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.

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.

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.

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.

Developing a synthetic psychosocial stress measure and harmonizing CVD-risk data: a way forward to GxE meta- and mega-analyses.

OBJECTIVES: Among many challenges in cardiovascular disease (CVD) risk prediction are interactions of genes with stress, race, and/or sex and developing robust estimates of these interactions. Improved power with larger sample size contributed by the accumulation of epidemiological data could be helpful, but integration of these datasets is difficult due the absence of standardized phenotypic measures. In this paper, we describe the details of our undertaking to harmonize a dozen datasets and provide a detailed account of a number of decisions made in the process. RESULTS: We harmonized candidate genetic variants and CVD-risk variables related to demography, adiposity, hypertension, lipodystrophy, hypertriglyceridemia, hyperglycemia, depressive symptom, and chronic psychosocial stress from a dozen studies. Using our synthetic stress algorithm, we constructed a synthetic chronic psychosocial stress measure in nine out of twelve studies where a formal self-rated stress measure was not available. The mega-analytic partial correlation between the stress measure and depressive symptoms while controlling for the effect of study variable in the combined dataset was significant (Rho = 0.27, p < 0.0001). This evidence of the validity and the detailed account of our data harmonization approaches demonstrated that it is possible to overcome the inconsistencies in the collection and measurement of human health risk variables.

Usefulness of Myocardial Annular Velocity Change During Mental Stress to Predict Cardiovascular Outcome in Patients With Coronary Artery Disease (From the Responses of Mental Stress-Induced Myocardial Ischemia to Escitalopram Treatment Trial).

Mental stress-induced myocardial ischemia is common and a prognostic factor of adverse cardiovascular outcomes in patients with coronary artery disease (CAD). The present study aimed at examining associations between mental stress-induced myocardial annular velocity (MAV) and cardiovascular outcome in patients with CAD. MAV, specifically, diastolic early (e'), diastolic late (a'), and systolic (s') velocities were obtained at rest and during mental stress testing in 224 patients with clinically stable CAD. Using Cox regression models, age, sex, and baseline-adjusted mental stress-induced MAV measures were examined as predictors of a priori defined composite event term that comprised all-cause mortality and/or nonfatal cardiovascular events, resulting in an unplanned hospitalization (major adverse cardiovascular events [MACE]). Median follow-up was 4 years. The sample was predominantly male, Caucasian with New York Heart Association functional class I and a mean age of 63 ± 10.2 years. MS-induced changes in e' (hazard ratio [HR] = .73) and s' (HR = .73) were significant (p <0.05) predictors of MACE, and the change in a' (HR = .74) was marginal (p = 0.05). The pattern of the relation for each MAV measure was such that patients with a greater decrease in e' and/or s' velocity had a higher probability of experiencing an MACE, and the association of the change in a' and MACE was marginal (p = 0.05), but the same tendency. The associations between MS-induced values of e' and a' for MACE were independent of resting levels. Mental stress-induced MAV changes independently predict an adverse cardiovascular outcome in patients with stable CAD.

Brain-derived neurotrophic factor rs6265 (Val66Met) polymorphism is associated with disease severity and incidence of cardiovascular events in a patient cohort.

BACKGROUND: The rs6265 (Val66Met) single-nucleotide polymorphism in the BDNF gene has been related to a number of endophenotypes that have in turn been shown to confer risk for atherosclerotic cardiovascular disease (CVD). To date, however, very few studies have examined the association of the Val66Met single-nucleotide polymorphism with CVD clinical outcomes. METHODS: In a cohort of 5,510 Caucasian patients enrolled in the CATHeterization GENetics (CATHGEN) study at Duke University Hospital between 2001 and 2011, we determined the severity of coronary artery disease (CAD) and CVD event incidence through up to 11.8years of follow-up. We examined the association of Val66Met genotype with time-to-death or myocardial infarction, adjusting for age, sex, CAD risk variables, and CAD severity measures. RESULTS: The Val/Val genotype was associated with a higher risk than Met carriers for clinical CVD events (P=.034, hazard ratio 1.12, 95% CI 1.01-1.24). In addition, compared with Met carriers, individuals with the Val/Val genotype had a greater odds of having more diseased vessels (odds ratio 1.17, 95% CI 1.06-1.30, P=.002), and lower left ventricular ejection fraction (ß=-0.72, 95% CI, -1.42 to -0.02, P=.044). CONCLUSIONS: The Val/Val genotype was associated with greater severity of CAD and incidence of CVD-related clinical events in a patient sample. If these findings are confirmed in further research, intervention studies in clinical groups with the Val/Val genotype could be undertaken to prevent disease and improve prognosis.

