Genome-Wide Genetic Analysis of Dropout in a Controlled Exercise Intervention in Sedentary Adults With Overweight or Obesity and Cardiometabolic Disease.

BACKGROUND: Despite the benefits of exercise, many individuals are unable or unwilling to adopt an exercise intervention. PURPOSE: The purpose of this analysis was to identify putative genetic variants associated with dropout from exercise training interventions among individuals in the STRRIDE trials. METHODS: We used a genome-wide association study approach to identify genetic variants in 603 participants initiating a supervised exercise intervention. Exercise intervention dropout occurred when a subject withdrew from further participation in the study or was otherwise lost to follow-up. RESULTS: Exercise intervention dropout was associated with a cluster of single-nucleotide polymorphisms with the top candidate being rs722069 (T/C, risk allele = C) (unadjusted p = 2.2 × 10-7, odds ratio = 2.23) contained within a linkage disequilibrium block on chromosome 16. In Genotype-Tissue Expression, rs722069 is an expression quantitative trait locus of the EARS2, COG7, and DCTN5 genes in skeletal muscle tissue. In subsets of the STRRIDE genetic cohort with available muscle gene expression (n = 37) and metabolic data (n = 82), at baseline the C allele was associated with lesser muscle expression of EARS2 (p < .002) and COG7 (p = .074) as well as lesser muscle concentrations of C2- and C3-acylcarnitines (p = .026). CONCLUSIONS: Our observations imply that exercise intervention dropout is genetically moderated through alterations in gene expression and metabolic pathways in skeletal muscle. Individual genetic traits may allow the development of a biomarker-based approach for identifying individuals who may benefit from more intensive counseling and other interventions to optimize exercise intervention adoption. CLINICAL TRIAL INFORMATION: STRRIDE I = NCT00200993; STRRIDE AT/RT = NCT00275145; STRRIDE-PD = NCT00962962.

Regular participation in exercise can provide a myriad of health benefits. Although individuals recognize these benefits, many are unable or unwilling to adopt an exercise intervention once initiated. The purpose of this analysis was to identify genetic variants associated with dropout from an exercise training intervention. We found exercise intervention dropout to be genetically moderated through changes in gene expression and metabolic pathways in muscle. Thus, individual genetic traits may allow for the development of a biomarker-based targeted approach for identifying individuals who may benefit from more intensive counseling and interventions to optimize the adoption of an exercise intervention program.

Relationship Between Psychosocial Stress and Blood Pressure: The National Heart, Lung, and Blood Institute Family Heart Study.

Introduction: Various domains of psychosocial stress have been significantly related to blood pressure. However, ambiguity is present in how these relationships are defined in the literature. Objective: To add to the existing literature and examine the relationship between psychosocial stress (financial strain and job strain) and other cofactors on blood pressure. Methods: This secondary analysis is designed to analyze the relationship between levels of job and financial stress and blood pressure outcomes among participants in the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study 2004-2008. The descriptive, cross-sectional design uses data from a subset of study participants, 350 White and 195 Black (n = 545), 338 female (62%), and all aged 18-56 years. Psychosocial stress was measured using the Singh Stress Scale. Resting systolic (SBP) and diastolic (DBP) blood pressure values obtained on a stress reactivity protocol day in the primary study, as well as calculated mean arterial pressure (MAP) were used for this analysis. Multivariate linear regression analyses were used to explore the relationship between psychosocial stress and blood pressure. Results: In this young cohort, self-report of either financial strain or job strain was associated with lower blood pressure levels than those of participants who reported neither stressor. Differential sex and race effects appear to contribute to these results. Blood pressure levels were not significantly associated with self-report of both stressors. Conclusion: Understanding the effects of various forms of stress on blood pressure may inform more precise HTN risk-factor screening and interventions to improve BP management.

Sex and race differences of cerebrospinal fluid metabolites in healthy individuals.

