Shaoyong Su

Obesity related methylation changes in DNA of peripheral blood leukocytes

BackgroundDespite evidence linking obesity to impaired immune function, little is known about the specific mechanisms. Because of emerging evidence that immune responses are epigenetically regulated, we hypothesized that DNA methylation changes are involved in obesity induced immune dysfunction and aimed to identify these changes.MethodWe conducted a genome wide methylation analysis on seven obese cases and seven lean controls aged 14 to 18 years from extreme ends of the obesity distribution and performed further validation of six CpG sites from six genes in 46 obese cases and 46 lean controls aged 14 to 30 years.ResultsIn comparison with the lean controls, we observed one CpG site in the UBASH3A gene showing higher methylation levels and one CpG site in the TRIM3 gene showing lower methylation levels in the obese cases in both the genome wide step (P = 5 × 10-6 and P = 2 × 10-5 for the UBASH3A and the TRIM3 gene respectively) and the validation step (P = 0.008 and P = 0.001 for the UBASH3A and the TRIM3 gene respectively).ConclusionsOur results provide evidence that obesity is associated with methylation changes in blood leukocyte DNA. Further studies are warranted to determine the causal direction of this relationship as well as whether such methylation changes can lead to immune dysfunction.See commentary: http://www.biomedcentral.com/1741-7015/8/88/abstract

Depressive Symptoms and Metabolic Syndrome: Is Inflammation the Underlying Link?

BACKGROUND Behavioral alterations, including depression, are frequent in individuals with the metabolic syndrome (MetS). Recent findings suggest that chronic activation of innate immunity might be involved. The objective of this study was to examine the relationship between MetS and depressive symptoms and to elucidate the involvement of inflammation in this relationship. METHODS Participants were 323 male twins, with and without MetS and free of symptomatic cardiovascular disease, drawn from the Vietnam Era Twin Registry. Depressive symptoms were measured with the Beck Depression Inventory (BDI). Inflammatory status was assessed using C-reactive protein (CRP) and interleukin-6 (IL-6); twins with both CRP and IL-6 levels above the median were classified as having an elevated inflammatory status. Factor analysis was performed on individual BDI items to extract specific symptom dimensions (neurovegetative, mood, affective-cognitive). RESULTS Subjects with MetS had more depressive symptoms than those without. Depressive symptoms with neurovegetative features were more common and more robustly associated with MetS. Both the BDI total score and each symptom subscore were associated with inflammatory biomarkers. After adjusting for age, education, and smoking status, the MetS was significantly associated with the BDI total score and the neurovegetative score. After further adjusting for inflammation, the coefficient for MetS decreased somewhat but remained statistically significant for the BDI neurovegetative subscore. When controlling for the MetS, inflammation remained significantly associated with the BDI mood subscore. CONCLUSIONS The MetS is associated with higher depressive symptomatology characterized primarily by neurovegetative features. Inflammation is one determinant of depressive symptoms in individuals with MetS.

Decreased heart rate variability is associated with higher levels of inflammation in middle-aged men

BACKGROUND Many traditional risk factors for coronary artery disease (CAD) are associated with altered autonomic function. Inflammation may provide a link between risk factors, autonomic dysfunction, and CAD. We examined the association between heart rate variability (HRV), a measure of autonomic function, and inflammation, measured by C-reactive protein (CRP) and interleukin-6 (IL-6). METHODS We examined 264 middle-aged male twins free of symptomatic CAD. All underwent ambulatory electrocardiogram monitoring and 24-hour ultra low, very low, low, and high-frequency power were calculated using power spectral analysis. C-reactive protein and IL-6 were measured, and risk factors including age, smoking, hypertension, lipids, diabetes, body mass index (BMI), depression, and physical activity were assessed. RESULTS Physical activity, BMI, high-density lipoprotein cholesterol, smoking, depression, and hypertension were directly associated with CRP and IL-6 and inversely associated with one or more HRV variables. There was a graded inverse relationship between all HRV parameters (except high frequency) and CRP and IL-6. After adjustment for age, BMI, activity, high-density lipoprotein, smoking, hypertension, depression, and diabetes, ultra low frequency and very low frequency remained significant predictors of CRP (P < .01). CONCLUSIONS C-reactive protein is associated with decreased HRV, even after controlling for traditional CAD risk factors. Autonomic dysregulation leading to inflammation may represent one pathway through which traditional risk factors promote development of CAD.