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism interacts with gender to influence cortisol responses to mental stress.

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been associated with cortisol responses to stress with gender differences reported, although the findings are not entirely consistent. To evaluate the role of Val66Met genotype and gender on cortisol responses to stress, we conducted a 45-min mental stress protocol including four tasks and four rest periods. Blood cortisol was collected for assay immediately before and after each task and rest period. A significant two-way interaction of Val66Met genotype×gender (P=0.022) was observed on the total area under the curve (AUC), a total cortisol response over time, such that the Val/Val genotype was associated with a larger cortisol response to stress as compared to the Met group in women but not in men. Further contrast analyses between the Val/Val and Met group for each stress task showed a similar increased cortisol pattern among women Val/Val genotype but not among men. The present findings indicate the gender differences in the effect of Val66Met genotype on the cortisol responses to stress protocol, and extend the evidence for the importance of gender and the role of Val66Met in the modulation of stress reactivity and subsequent depression prevalence. Further studies and the underlying mechanism need to be investigated, which may provide an insight for prevention, intervention, and treatment strategies that target those at high risk.

Population differences in associations of serotonin transporter promoter polymorphism (5HTTLPR) di- and triallelic genotypes with blood pressure and hypertension prevalence.

Based on prior research finding the 5HTTLPR L allele associated with increased cardiovascular reactivity to laboratory stressors and increased risk of myocardial infarction, we hypothesized that the 5HTTLPR L allele will be associated with increased blood pressure (BP) and increased hypertension prevalence in 2 large nationally representative samples in the United States and Singapore. METHODS: Logistic regression and linear models tested associations between triallelic (L'S', based on rs25531) 5HTTLPR genotypes and hypertension severity and mean systolic and diastolic blood pressure (SBP and DBP) collected during the Wave IV survey of the National Longitudinal Study of Adolescent to Adult Health (Add Health, N=11,815) in 2008-09 and during 2004-07 in 4196 Singaporeans. RESULTS: In US Whites, L' allele carriers had higher SBP (0.9 mm Hg, 95% CI=0.26-1.56) and greater odds (OR=1.23, 95% CI=1.10-1.38) of more severe hypertension than those with S'S' genotypes. In African Americans, L' carriers had lower mean SBP (-1.27mm Hg, 95% CI=-2.53 to -0.01) and lower odds (OR = 0.78, 95% CI=0.65-0.94) of more severe hypertension than those with the S'S' genotype. In African Americans, those with L'L' genotypes had lower DBP (-1.13mm Hg, 95% CI=-2.09 to -0.16) than S' carriers. In Native Americans, L' carriers had lower SBP (-6.05mm Hg, 95% CI=-9.59 to -2.51) and lower odds of hypertension (OR = 0.34, 95% CI=0.13-0.89) than those with the S'S' genotype. In Asian/Pacific Islanders those carrying the L' allele had lower DBP (-1.77mm Hg, 95% CI=-3.16 to -0.38) and lower odds of hypertension (OR = 0.68, 95% CI=0.48-0.96) than those with S'S'. In the Singapore sample S' carriers had higher SBP (3.02mm Hg, 95% CI=0.54-5.51) and DBP (1.90mm Hg, 95% CI=0.49-3.31) than those with the L'L' genotype. CONCLUSIONS: These findings suggest that Whites carrying the L' allele, African Americans and Native Americans with the S'S' genotype, and Asians carrying the S' allele will be found to be at higher risk of developing cardiovascular disease and may benefit from preventive measures.

Depression, Stressful Life Events, and the Impact of Variation in the Serotonin Transporter: Findings from the National Longitudinal Study of Adolescent to Adult Health (Add Health).

BACKGROUND: The low transcriptionally efficient short-allele of the 5HTTLPR serotonin transporter polymorphism has been implicated to moderate the relationship between the experience of stressful life events (SLEs) and depression. Despite numerous attempts at replicating this observation, results remain inconclusive. METHODS: We examined this relationship in young-adult Non-Hispanic white males and females between the ages of 22 and 26 (n = 4724) participating in the National Longitudinal Study of Adolescent to Adult Health (Add Health) with follow-up information every six years since 1995. RESULTS: Linear and logistic regression models, corrected for multiple testing, indicated that carriers of one or more of the S-alleles were more sensitive to stress than those with two L-alleles and at a higher risk for depression. This relationship behaved in a dose-response manner such that the risk for depression was greatest among those who reported experiencing higher numbers of SLEs. In post-hoc analyses we were not able to replicate an interaction effect for suicide ideation but did find suggestive evidence that the effects of SLEs and 5HTTLPR on suicide ideation differed for males and females. There were no effects of childhood maltreatment. DISCUSSION: Our results provide partial support for the original hypothesis that 5-HTTLPR genotype interacts with the experience of stressful life events in the etiology of depression during young adulthood. However, even with this large sample, and a carefully constructed a priori analysis plan, the results were still not definitive. For the purposes of replication, characterizing the 5HTTLPR in other large data sets with extensive environmental and depression measures is needed.

