Nocturnal blood pressure dipping, blood pressure variability, and cognitive function in early and middle-aged adults.

Higher nighttime blood pressure (BP), less BP dipping, and higher BP variability have been linked with worse cognitive function in the elderly. The goal of this study is to explore whether this relationship already exists in early and middle adulthood. We further examined whether ethnic differences between African Americans and European Americans in BP parameters can explain ethnic differences in cognitive function. 24-h ambulatory BP monitoring and cognitive function were obtained from 390 participants (average age: 37.2 years with a range of 25-50; 54.9% African Americans; 63.6% females). We observed that higher nighttime BP, decreased dipping, and higher variability were significantly associated with lower scores on the Picture Sequence Memory Test. Significant negative associations between variability and overall composite scores were also observed. No significant associations between average 24-h or daytime BP and cognitive function were observed. Ethnic differences in nighttime diastolic pressures and dipping can explain 6.81% to 10.8% of the ethnicity difference in the score of the Picture Sequence Memory Test (ps < .05). This study suggests that the associations of nighttime BP, dipping, and variability with cognitive function already exist in young and middle-aged adults. Ethnic differences in nighttime BP and dipping can at least partially explain ethnic differences in cognitive function. The stronger association of these parameters with cognitive function than daytime or average BP in this age range raises the importance of using ambulatory BP monitoring for more precise detection of abnormal BP patterns in young adulthood.

Racial disparities in the relationship of regional socioeconomic status and colorectal cancer survival in the five regions of Georgia.

INTRODUCTION: The study's purpose was to examine 5-year colorectal cancer (CRC) survival rates between White and Black patients. We also determined whether regional socioeconomic status (SES) is associated with CRC survival between White and Black patients in the Clayton, West Central, East Central, Southeast, and Northeast Georgia public health districts. METHODS: We performed a retrospective cohort analysis using data from the 1975 to 2016 Surveillance, Epidemiology, and End Results program. The 2015 United States Department of Agriculture Economic Research Services county typology codes were used to identify region-level SES with persistent poverty, low employment, and low education. Kaplan-Meier method and Cox proportional hazard regression were performed. RESULTS: Among 10,876 CRC patients (31.1% Black patients), 5-year CRC survival rates were lower among Black patients compared to White patients (65.4% vs. 69.9%; p < 0.001). In multivariable analysis, White patients living in regions with persistent poverty had a 1.1-fold increased risk of CRC death (HR, 1.12; 95% CI, 1.00-1.25) compared to those living in non-persistent poverty regions. Among Black patients, those living in regions with low education were at a 1.2-fold increased risk of CRC death (HR, 1.19; 95% CI, 1.01-1.40) compared to those living in non-low education regions. DISCUSSION AND CONCLUSIONS: Black patients demonstrated lower CRC survival rates in Georgia compared to their White counterparts. White patients living in regions with persistent poverty, and Black patients living in regions with low education had an increased risk of CRC death. Our findings provide important evidence to all relevant stakeholders in allocating health resources aimed at CRC early detection and prevention and timely referral for CRC treatment by considering the patient's regional SES in Georgia.

Blunted rest-activity circadian rhythm increases the risk of all-cause, cardiovascular disease and cancer mortality in US adults.

To examine whether rest-activity circadian rhythm parameters can predict all-cause, cardiovascular disease and cancer mortality in a general adult population of the US. We further compared the mortality predictive performance of these parameters with that of traditional risk factors. This study included 7,252 adults from US National Health and Nutrition Examination Surveys (NHANES) 2011-2014, who had wrist accelerometer data obtained at baseline and follow-up status linked to the National Death Index records (2011-2019). During a median of 81 months (interquartile range, 69-94 months) of follow-up, 674 (9.3%) deaths occurred. There were inverse associations between relative amplitude (RA) and all-cause mortality, cardiovascular disease and cancer mortality with increased quartiles RA associated with lower mortality risk (all P < 0.05). The Hazard Ratios ranged from 0.61 to 0.79. Furthermore, RA outperformed all the tested traditional predictors of all-cause mortality with the exception of age. This study suggests that participants with blunted rest-activity circadian rhythms had a higher risk of all-cause, cardiovascular disease and cancer mortality. Future studies will be needed to test whether interventions that regulate rest-activity circadian activity rhythms will improve health outcomes.

