular health among adolescents. Methods: We used data from a sample of 263 adolescents participating in the population-based Penn State Child Cohort follow-up exam (N=421). Dual-energy X-ray absorptiometry was used to measure visceral and subcutaneous fat areas (VAT; SAT, in cm 2 ) in each participant. We extracted DNA from peripheral leukocytes and subjected it to enhanced, reduced representation bisulfite sequencing. A high-throughput assay provided single nucleotide resolution of DNA methylation in cytosine-phosphate-guanine (CpG) sites and surrounding regions. We excluded bases with 〈 10x coverage or available from 〈 20 individuals. We analyzed a total of 1,609,424 methylation sites. We used linear regression models to assess the association between site-specific methylation level (expressed as %) and VAT and SAT. We adjusted all models for age, race, sex, and body mass index (BMI) percentile. We used Bonferroni-adjusted statistical tests to identify sites significantly related to VAT and separately, SAT. We mapped the VAT- and SAT-associated sites to the hg19 assembly and subjected them to Ingenuity Pathway Analysis (IPA) wherein mapped gene sets were examined for enrichment of downstream function and diseases. Results: On average, the sample was 55% male, 79% white and aged 16.7 (standard deviation = 2.2) years. VAT and SAT were significantly associated with methylation at 296 sites within 193 genes and 101 sites within 87 genes, respectively. Among them, seven genes related to VAT and five related to SAT were associated with CAD. IPA revealed that CAD-related genes were significantly enriched in both gene sets (for VAT: p=1.97x10 -2 ; SAT: p=9.67x10 -3 ). Genes related to VAT also were significantly enriched in endothelial activation (p=8.16x10 -3 ), fibrogenesis (p=5.01x10 -5 ), and dyslipidemia (p=7.99x10 -3 ). Indeed, higher VAT was associated with hypomethylation of CD14 and hypermethylation of GNMT , while higher SAT was associated with hypermethylation of ADRB1 and hypomethylation of TUBB4A . Conclusion: If externally validated, our data would suggest that (1) abdominal obesity in adolescence is associated with DNA methylation of genes related to cardiovascular health, independent of BMI; and (2) visceral adiposity has a more prominent association with cardiovascular health through DNA methylation of genes with roles in atherogenesis.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.135.suppl_1.p135
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 1466401-X
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  • 5
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    Abstract P136: Cardiometabolic Burden in Adolescents is Associated with DNA Methylation in Genes Related to Cardiovascular Disease Risk
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Circulation Vol. 135, No. suppl_1 ( 2017-03-07)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 135, No. suppl_1 ( 2017-03-07)
    Abstract: Background: Metabolic syndrome is related to increased cardiovascular disease (CVD) risk. Although continuous metabolic syndrome score (cMets) is a marker of cardiometabolic burden in adolescence, the relationship between cardiometabolic burden and DNA methylation has been rarely assessed at this stage of the life course. Hypothesis: Cardiometabolic burden is related to methylation levels in genes related to CVD risk in adolescents. Methods: A sample of 263 independent adolescents from the population-based Penn State Child Cohort follow-up exam (N=421) was used in this analysis. cMets was calculated as the sum of standardized residuals of five established cardiometabolic risk factors, namely waist circumference, mean arterial pressure, homeostatic model assessment of insulin resistance, triglycerides, and high density lipoprotein cholesterol (HDL) concentration. cMets was log-transformed to improve the distribution. Peripheral leukocyte DNA was extracted and subjected to enhanced, reduced representation bisulfite sequencing. The assay provided single nucleotide resolution of DNA methylation in cytosine-phosphate-guanine (CpG) sites and surrounding regions. Bases with 〈 10x coverage were excluded, resulting a total of 1,609,424 methylation sites. Linear regression was used to model the association between site-specific methylation level and cMets. All models were adjusted for age, race, and sex. A p 〈 10x10 -8 was used to determine statistical significance. The significant sites were mapped to the hg19 assembly and subjected to Ingenuity Pathway Analysis (IPA) wherein mapped gene sets were examined for enrichment of downstream function and diseases. Permutations were further performed to confirm the robustness of our findings. Results: On average, the sample was 55% male, 79% white, and aged 16.7 (standard deviation = 2.2) years. cMetS was significantly associated with 52 sites within 43 genes. Among the genes, three were related to glucose tolerance, two to endothelial function, and two more to oxidative stress. IPA indicated that genes associated with these functions were significantly enriched for glucose tolerance (p=0.029), endothelial function (p=0.009), and oxidative stress (p=0.028). Indeed, high cMetS was associated with hypermethylation of PRKCD , which is related to diabetes risk, and PRDX5 , which encodes anti-oxidant peroxiredoxin-5. Higher cMetS also was associated with hypomethylation of ID3 . Conclusion: Despite validation is pending, these preliminary findings suggest that cardiometabolic burden in adolescents is related to DNA methylation in genes related to CVD risk factors in adulthood, including glucose tolerance, endothelial function, and oxidative stress.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.135.suppl_1.p136
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 1466401-X
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  • 6
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    Abstract P312: Lack of Association Between Habitual Sleep Duration and Obesity Measures in Adolescents with Adequate Sleep
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Circulation Vol. 133, No. suppl_1 ( 2016-03)
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 133, No. suppl_1 ( 2016-03)
    Abstract: Introduction: In general, 7-8 hours/night of sleep is considered as adequate amount of sleep. Although subjectively reported sleep duration has been associated with obesity, the relationship between objectively-measured sleep duration and obesity has been reported inconsistently. Hypothesis: We assessed the hypothesis that there is lack of association between objectively-measured sleep duration and obesity measures in adolescents who generally sleep adequately. Methods: We used data from 421 adolescents in the Penn State Child Cohort follow-up examination. Polysomnography (PSG) was used to objectively measure the sleep duration for one night. Actigraphy was used for 7 consecutive nights to objectively measure and calculate each participant’s habitual mean sleep duration. Anthropometric measurements, including waist circumference, weight, and height, were collected from each participant. Age and sex-specific BMI percentile was calculated. The participants also underwent a dual-energy x-ray absorptiometry scan to assess abdominal obesity, as measured by Android/Gynoid (A/G) fat ratio, Android/whole body (A/W) fat proportion, visceral fat area, and subcutaneous fat area. Multivariable adjusted linear regression was used to analyze the association between sleep duration and obesity measures. Results: The means (SD) of the PSG and actigraphy-measured sleep duration were 7.4 (0.9) and 7.0 (0.8) hours, respectively. As shown in the table, objectively-measured sleep duration was not significantly associated with BMI percentile, after controlling for age, race, sex, and AHI. After further adjustment for BMI percentile, none of the regression coefficients between sleep duration and abdominal obesity measures reached statistical significance. Conclusions: In adolescents with generally adequate amount of sleep, there is lack of association between habitual sleep duration and obesity measures. The findings should not be generalized to adolescents whose sleep duration is outside the range of our data.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/circ.133.suppl_1.p312
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
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