INTRODUCTION: Analyses of cerebrospinal fluid (CSF) metabolites in large, healthy samples have been limited and potential demographic moderators of brain metabolism are largely unknown. OBJECTIVE: Our objective in this study was to examine sex and race differences in 33 CSF metabolites within a sample of 129 healthy individuals (37 African American women, 29 white women, 38 African American men, and 25 white men). METHODS: CSF metabolites were measured with a targeted electrochemistry-based metabolomics platform. Sex and race differences were quantified with both univariate and multivariate analyses. Type I error was controlled for by using a Bonferroni adjustment (0.05/33 = .0015). RESULTS: Multivariate Canonical Variate Analysis (CVA) of the 33 metabolites showed correct classification of sex at an average rate of 80.6% and correct classification of race at an average rate of 88.4%. Univariate analyses revealed that men had significantly higher concentrations of cysteine (p < 0.0001), uric acid (p < 0.0001), and N-acetylserotonin (p = 0.049), while women had significantly higher concentrations of 5-hydroxyindoleacetic acid (5-HIAA) (p = 0.001). African American participants had significantly higher concentrations of 3-hydroxykynurenine (p = 0.018), while white participants had significantly higher concentrations of kynurenine (p < 0.0001), indoleacetic acid (p < 0.0001), xanthine (p = 0.001), alpha-tocopherol (p = 0.007), cysteine (p = 0.029), melatonin (p = 0.036), and 7-methylxanthine (p = 0.037). After the Bonferroni adjustment, the effects for cysteine, uric acid, and 5-HIAA were still significant from the analysis of sex differences and kynurenine and indoleacetic acid were still significant from the analysis of race differences. CONCLUSION: Several of the metabolites assayed in this study have been associated with mental health disorders and neurological diseases. Our data provide some novel information regarding normal variations by sex and race in CSF metabolite levels within the tryptophan, tyrosine and purine pathways, which may help to enhance our understanding of mechanisms underlying sex and race differences and potentially prove useful in the future treatment of disease.

Evaluating the precision of EBF1 SNP x stress interaction association: sex, race, and age differences in a big harmonized data set of 28,026 participants.

In prior work, we identified a novel gene-by-stress association of EBF1's common variation (SNP rs4704963) with obesity (i.e., hip, waist) in Whites, which was further strengthened through multiple replications using our synthetic stress measure. We now extend this prior work in a precision medicine framework to find the risk group using harmonized data from 28,026 participants by evaluating the following: (a) EBF1 SNPxSTRESS interaction in Blacks; (b) 3-way interaction of EBF1 SNPxSTRESS with sex, race, and age; and (c) a race and sex-specific path linking EBF1 and stress to obesity to fasting glucose to the development of cardiometabolic disease risk. Our findings provided additional confirmation that genetic variation in EBF1 may contribute to stress-induced human obesity, including in Blacks (P = 0.022) that mainly resulted from race-specific stress due to "racism/discrimination" (P = 0.036) and "not meeting basic needs" (P = 0.053). The EBF1 gene-by-stress interaction differed significantly (P = 1.01e-03) depending on the sex of participants in Whites. Race and age also showed tentative associations (Ps = 0.103, 0.093, respectively) with this interaction. There was a significant and substantially larger path linking EBF1 and stress to obesity to fasting glucose to type 2 diabetes for the EBF1 minor allele group (coefficient = 0.28, P = 0.009, 95% CI = 0.07-0.49) compared with the same path for the EBF1 major allele homozygotes in White females and also a similar pattern of the path in Black females. Underscoring the race-specific key life-stress indicators (e.g., racism/discrimination) and also the utility of our synthetic stress, we identified the potential risk group of EBF1 and stress-induced human obesity and cardiometabolic disease.

Correction to: Low Life Course Socioeconomic Status (SES) Is Associated with Negative NEO PI-R Personality Patterns.

After the publication of the original article, the Editor was notified by Duke University that they have determined the authorship to be incomplete. Consequently, Dr Edward Suarez has been added as a co-author to represent his contribution to the conception and design of the work and acquisition of the data.

Length Polymorphisms in the Angiotensin I-Converting Enzyme Gene and the Serotonin-Transporter-Linked Polymorphic Region Constitute a Risk Haplotype for Depression in Patients with Coronary Artery Disease.