Diurnal Cortisol Slope and Nighttime Blood Pressure: A Study in European Americans and African Americans.

OBJECTIVES: African Americans (AAs) have higher nighttime blood pressure (BP) than European Americans (EAs). Stress has been suggested to play a role in this difference, but the mechanism is not well-understood. Flatter diurnal cortisol slope (DCS) is a well-known biological marker of stress. The objectives of this study were to: 1) examine ethnic differences in DCS; 2) evaluate the association between DCS and nighttime BP; and 3) determine the extent to which ethnic differences in nighttime BP can be explained by ethnic differences in DCS. METHODS: A total of 510 participants (age range: 14-35 years; 49.6% AAs, 54.5% females) provided four salivary cortisol samples at bedtime, wakeup, 30-minutes post-wakeup, and 60-minutes post-wakeup. Additionally, participants wore an ambulatory BP monitor for 24 hours. DCS was calculated as the average of the three morning samples minus the bedtime measurement. RESULTS: After adjustment for age, sex, BMI, and smoking, AAs had blunted DCS (P=.018) and higher nighttime systolic BP (SBP) and diastolic BP (DBP) (Ps<.001) compared with EAs. The DCS was inversely related to nighttime SBP and this relationship did not depend on ethnicity. The ethnic difference of nighttime SBP was significantly attenuated upon addition of DCS to the model. Mediation test showed that 9.5% of ethnic difference in nighttime SBP could be explained by DCS (P=.039). CONCLUSION: This study confirms ethnic differences in DCS and nighttime BP and further demonstrates that the ethnic differences in DCS can, at least partially, explain the ethnic differences found in nighttime BP.

High-Mobility Group Box-1 Is Associated With Obesity, Inflammation, and Subclinical Cardiovascular Risk Among Young Adults: A Longitudinal Cohort Study.

OBJECTIVE: We aimed to characterize circulating HMGB1 (high-mobility group box-1) levels, one of the better-characterized damage-associated molecular patterns, with respect to age, sex, and race in the general population, and investigate the longitudinal associations of HMGB1 with inflammatory markers, obesity, and preclinical markers of cardiovascular disease. Approach and Results: The analyses included 489 participants (50% Blacks, aged 24.6±3.3 years at the first visit) with up to 4 follow-up visits (1149 samples) over a maximum of 8.5 years. Systolic blood pressure, diastolic blood pressure, carotid-femoral pulse wave velocity, and carotid intima-media thickness together with plasma HMGB1, hs-CRP (high-sensitivity C-reactive protein), IFN-γ (interferon-γ), IL-6 (interleukin-6), IL-10 (interleukin-10), and TNF-α (tumor necrosis factor-α) were measured at each visit. At baseline, plasma HMGB1 concentrations were higher in Blacks compared with Whites (3.86 versus 3.20 ng/mL, P<0.001), and in females compared with males (3.75 versus 3.30 ng/mL, P=0.005). HMGB1 concentrations increased with age (P=0.007), and higher levels of obesity measures (P<0.001). Without adjustment for age, sex, race, and body mass index, HMGB1 concentrations were positively associated with hs-CRP, IL-6, TNF-α, systolic blood pressure, diastolic blood pressure, and carotid-femoral pulse wave velocity (P<0.05) but not IL-10, IFN-γ or carotid intima-media thickness. After covariate adjustments, the associations of HMGB1 with hs-CRP, and carotid-femoral pulse wave velocity remained statistically significant (P<0.05). CONCLUSIONS: This study demonstrates the age, sex, and race differences in circulating HMGB1. The increasing circulating concentrations of HMGB1 with age suggest a potential role of HMGB1 in the pathogenesis of chronic low-grade inflammation, obesity, and subclinical cardiovascular disease risk.

Cigarette smoking related DNA methylation in peripheral leukocytes and cardiovascular risk in young adults.