Computing a Synthetic Chronic Psychosocial Stress Measurement in Multiple Datasets and its Application in the Replication of G × E Interactions of the EBF1 Gene.

Chronic psychosocial stress adversely affects health and is associated with the development of disease [Williams, 2008]. Systematic epidemiological and genetic studies are needed to uncover genetic variants that interact with stress to modify metabolic responses across the life cycle that are the proximal contributors to the development of cardiovascular disease and precipitation of acute clinical events. Among the central challenges in the field are to perform and replicate gene-by-environment (G × E) studies. The challenge of measurement of individual experience of psychosocial stress is magnified in this context. Although many research datasets exist that contain genotyping and disease-related data, measures of psychosocial stress are often either absent or vary substantially across studies. In this paper, we provide an algorithm to create a synthetic measure of chronic psychosocial stress across multiple datasets, applying a consistent criterion that uses proxy indicators of stress components. We validated the computed scores of chronic psychosocial stress by observing moderately strong and significant correlations with the self-rated chronic psychosocial stress in the Multi-Ethnic Study of Atherosclerosis Cohort (Rho = 0.23, P < 0.0001) and with the measures of depressive symptoms in five datasets (Rho = 0.15-0.42, Ps = 0.005 to <0.0001) and by comparing the distributions of the self-rated and computed measures. Finally, we demonstrate the utility of this computed chronic psychosocial stress variable by providing three additional replications of our previous finding of gene-by-stress interaction with central obesity traits [Singh et al., 2015].

Gene by stress genome-wide interaction analysis and path analysis identify EBF1 as a cardiovascular and metabolic risk gene.

We performed gene-environment interaction genome-wide association analysis (G × E GWAS) to identify SNPs whose effects on metabolic traits are modified by chronic psychosocial stress in the Multi-Ethnic Study of Atherosclerosis (MESA). In Whites, the G × E GWAS for hip circumference identified five SNPs within the Early B-cell Factor 1 (EBF1) gene, all of which were in strong linkage disequilibrium. The gene-by-stress interaction (SNP × STRESS) term P-values were genome-wide significant (Ps = 7.14E-09 to 2.33E-08, uncorrected; Ps = 1.99E-07 to 5.18E-07, corrected for genomic control). The SNP-only (without interaction) model P-values (Ps = 0.011-0.022) were not significant at the conventional genome-wide significance level. Further analysis of related phenotypes identified gene-by-stress interaction effects for waist circumference, body mass index (BMI), fasting glucose, type II diabetes status, and common carotid intimal-medial thickness (CCIMT), supporting a proposed model of gene-by-stress interaction that connects cardiovascular disease (CVD) risk factor endophenotypes such as central obesity and increased blood glucose or diabetes to CVD itself. Structural equation path analysis suggested that the path from chronic psychosocial stress to CCIMT via hip circumference and fasting glucose was larger (estimate = 0.26, P = 0.033, 95% CI = 0.02-0.49) in the EBF1 rs4704963 CT/CC genotypes group than the same path in the TT group (estimate = 0.004, P = 0.34, 95% CI = -0.004-0.012). We replicated the association of the EBF1 SNPs and hip circumference in the Framingham Offspring Cohort (gene-by-stress term P-values = 0.007-0.012) as well as identified similar path relationships. This observed and replicated interaction between psychosocial stress and variation in the EBF1 gene may provide a biological hypothesis for the complex relationship between psychosocial stress, central obesity, diabetes, and cardiovascular disease.

Associations between central nervous system serotonin, fasting glucose, and hostility in African American females.