Genetic variations affecting the course of depressive symptoms in patients with coronary artery disease (CAD) have not yet been well studied. Therefore, we set out to investigate whether distinct haplotypes of the two insertion/deletion polymorphisms in the serotonin-transporter-linked polymorphic region (5-HTTLPR) and the angiotensin I-converting enzyme (ACE) gene located on chromosome 17 can be identified as risk factors for trajectories of depression. Clinical and genotyping data were derived from 507 depressed CAD patients participating in the randomized, controlled, multicenter Stepwise Psychotherapy Intervention for Reducing Risk in Coronary Artery Disease (SPIRR-CAD) trial, of whom the majority had an acute cardiac event before study inclusion. Depression scores on the Hospital Anxiety and Depression Scale (HADS) were assessed at baseline and at five follow-up time points up to 2 years after study entrance. At baseline, depression scores did not significantly differ between patients carrying the risk haplotype ACE D/D, 5-HTTLPR I/I (n = 46) and the non-risk haplotypes (n = 461, 10.9 ± 2.7 versus 10.4 ± 2.5, p = 0.254). HADS-depression scores declined from study inclusion during the first year irrespective of the genotype. At each follow-up time point, HADS-depression scores were significantly higher in ACE D/D, 5-HTTLPR I/I carriers than in their counterparts. Two years after study inclusion, the mean HADS depression score remained 1.8 points higher in patients with the risk haplotype as compared to subjects not carrying this haplotype (9.9 ± 4.2 versus 8.1 ± 4.0, p = 0.009). In summary, the presence of the ACE D/D, 5-HTTLPR I/I haplotype may be a vulnerability factor for comorbid depressive symptoms in CAD patients.

Systolic Blood Pressure and Socioeconomic Status in a large multi-study population.

The present study used harmonized data from eight studies (N = 28,891) to examine the association between socioeconomic status (SES) and resting systolic blood pressure (SBP). The study replicates and extends our prior work on this topic by examining potential moderation of this association by race and gender. We also examined the extent to which body mass index (BMI), waist circumference (WC), and smoking might explain the association between SES and SBP. Data were available from six race/gender groups: 9200 Black women; 2337 Black men; 7248 White women; 6519 White men; 2950 Hispanic women; and 637 Hispanic men. Multivariable regression models showed that greater annual household income was associated with lower SBP in all groups except Hispanic men. The magnitude and form of this negative association differed across groups, with White women showing the strongest linear negative association. Among Black men and Hispanic women, the association was curvilinear: relatively flat among lower income levels, but then negative among higher income ranges. Education also was independently, negatively related to SBP, though evidence was weaker for race and gender differences in the strength of the association. Higher BMI and WC were associated with higher SBP, and current smoking with lower SBP. Inclusion of these risk factors resulted in only a modest change in the magnitude of the SBP and SES relation, accounting on average about 0.4 mmHg of the effect of income and 0.2 mmHg of the effect of education-effects unlikely to be clinically significant. Further understanding of mechanisms underlying the association between SBP and SES may improve risk stratification in clinical settings and potentially inform interventions aimed at reductions in social disparities in health.

Epigenome-Wide Association Study for All-Cause Mortality in a Cardiovascular Cohort Identifies Differential Methylation in Castor Zinc Finger 1 (CASZ1).

Background DNA methylation is implicated in many chronic diseases and may contribute to mortality. Therefore, we conducted an epigenome-wide association study (EWAS) for all-cause mortality with whole-transcriptome data in a cardiovascular cohort (CATHGEN [Catheterization Genetics]). Methods and Results Cases were participants with mortality≥7 days postcatheterization whereas controls were alive with≥2 years of follow-up. The Illumina Human Methylation 450K and EPIC arrays (Illumina, San Diego, CA) were used for the discovery and validation sets, respectively. A linear model approach with empirical Bayes estimators adjusted for confounders was used to assess difference in methylation (Δß). In the discovery set (55 cases, 49 controls), 25 629 (6.5%) probes were differently methylated (P<0.05). In the validation set (108 cases, 108 controls), 3 probes were differentially methylated with a false discovery rate-adjusted P<0.10: cg08215811 (SLC4A9; log2 fold change=-0.14); cg17845532 (MATK; fold change=-0.26); and cg17944110 (castor zinc finger 1 [CASZ1]; FC=0.26; P<0.0001; false discovery rate-adjusted P=0.046-0.080). Meta-analysis identified 6 probes (false discovery rate-adjusted P<0.05): the 3 above, cg20428720 (intergenic), cg17647904 (NCOR2), and cg23198793 (CAPN3). Messenger RNA expression of 2 MATK isoforms was lower in cases (fold change=-0.24 [P=0.007] and fold change=-0.61 [P=0.009]). The CASZ1, NCOR2, and CAPN3 transcripts did not show differential expression (P>0.05); the SLC4A9 transcript did not pass quality control. The cg17944110 probe is located within a potential regulatory element; expression of predicted targets (using GeneHancer) of the regulatory element, UBIAD1 (P=0.01) and CLSTN1 (P=0.03), were lower in cases. Conclusions We identified 6 novel methylation sites associated with all-cause mortality. Methylation in CASZ1 may serve as a regulatory element associated with mortality in cardiovascular patients. Larger studies are necessary to confirm these observations.