There is strong evidence linking changes in DNA methylation with cigarette smoking, and smoking has long been associated with cardiovascular disease; however not many studies have investigated the effects of smoking related DNA methylation changes on cardiovascular risk, especially in young adults. We explored this relationship in 480 African American and European American men and women aged 27.3 ±â€¯3.5. Out of the DNA methylation data obtained from Illumina 450 k in peripheral leukocytes, 62 CpG sites that have been associated with smoking in multiple studies were selected. Of these, 48 were significantly related to smoking within our population. These CpG sites were then used to predict 2 subclinical markers of cardiovascular health: carotid intima media thickness and left ventricular mass (LVM). There was a significant association (FDR < 0.05) between LVM and 13 of these CpG sites. We constructed a DNA methylation score using these CpG sites and found a significant association between this score and LVM (p < 0.01). Mediation test showed that 36.5% of the effect of smoking on LVM could be explained by this methylation score. Our data suggests that, in young adult populations, cigarette smoking related DNA methylation changes are already associated with changes in subclinical markers of cardiovascular health.

Ethnic Differences in Nighttime Melatonin and Nighttime Blood Pressure: A Study in European Americans and African Americans.

BACKGROUND: Ethnic differences in nighttime blood pressure (BP) have long been documented with African Americans (AAs) having higher BP than European Americans (EAs). At present, lower nighttime melatonin, a key regulator of circadian rhythms, has been associated with higher nighttime BP levels in EAs. This study sought to test the hypothesis that AAs have lower nighttime melatonin secretion compared with EAs. We also determined if this ethnic difference in melatonin could partially explain the ethnic difference in nighttime BP. METHODS: A total of 150 young adults (71 AA; 46% females; mean age: 27.7 years) enrolled in the Georgia Stress and Heart study provided an overnight urine sample for the measurement of 6-sulfatoxymelatonin, a major metabolite of melatonin. Urine melatonin excretion (UME) was calculated as the ratio between 6-sulfatoxymelatonin concentration and creatinine concentration. Twenty-four-hour ambulatory BP was assessed and nighttime systolic BP (SBP) was used as a major index of BP regulation. RESULTS: After adjustment of age, sex, body mass index, and smoking, AAs had significantly lower UME (P = 0.002) and higher nighttime SBP than EAs (P = 0.036). Lower UME was significantly associated with higher nighttime SBP and this relationship did not depend on ethnicity. The ethnicity difference in nighttime SBP was significantly attenuated after adding UME into the model (P = 0.163). CONCLUSION: This study is the first to document the ethnic difference in nighttime melatonin excretion, demonstrating that AAs have lower melatonin secretion compared with EAs. Furthermore, the ethnic difference in nighttime melatonin can partially account for the established ethnic difference in nighttime SBP.

Longitudinal association of inflammation with depressive symptoms: A 7-year cross-lagged twin difference study.

BACKGROUND: The direction of the association between inflammation and depressive symptoms remains inconsistent. The objective of this study was to evaluate the temporal relationship between inflammation and depressive symptoms, and to assess the role of genetic factors on this association. METHODS: In this longitudinal cross-lagged twin difference study, we examined 166 (83 pairs) middle-aged male twins recruited from the Vietnam Era Twin Registry, who were assessed at baseline and after 7 years of follow-up. We assayed plasma levels of two inflammatory biomarkers, interleukin-6 (IL-6) and high sensitivity C-reactive protein (CRP) and measured depressive symptoms using the Beck Depression Inventory-II (BDI). To evaluate the direction of the association, we constructed multivariable mixed-effects regression models and calculated standardized beta-coefficients to compare the strength of the within-pair association for both pathways. We then conducted a stratified analysis by zygosity and assessed the associations in monozygotic and dizygotic twin pairs separately. RESULTS: The 166 twins were 95% white and had a mean (SD) age of 54 (3) years at baseline. The cross-lagged analysis showed significant and positive associations from visit 1 IL-6 to visit 2 BDI across all models (beta-coefficients ranging from 0.18 to 0.22). However, the opposite pathway (visit 1 BDI to visit 2 IL-6) was not significant after adjusting for confounding factors. In contrast, visit 1 BDI was significantly associated with visit 2 CRP in all models (beta-coefficients ranging from 0.23 to 0.33), while the opposite pathway (visit 1 CRP to visit 2 BDI) showed no significant association. When stratifying by zygosity, significant associations from IL-6 to depression were only seen in monozygotic twins, but associations from depression to CRP were more robust in dizygotic twins, which implies that genetic factors may play a role in this association. CONCLUSIONS: The association between inflammation and depression may be bidirectional. Elevated IL-6 levels are more likely to be a risk factor of depression rather than a consequence, while the opposite may be true for elevated CRP. The biological underpinnings of these bidirectional pathways need further evaluation.