A genome-wide methylation study on obesity: Differential variability and differential methylation

Besides differential methylation, DNA methylation variation has recently been proposed and demonstrated to be a potential contributing factor to cancer risk. Here we aim to examine whether differential variability in methylation is also an important feature of obesity, a typical non-malignant common complex disease. We analyzed genome-wide methylation profiles of over 470,000 CpGs in peripheral blood samples from 48 obese and 48 lean African-American youth aged 14–20 y old. A substantial number of differentially variable CpG sites (DVCs), using statistics based on variances, as well as a substantial number of differentially methylated CpG sites (DMCs), using statistics based on means, were identified. Similar to the findings in cancers, DVCs generally exhibited an outlier structure and were more variable in cases than in controls. By randomly splitting the current sample into a discovery and validation set, we observed that both the DVCs and DMCs identified from the first set could independently predict obesity status in the second set. Furthermore, both the genes harboring DMCs and the genes harboring DVCs showed significant enrichment of genes identified by genome-wide association studies on obesity and related diseases, such as hypertension, dyslipidemia, type 2 diabetes and certain types of cancers, supporting their roles in the etiology and pathogenesis of obesity. We generalized the recent finding on methylation variability in cancer research to obesity and demonstrated that differential variability is also an important feature of obesity-related methylation changes. Future studies on the epigenetics of obesity will benefit from both statistics based on means and statistics based on variances.

Association of Major Depressive Disorder with Serum Myeloperoxidase and Other Markers of Inflammation: A Twin Study

BACKGROUND Major depressive disorder (MDD) has been linked to inflammation, but this association may be due to common precursors to both depression and inflammation. Myeloperoxidase (MPO) is an inflammatory enzyme produced by activated leukocytes that predicts risk of coronary heart disease. We sought to examine whether MPO and other markers of inflammation are associated with MDD and whether the association is confounded by genetic or other shared familial factors. METHODS We examined 178 monozygotic and dizygotic middle-aged male twin pairs. We assessed MDD with the Structured Clinical Interview for DSM-IV. Blood markers of inflammation included MPO, interleukin-6, white blood cell count, C-reactive protein, tumor necrosis factor (TNF)-alpha, the TNF-alpha soluble receptor II, and fibrinogen. Analyses were conducted in the overall sample and among 67 twin pairs discordant for MDD using mixed effects regression. RESULTS Twins with a history of MDD had 32% higher levels of MPO (p < .0001); this difference persisted after adjusting for other risk factors. Among dizygotic MDD-discordant twin pairs, twins with MDD had 77% higher MPO than their brothers without MDD, after adjusting for other factors (p < .0001). In contrast, no significant association was found in monozygotic twins (p = .13). Similar, but weaker, associations were found between MDD and other inflammatory biomarkers. CONCLUSIONS Myeloperoxidase is a useful biomarker of immune activation in MDD. However, the association between inflammation and MDD is largely due to common genetic liability. Our results are consistent with the hypothesis that genes promoting inflammation are involved in the pathogenesis of MDD.

A longitudinal study in youth of heart rate variability at rest and in response to stress.

BACKGROUND Few longitudinal studies have examined ethnic and sex differences, predictors and tracking stabilities of heart rate variability (HRV) at rest and in response to stress in youths and young adults. METHODS Two evaluations were performed approximately 1.5 years apart on 399 youths and young adults (189 European Americans [EAs] and 210 African Americans [AAs]; 190 males and 209 females). HRV was measured at rest and during a video game challenge. RESULTS AAs showed significantly higher resting root mean square of successive differences (RMSSD) of normal R-R intervals and high-frequency (HF) power than EAs (ps<0.01). Females displayed larger decrease of RMSSD and HF during video game challenge than males (ps<0.05). These ethnic and sex differences were consistent across 1.5 years. No significant sex difference of resting HRV or ethnic difference of HRV response to stress was observed. In addition to age, ethnicity or sex, baseline resting HRV or HRV response to stress are predictors of the corresponding variables 1.5 years later (ps<0.01). Furthermore, weight gain indexed by either body mass index or waist circumference predicts declined resting HRV levels during follow up (ps<0.05). Tracking stabilities were high (>0.5) for resting HRV, but relatively low (<0.3) for HRV in response to stress. CONCLUSION AAs show higher resting HRV than EAs, and females display greater HRV response to stress than males; and these ethnic and sex differences are consistent across 1.5 years. Resting HRV declines with weight gain.

Common genetic contributions to depressive symptoms and inflammatory markers in middle-aged men: the Twins Heart Study.