BACKGROUND: Previous research has shown an association between hostility and fasting glucose in African American women. Central nervous system serotonin activity is implicated both in metabolic processes and in hostility related traits. PURPOSE: The purpose of this study is to determine whether central nervous system serotonin influences the association between hostility and fasting glucose in African American women. METHODS: The study consisted of 119 healthy volunteers (36 African American women, 27 White women, 21 White males, and 35 African American males, mean age 34 ± 8.5 years). Serotonin related compounds were measured in cerebrospinal fluid. Hostility was measured by the Cook-Medley Hostility Scale. RESULTS: Hostility was associated with fasting glucose and central nervous system serotonin related compounds in African American women only. Controlling for the serotonin related compounds significantly reduced the association of hostility to glucose. CONCLUSIONS: The positive correlation between hostility and fasting glucose in African American women can partly be explained by central nervous system serotonin function.

A putatively functional polymorphism in the HTR2C gene is associated with depressive symptoms in white females reporting significant life stress.

Psychosocial stress is well known to be positively associated with subsequent depressive symptoms. Cortisol response to stress may be one of a number of biological mechanisms that links psychological stress to depressive symptoms, although the precise causal pathway remains unclear. Activity of the x-linked serotonin 5-HTR2C receptor has also been shown to be associated with depression and with clinical response to antidepressant medications. We recently demonstrated that variation in a single nucleotide polymorphism on the HTR2C gene, rs6318 (Ser23Cys), is associated with different cortisol release and short-term changes in affect in response to a series of stress tasks in the laboratory. Based on this observation, we decided to examine whether rs6318 might moderate the association between psychosocial stress and subsequent depressive symptoms. In the present study we use cross-sectional data from a large population-based sample of young adult White men (N = 2,366) and White women (N = 2,712) in the United States to test this moderation hypothesis. Specifically, we hypothesized that the association between self-reported stressful life events and depressive symptoms would be stronger among homozygous Ser23 C females and hemizygous Ser23 C males than among Cys23 G carriers. In separate within-sex analyses a genotype-by-life stress interaction was observed for women (p = .022) but not for men (p = .471). Homozygous Ser23 C women who reported high levels of life stress had depressive symptom scores that were about 0.3 standard deviations higher than female Cys23 G carriers with similarly high stress levels. In contrast, no appreciable difference in depressive symptoms was observed between genotypes at lower levels of stress. Our findings support prior work that suggests a functional SNP on the HTR2C gene may confer an increased risk for depressive symptoms in White women with a history of significant life stress.

A functional polymorphism in the HTR2C gene associated with stress responses: a validation study.

Previously we have shown that a functional nonsynonymous single nucleotide polymorphism (SNP), rs6318 on the HTR2C gene located on the X-chromosome, is associated with hypothalamic-pituitary-adrenal axis response to a laboratory stress recall task. The present paper reports a validation of the cortisol response to stress in a second, independent sample. The study population consisted of 60 adult participants (73.3% males). Consistent with our prior findings, compared to Cys23 G allele carriers, persons homozygous for the Ser23C allele had a significantly greater average cortisol response (p=0.007) and area under the curve (p=0.021) over the course of an emotional stress recall protocol. Also parallel to our prior report, the change in cortisol from baseline to the average during the stress protocol was roughly twice as large among Ser23C homozygotes than among persons with Cys23 G. These findings validate our initial observation of association between rs6318 and cortisol response to an acute stressor, and extend the results to include females.

Socioeconomic indices as independent correlates of C-reactive protein in the National Longitudinal Study of Adolescent Health.

OBJECTIVES: To examine the association between socioeconomic status (SES) and C-reactive protein (CRP) to understand how SES may increase the risk of cardiovascular disease and thus identify targets for prevention measures. METHODS: Path models were used to examine direct and indirect associations of four indices of SES (objective early life built environment ratings, parental and participant education, and income) with CRP measured during early adulthood using data from the National Longitudinal Adolescent Health Study (n = 11,371; mean age = 29 years, range = 24-32 years; 53.8% women, 28.0% black participants). The present study examined potential mediation of the association of SES with CRP by way of body mass index (BMI), smoking, and alcohol consumption within white and black men and women. RESULTS: BMI was a mediator of the relation between parent education and CRP for white men (path coefficient [γ] = -0.05, p < .001) and women (γ = -0.05, p < .001). Smoking mediated the income-CRP (γ = -0.01, p < .01) and the education-CRP (γ = -0.07, p < .001) relation for white men. BMI mediated the relation between all measures of SES and CRP for white women (γ values between -0.02 and -0.05; p values < .01). None of the risk factors mediated the SES-CRP relation in black participants. CONCLUSIONS: These findings indicate that the association of SES with CRP is influenced by both the timing and type of SES measure examined. In addition, race and sex play a role in how potential mediators are involved with the SES-CRP relationship, such that BMI and smoking were mediators in white men, whereas BMI was the sole mediator in white women.