Determinants of pulse wave velocity trajectories from youth to young adulthood: the Georgia Stress and Heart Study.

OBJECTIVE: Increased arterial stiffness measured by pulse wave velocity (PWV) has been shown to be an important parameter of cardiovascular risk. Longitudinal development of PWV from youth to early adulthood and its possible sociodemographic, anthropometric, hemodynamic and behavioral moderators will be illustrated. METHODS: Individual growth curves of carotid-distal PWV across age were created for 559 African American and European American men and women with a maximum of five assessments over an average of 7-year follow-up (mean age at participants' first assessment, 22.3 ±â€Š3.4). RESULTS: African Americans and men had significantly higher PWV than did European Americans and women (Ps < 0.01), respectively. A three-way interaction (P < 0.001) between age, sex and ethnicity was observed with African American men displaying a larger rate of increase in PWV with age than the other three ethnic and sex groups. The ethnicity and sex effects on PWV persisted when controlling for other moderators. Waist circumference was the strongest anthropometric predictor but its effect on PWV was only significant in women. Mean arterial pressure was the strongest hemodynamic predictor, marital status of parents was the strongest socioeconomic predictor and marijuana use was the strongest behavioral predictor of PWV. The best-fitting full model explained in total 59.4% of the between-subject variance in PWV with ethnicity, sex and age explaining 25.6%. CONCLUSION: We observed significant ethnic and sex differences in longitudinal trajectories of PWV in youth and young adults. In addition, individual differences in PWV growth can largely be explained by mean arterial pressure, waist, marital status of parents and marijuana use.

Growth of Carotid Intima-Media Thickness in Black and White Young Adults.

BACKGROUND: There are few longitudinal studies that have comprehensively examined the intima-media thickness (IMT) growth pattern and its determinants among racial population groups. METHODS AND RESULTS: Mean and maximum IMT were measured by B-mode ultrasonography up to 3 times in 253 white and 268 black participants, aged 13 to 36 years (mean age±standard deviation 24±3.2 years old). The development of IMT was assessed using individual growth curve modeling. A total of 521 participants with 1015 IMT measurements were eligible for this study. We found higher IMT in both left and right sides in blacks compared to whites (P<0.001) in young adulthood. Both whites and blacks showed a strong linear increase in mean IMT with age. Body mass index and father's education level were associated with mean IMT, and only body mass index was associated with maximum IMT (P<0.05). We did not observe an interaction between age and race/ethnicity on the growth of IMT, suggesting that blacks and whites developed IMT in similar patterns. Interestingly, we found a faster increase in mean left-side IMT than mean right-side IMT (χ2=11.5, P<0.001) in both black and white subjects as well as in males and females. CONCLUSIONS: Our findings provide compelling prospective evidence that blacks may have thicker IMT compared to whites as young adults. These racial differences could not be explained by traditional risk factors. This implies that differences in this precursor of atherosclerosis may explain racial disparity in cerebrovascular disease.

Differential methylation tests of regulatory regions.