Objective: To examine the extent to which a common genetic pathway is also involved in the relationship between depressive symptoms, in the absence of major depressive disorder (MDD), and inflammation. Recent data suggested that MDD and inflammation share common genes. Methods: We recruited 188 male twins from the Vietnam Era Twin Registry who were free of symptomatic coronary artery disease and MDD, with mean ± standard deviation (SD) age of 55 ± 2.75 years, including 54 monozygotic and 40 dizygotic twin pairs. These pairs were assessed for two inflammatory markers, interleukin (IL)-6 and C-reactive protein (CRP). Current depressive symptoms were measured with the Beck Depression Inventory-II. Generalized estimating equations were used to examine the phenotypic association between depression and inflammatory markers. Biometrical genetic modeling was performed to estimate the genetic and environmental contributions to this association. Results: An association was observed between severity of current depressive symptoms and increased levels of inflammatory markers (p < .001 for IL-6 and p = .005 for CRP). After adjustment for other factors, the association was slightly attenuated but remained statistically significant for IL-6 (p = .002). The heritability of IL-6, CRP, and depressive symptoms were estimated as 0.37, 0.65, and 0.48, respectively. Genetic modeling found a significant genetic correlation between IL-6 and depressive symptoms (rG = 0.22, p = .046), indicating that about 66% of the covariance between them can be explained by shared genetic influences. Conclusions: Current depressive symptoms are significantly correlated with inflammatory markers. This covariation is due, in large part, to genes that are common to depressive symptoms and inflammation. CAD = coronary artery disease; MDD = major depressive disorder; IL-6 = interleukin-6; CRP = C-reactive protein; THS = Twins Heart Study; VET = Vietnam Era Twin; MZ = monozygotic; DZ = dizygotic; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; WHR = waist-hip ratio; BDI-II = Beck Depression Inventory-II; GEE = generalized estimating equation; AIC = Akaikes information criterion; CRH = corticotrophin-releasing hormone; HPA = hypothalamic-pituitary-adrenal; SD = standard deviation; Ln = logarithm transformation; CI = Confidence Interval; −2LL = −2×Log (Likelihood).

Genetic influences on heart rate variability at rest and during stress.

We tested whether the heritability of heart rate variability (HRV) under stress is different from rest and its dependency on ethnicity or gender. HRV indexed by root mean square of successive differences (RMSSD) and high-frequency (HF) power was measured at rest and during 3 stressors in 427 European and 308 African American twins. No ethnic or gender differences were found for any measures. There was a nonsignificant increase in heritability of RMSSD (from 0.48 to 0.58) and HF (from 0.50 to 0.58) under stress. Up to 81% and 60% of the heritabilities of RMSSD and HF under stress could be attributed to genes influencing rest levels. The heritabilities due to genes expressed under stress were 0.11 for RMSSD and 0.23 for HF. The findings suggest that, independent of ethnicity and gender, HRV regulation at rest and under stress is largely influenced by the same genes with a small but significant contribution of stress-specific genetic effects.

Adverse Childhood Experiences Are Associated With Detrimental Hemodynamics and Elevated Circulating Endothelin-1 in Adolescents and Young Adults

Growing evidence suggests that adverse childhood experiences (ACEs) increase the risks for coronary heart disease and hypertension in mid and late adulthood. We previously reported that early life stress induces a hyperreactive endothelin-dependent cardiovascular phenotype in a rat model. In the present study, we evaluated whether exposure to ACEs is associated with greater peripheral resistance, arterial stiffness, blood pressure, or elevated circulating endothelin-1 levels in humans. In 221 healthy adolescents and young adults (mean age, 21 years; range, 13–29 years), we found a graded association of ACE exposure with plasma endothelin-1 levels, of which on average 18% and 24% were higher in participants with 1 ACE and ≥2 ACEs, respectively, compared with those with no ACEs (P=0.001). Participants with moderate/severe exposure to ACEs (≥2 ACEs) had significantly higher total peripheral resistance index (+12%), diastolic blood pressure (+5%), and pulse wave velocity (+9%) compared with those who were not exposed. These associations were independent of age, race, sex, body mass index, and childhood socioeconomic status. Our results indicate that early life stress promotes cardiovascular disease risk, specifically detrimental vascular and cardiac function, detectable in young adulthood.

A longitudinal study of blood pressure variability in African-American and European American youth.

Objectives High blood pressure variability is increasingly used as a predictor of target-organ damage and cardiovascular events. However, little is known about blood pressure variability changes with age and its possible sociodemographic, anthropometric, and genetic moderators. Methods Twenty-four-hour ambulatory blood pressure was measured up to 12 times over a 15-year period in 344 European Americans and 297 African–Americans with an average age of 14 years at the initial visit. Blood pressure variability was indexed by the weighted 24-h standard deviation of ambulatory blood pressure recordings. Results Both systolic and diastolic blood pressure variability increased with age and ambulatory blood pressure mean values. Men had higher levels of blood pressure variability (P < 0.001) and showed steeper linear increase rates with age than women. African–Americans showed higher values of blood pressure variability (P < 0.05) than European Americans. Body mass index and waist circumference were also associated with higher blood pressure variability levels (P < 0.001). Individuals with higher fathers education level showed lower blood pressure variability. In the full model which included all the above factors, ethnic difference in systolic blood pressure variability was no longer significant. Conclusion The results of the present study suggest that men and African–Americans have higher blood pressure variability than women and European Americans. Apart from these ethnicity and sex effects, blood pressure variability increases with increases in age (especially in men), ambulatory blood pressure mean values and adiposity as well as decreased socioeconomic status.