Relationship Between Optimism and Outcomes in Patients With Chronic Angina Pectoris.

Greater optimism regarding recovery from chronic illness is associated with improved quality of life and clinical outcomes. We performed a post-hoc analysis on the association between optimism and outcomes in Ranolazine in Patients with Incomplete Revascularization after Percutaneous Coronary Intervention (RIVER-PCI), a randomized trial in patients with chronic angina pectoris who had incomplete revascularization following percutaneous coronary intervention. At baseline, patients answered how much they agreed with the phrase, "I am optimistic about my future and returning to a normal lifestyle." We evaluated the association between baseline optimism and time to ischemia-driven hospitalization or revascularization using a Cox model, and the association between baseline optimism and change in frequency of angina pectoris using a mixed measures model. Of 2,389 patients, 782 (33.2%) were very optimistic ("strongly agree"), 1,000 (42.4%) were optimistic ("agree"), 451 (19.1%) were neutral ("undecided"), and 123 (5.2%) were not optimistic ("disagree" or "strongly disagree"). Very optimistic patients had a lower prevalence of co-morbidities and less severe angina at baseline than less optimistic patients. The rate of ischemia-driven revascularization or hospitalization was higher in neutral and not optimistic patients compared with very optimistic patients; this finding persisted after adjustment for co-morbidities and baseline angina frequency (hazard ratio 1.42, 95% confidence interval 1.14 to 1.77 for neutral vs very optimistic; hazard ratio 1.38, 95% confidence interval 0.98 to 1.94 for not optimistic vs very optimistic). Neutral and not optimistic patients also had less improvement in angina than very optimistic patients. In conclusion, in patients with angina, those with more self-reported optimism had better health status outcomes. Whether structured interventions targeting optimism improve outcomes in these patients warrants further study.

The role of genetic and environmental influences on the association between childhood ADHD symptoms and BMI.

BACKGROUND/OBJECTIVES: Although childhood attention deficit hyperactivity disorder (ADHD) has been previously associated with concurrent and later obesity in adulthood, the etiology of this association remains unclear. The objective of this study is to determine the shared genetic effects of ADHD symptoms and BMI in a large sample of sibling pairs, consider how these shared effects may vary over time, and examine potential sex differences. SUBJECT/METHODS: Sibling pair data were obtained from the National Longitudinal Study of Adolescent to Adult Health (Add Health); childhood ADHD symptoms were reported retrospectively during young adulthood, while three prospective measurements of BMI were available from young adulthood to later adulthood. Cholesky decomposition models were fit to this data using Mx and maximum-likelihood estimation. The twin and sibling sample for these analyses included: 221 monozygotic (MZ) pairs (92 male-male, 139 female-female), 228 dizygotic (DZ) pairs (123 male-male, 105 female-female), 471 full-sibling (FS) pairs (289 male-male, 182 female-female), 106 male-female DZ twin pairs, and 234 male-female FS pairs. RESULTS: The magnitude of the association between childhood ADHD symptoms and BMI changed over time and by sex. The etiological relationship between childhood ADHD symptoms and the three prospective measurements of BMI differed for males and females, such that unique or non-shared environmental influences contributed to the relationship within males and genetic factors contributed to the relationship within females. Specifically, among females, genetic influences on childhood ADHD symptoms were partially shared with those effecting BMI and increased from adolescence to later adulthood (genetic correlation = 0.20 (95% CI: 0.07-0.36) in adolescence and 0.24 (95% CI: 0.10, 0.41) in adulthood). CONCLUSION: Genetic influences on ADHD symptoms in childhood are partially shared with those effecting obesity. However, future research is needed to determine why this association is limited to females.

The Effects of Tryptophan Enhancement and Depletion on Plasma Catecholamine Levels in Healthy Individuals.