Differential methylation of regulatory elements is critical in epigenetic researches and can be statistically tested. We developed a new statistical test, the generalized integrated functional test (GIFT), that tests for regional differences in methylation based on the methylation percent at each CpG site within a genomic region. The GIFT uses estimated subject-specific profiles with smoothing methods, specifically wavelet smoothing, and calculates an ANOVA-like test to compare the average profile of groups. In this way, possibly correlated CpG sites within the regulatory region are compared all together. Simulations and analyses of data obtained from patients with chronic lymphocytic leukemia indicate that GIFT has good statistical properties and is able to identify promising genomic regions. Further, GIFT is likely to work with multiple different types of experiments since different smoothing methods can be used to estimate the profiles of data without noise. Matlab code for GIFT and sample data are available at http://www.augusta.edu/mcg/biostatepi/people/software/gift.html.

Adverse childhood experiences and blood pressure trajectories from childhood to young adulthood: the Georgia stress and Heart study.

BACKGROUND: The purposes of this study were to assess the long-term effect of adverse childhood experiences (ACEs) on blood pressure (BP) trajectories from childhood to young adulthood and to examine whether this relation is explained by childhood socioeconomic status (SES) or risk behaviors that are associated with ACEs. METHODS AND RESULTS: Systolic and diastolic BPs were measured up to 16 times (13 times on average) over a 23-year period in 213 African Americans and 181 European Americans 5 to 38 years of age. Retrospective data on traumatic experiences before 18 years of age were collected, including abuse, neglect, and household dysfunction. Individual growth curve modeling within a multilevel framework was used to examine the relation between exposure to ACEs and BP development. No main effect of ACEs on average BP levels was found. However, a significant interaction of ACE score with age(3) was observed (systolic BP, P=0.033; diastolic BP, P=0.017). Subjects who experienced multiple traumatic events during childhood showed a faster rise in BP levels after 30 years of age than those without ACEs. As expected, a graded association of ACEs with childhood socioeconomic status and negative health behaviors was observed (P<0.001). The ACE-systolic BP relation was not explained by these factors, whereas the ACE-diastolic BP relation was partially mediated by illicit drug use. CONCLUSION: In this novel longitudinal study, we observed that participants who were exposed to multiple ACEs displayed a greater increase in BP levels in young adulthood compared with their counterparts without ACEs.

Familial aggregation and childhood blood pressure.

There is growing concern about elevated blood pressure (BP) in children. The evidence for familial aggregation of childhood BP is substantial. Twin studies have shown that a large part of the familial aggregation of childhood BP is due to genes. The first part of this review provides the latest progress in gene finding for childhood BP, focusing on the combined effects of multiple loci identified from the genome-wide association studies on adult BP. We further review the evidence on the contribution of the genetic components of other family risk factors to the familial aggregation of childhood BP including obesity, birth weight, sleep quality, sodium intake, parental smoking, and socioeconomic status. At the end, we emphasize the promise of using genomic-relatedness-matrix restricted maximum likelihood (GREML) analysis, a method that uses genome-wide data from unrelated individuals, in answering a number of unsolved questions in the familial aggregation of childhood BP.

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.

A method to detect differentially methylated loci with next-generation sequencing.

Epigenetic changes, especially DNA methylation at CpG loci have important implications in cancer and other complex diseases. With the development of next-generation sequencing (NGS), it is feasible to generate data to interrogate the difference in methylation status for genome-wide loci using case-control design. However, a proper and efficient statistical test is lacking. There are several challenges. First, unlike methylation experiments using microarrays, where there is one measure of methylation for one individual at a particular CpG site, here we have the counts of methylation allele and unmethylation allele for each individual. Second, due to the nature of sample preparation, the measured methylation reflects the methylation status of a mixture of cells involved in sample preparation. Therefore, the underlying distribution of the measured methylation level is unknown, and a robust test is more desirable than parametric approach. Third, currently NGS measures methylation at over 2 million CpG sites. Any statistical tests have to be computationally efficient in order to be applied to the NGS data. Taking these challenges into account, we propose a test for differential methylation based on clustered data analysis by modeling the methylation counts. We performed simulations to show that it is robust under several distributions for the measured methylation levels. It has good power and is computationally efficient. Finally, we apply the test to our NGS data on chronic lymphocytic leukemia. The results indicate that it is a promising and practical test.

A genetic risk variant for myocardial infarction on chromosome 6p24 is associated with impaired central hemodynamic indexes.

BACKGROUND: Genome-wide association studies (GWAS) have identified novel variants associated with myocardial infarction (MI) in Caucasians. We hypothesized that those variants whose mechanism of risk is currently unknown, confer risk via pathways mediating arterial wave reflections which is an increasingly recognized risk factor for cardiovascular disease. METHODS: Single-nucleotide polymorphisms (SNPs) at eight MI risk loci were genotyped and correlated with noninvasively determined pulse wave analysis (PWA)-derived central hemodynamic indexes (augmentation index (AIx); augmented pressure (AP); time to reflected wave (TrW) and central systolic blood pressure (SBP) and diastolic BP (DBP)) in two independent Caucasian populations including (i) those free of measured cardiovascular risk factors (n = 133) and (ii) a community-based population (n = 270). RESULTS: Of the eight SNPs examined in the healthy group, the variants at loci 6p24 (AIx and AP both P < 0.001, TrW P = 0.02) and 21q22 (AIx P = 0.002, TrW P = 0.037) were significantly associated with PWA indexes. In the replication group, only the 6p24 variant correlated with these phenotypes (AIx P = 0.005, AP P = 0.049, TrW P = 0.013). In the pooled population (n = 403), no new associations were identified but the association with 6p24 and AIx remained significant even after Bonferroni correction and adjustment for covariates including age, mean arterial pressure, height, gender, glucose, cholesterol, body mass index (BMI), and smoking (AIx (P = 0.03)). Each copy of the risk allele C increased the AIx by 3.5%. CONCLUSIONS: The GWAS discovered MI risk variant at 6p24 in the protein phosphatase 1 regulator gene (PHACTR1) is associated with adverse arterial wave reflection indexes and may mediate MI risk through this pathway.

Measurement of heritability of myocardial blood flow by positron emission tomography: the Twins Heart Study.

OBJECTIVE: To estimate the heritability of myocardial blood flow (MBF) and coronary flow reserve (CFR) measured with positron emission tomography (PET). DESIGN: Cross-sectional twin study. SETTING: General clinical research centre of a university hospital at Atlanta, USA. PATIENTS: A sample of 180 middle-aged (mean±SD 55±2.9 years) male twins, including 107 monozygotic and 73 dizygotic twins. MAIN OUTCOME MEASURES: All twins underwent imaging of MBF with PET (13)NH(3) at rest and after adenosine stress during a single imaging session. Structural equation modelling was used to estimate the heritability of MBF at rest and during adenosine stress, as well as of CFR. RESULTS: The basal MBF (mean±SD) was 0.69±0.20 ml/min/g, and the MBF during adenosine stress was 1.70±0.49 ml/min/g; the CFR was 2.62±0.99. There was substantial heritability for MBF both at rest (0.48, 95% CI 0.29 to 0.64) and during adenosine stress (0.51, 95% CI 0.29 to 0.68), as well as CFR (0.48, 95% CI 0.26 to 0.65). CONCLUSIONS: For the first time, a substantial genetic contribution to the interindividual variation in MBF and CFR measured with PET in middle-aged men has been demonstrated. The data suggest that a fruitful direction for future work would be the identification of genetic variants for early atherosclerotic stages assessed by PET imaging.

Heritability of renal function and inflammatory markers in adult male twins.

BACKGROUND: Loss of renal function is accompanied by a progressive increase in markers of inflammation; it is unknown whether they share common genetic pathways. STUDY DESIGN: We evaluated the shared heritability of estimated glomerular filtration rate (eGFR) and markers of inflammation and endothelial activation in 524 twin males from the Vietnam Era Twin Registry; 9 twins were excluded due to incomplete or incorrect data. Models were adjusted for age, race, body mass index, smoking, hypertension, diabetes mellitus, prior coronary artery disease and intercurrent medications. RESULTS: The mean eGFR was 89 ± 13 ml/min/1.73 m² (range 35-146); eGFR, intracellular adhesion molecule (ICAM) and TNF-α receptor (TNF-αR) were moderately heritable (all ∼50%), while IL-6 receptor (IL-6R) and P-selectin were highly heritable (68 and 76%, respectively). IL-6R and TNF-αR showed a significant inverse association with eGFR (p = 0.04 and p < 0.0001) while the association with ICAM and P-selectin was direct (p = 0.001 and p = 0.06). Bivariate structural equation models showed that the association between eGFR and biomarkers was due to unique environmental factors and there were no shared genetic pathways. CONCLUSION: We found no shared genetic pathways between renal function and inflammation. Thus, increased inflammation represents a response to declining renal function rather than being a mechanism contributing to renal deterioration.