OBJECTIVE: Central nervous system (CNS) serotonin (5-HT) exerts both excitatory and inhibitory effects on the sympathetic nervous system (SNS) in animals. In this study, we examine the effects of tryptophan enhancement and depletion on plasma catecholamine levels in humans. METHODS: The total sample consisted of 164 healthy men and women who were tested for 2 days. Seventy-nine participants were randomized to a tryptophan enhancement condition and 85 to a tryptophan depletion condition. Both protocols consisted of a "sham day," followed by an "active day." Blood samples for assessment of plasma norepinephrine and epinephrine levels were collected before and after tryptophan enhancement/depletion. Data were analyzed using general linear models. Separate analyses were conducted for each study arm and for each measure. RESULTS: In the depletion condition, both epinephrine (F(5,330) = 2.69, p = .021) and norepinephrine (F(5,335) = 2.79, p = .018) showed small increases on active versus "sham" depletion days. There were also significant day by time interactions for epinephrine (F(3,171) = 39.32, p < .0001) and norepinephrine (F(3,195) = 31.09, p < .0001) levels in the enhancement arm. Tryptophan infusion resulted in a marked increase in epinephrine (Premean = 23.92 (12.23) versus Postmean = 81.57 (62.36)) and decrease in norepinephrine (Premean = 257.2 (106.11) versus Postmean = 177.04 (87.15)), whereas levels of both catecholamines were stable on the "sham day." CONCLUSIONS: CNS 5-HT exerts both inhibitory and excitatory effects on SNS activity in humans, potentially due to stimulation of CNS 5-HT receptors that have shown to have inhibitory (5-HT1A) and excitatory (5-HT1A and/or 5-HT2) SNS effects in animal models.

Lack of Association of a Functional Polymorphism in the Serotonin Receptor Gene With Body Mass Index and Depressive Symptoms in a Large Meta-Analysis of Population Based Studies.

The serotonin receptor 5-HTR2C is thought to be involved in the function of multiple brain structures. Consequently, the HTR2C gene has been studied extensively with respect to its association with a variety of phenotypes. One coding variant in the HTR2C gene, Cys23Ser (rs6318), has been associated with depressive symptoms. and adiposity; however, these findings have been inconsistent. The reasons for this mixed picture may be due to low statistical power or due to other factors such as failure to account for possible interacting environmental factors, such as psychosocial stress. Further, the literature around this polymorphism is marked by limited inclusion of persons of African ancestry. The present study sought to overcome these limitations and definitively determine the relationship of this polymorphism with depressive and obesity phenotypes in a large sample meta-analysis. Thus, we harmonized individual level data from 10 studies including the Women's Health Initiative, CARDIA, ARIC, Framingham Offspring, and the Jackson Heart Study, resulting in a sample of 27,161 individuals (10,457 Black women, 2,819 Black men, 7,419 White women, and 6,466 White men). We conducted a random effects meta-analysis using individual level data to examine whether the Cys23Ser variant-either directly, or conditionally depending on the level of psychosocial stress-was associated with depressive symptoms and body mass index (BMI). We found that psychosocial stress was associated with both depression and BMI, but that Cys23Ser was not directly associated with, nor did it modify the associations of psychosocial stress with depression or BMI. Thus, in the largest study of this polymorphism, we have determined that rs6318 is not associated with depression, or BMI.

Stress management in the workplace for employees with hypertension: a randomized controlled trial.

While behavioral interventions can improve blood pressure (BP) in individuals with hypertension, getting such services to people who could benefit remains difficult. Workplace programs have potential as dissemination vehicles. The objective is to evaluate the effectiveness of a standardized stress management program delivered in groups at the workplace for reducing BP compared with enhanced usual care. This randomized controlled trial studied 92 urban medical center employees with hypertension randomized into two groups. The intervention was a 10-week group workshop on cognitive-behavioral coping skills. Enhanced usual care included self-help materials for BP reduction and physician referral. Intervention group participants' systolic BP (SBP) decreased 7.5 mm Hg over controls between baseline and follow-up, from 149.1 (95% CI: 146.0-152.1) to 140.0 (95% CI: 134.7-145.2), p < .001. The differential change between intervention and enhanced usual care groups (Group × Time interaction) was 7.5 mm Hg (t = -2.05; p = .04). Diastolic BP reductions were not significantly different. Scores on measures of emotional exhaustion and depressive rumination showed significant improvements and correlated with reductions in SBP. There was no significant change in the usual care group. A standardized worksite group intervention produced clinically meaningful reductions in SBP in participants with hypertension.