Serotonin transporter gene, depressive symptoms, and interleukin-6.

BACKGROUND: We explored the relationship of genetic variants of the serotonin transporter gene SLC6A4, a key regulator of the serotonergic neurotransmission, with both depressive symptoms and plasma interleukin-6 (IL-6) levels. METHODS AND RESULTS: We genotyped 20 polymorphisms in 360 male twins (mean age, 54 years) from the Vietnam Era Twin Registry. Current depressive symptoms were measured with the Beck Depression Inventory II. IL-6 was assessed using a commercially available ELISA kit. Genotype associations were analyzed using generalized estimating equations. To study how SLC6A4 genetic vulnerability influences the relationship between depressive symptoms and IL-6, bivariate models were constructed using structural equation modeling. Of the 20 polymorphisms examined, the effective number of independent tests was 6, and the threshold of significance after Bonferroni correction was 0.008. There were 6 single-nucleotide polymorphisms significantly associated with Beck Depression Inventory (P< or =0.008), including rs8071667, rs2020936, rs25528, rs6354, rs11080122, and rs8076005, and 1 single-nucleotide polymorphism was borderline associated (rs12150214, P=0.017). Of these 7 single-nucleotide polymorphisms, 3 were also significantly associated with IL-6 (P<0.008), including rs25528, rs6354, and rs8076005, and the other 4 were borderline associated (P=0.009 to 0.025). The subjects with 1 copy of the minor allele of these 7 single-nucleotide polymorphisms had higher Beck Depression Inventory scores and IL-6 levels. Further bivariate modeling revealed that approximately 10% of the correlation between Beck Depression Inventory and IL-6 could be explained by the SLC6A4 gene. CONCLUSIONS: Genetic vulnerability involving the SLC6A4 gene is significantly associated with both increased depressive symptoms and elevated IL-6 plasma levels. Common pathophysiological processes may link depression and inflammation, and implicate the serotonin pathway in neural-immune interactions.

Major depression and coronary flow reserve detected by positron emission tomography.

BACKGROUND: Major depressive disorder (MDD) is associated with coronary heart disease (CHD), but the mechanisms are unclear. The presence of MDD may increase CHD risk by affecting microvascular circulation. It is also plausible that genetic factors influencing MDD may overlap with those for CHD. We sought to examine the relationship between MDD and coronary flow reserve (CFR), the ratio of maximum flow during stress to flow at rest measured in milliliters per minute per gram of tissue. METHODS: We examined 289 male middle-aged twins, including 106 twins (53 twin pairs) discordant for a lifetime history of MDD and 183 control twins (unrelated to any twins in the experimental group) without MDD. To calculate CFR, we used positron emission tomography with nitrogen 13 ((13)N) ammonia to evaluate myocardial blood flow at rest and after adenosine stress. A standard perfusion defect score was also used to assess myocardial ischemia. RESULTS: There was no difference in myocardial ischemia between twins with and without MDD. Among the dizygotic twin pairs discordant for MDD, the CFR was 14% lower in the twins with MDD than in their brothers without MDD (2.36 vs 2.74) (P = .03). This association was not present in the monozygotic discordant pairs who were genetically matched (2.86 vs 2.64) (P = .19). The zygosity-MDD interaction after adjustment was significant (P = .006). The CFR in the dizygotic twins with MDD was also lower than in the control twins. CONCLUSIONS: Our results provide evidence for a shared genetic pathway between MDD and microvascular dysfunction. Common pathophysiologic processes may link MDD and early atherosclerosis.