E-selectin is one of a family of cell adhesion molecules (CAMs) that are expressed on the surfaces of endothelial cells as part of the inflammatory response to endothelial damage, and expression of these proteins is one indication of potential adverse changes in endothelial homeostasis, also known as endothelial dysfunction (Ross, 1999). Endothelial dysfunction in turn is an initiating step in the process of atherosclerosis, a leading cause of cardiovascular disease (Ross, 1999). Soluble E-selectin and related CAMs are thought to be shed from activated endothelial cells (Pigott et al., 1992) and are associated with atherosclerosis (Bonora, 2006; Galkina and Ley, 2007) as well as cardiovascular disease morbidity and mortality (Hwang et al., 1997; Blann and Lip, 2000; Zethelius et al., 2008). E-selectin in particular was a logical focus for the current study because while other CAMs, such as VCAM and ICAM, are expressed on multiple cell types (Springer, 1990), E-selectin is uniquely expressed by endothelial cells (Erbe et al., 1992), and prior research has linked exposure to discrimination with endothelial pathology (Troxel et al., 2003; Lewis et al., 2006).

While there is no direct evidence to date of a link between psychosocial stress and soluble E-selectin levels, stress exposure has been linked to endothelial dysfunction in human and animal models (Rozanski et al., 1999; Harris and Matthews, 2004; Das and O’Keefe, 2006), and hormones that are released during the stress response have direct effects on endothelial function (Wilbert-Lampen et al., 2006; Wilbert-Lampen et al., 2007). For example, disruption of stable social groups of cynomolgus monkeys resulted in damaged endothelial cells, an effect that involved activation of the sympathetic nervous system (Skantze et al., 1998). In healthy men, an experimental speech stressor temporarily impaired the ability of blood vessels to dilate in response to increased blood flow (Ghiadoni et al., 2000). A separate study showed that this effect was reversed by pre-treatment with metyrapone, a glucocorticoid antagonist (Broadley et al., 2005). Cultured human endothelial cells exposed to corticotropin-releasing hormone (Wilbert-Lampen et al., 2006) or beta-endorphin (Wilbert-Lampen et al., 2007), increase their release of endothelin-1, a vasoconstrictor, and (in the case of beta-endorphin) lower levels of nitric oxide, a vasodilator. The aggregate of these effects is unopposed vasoconstriction (Wilbert-Lampen et al., 2006; Wilbert-Lampen et al., 2007). Collectively, these prior studies show that ecological and laboratory stressors and exposure to stressor-related hormones both in vivo and in vitro impair endothelial function. The current study tested the hypothesis that perceived discrimination constitutes a kind of stress that predicts greater endothelial dysfunction, as measured by higher circulating concentrations of E-selectin.

The focus of the present study was perceived discrimination in general, not racism per se. While racism is a principal focus of research on the health effects of discrimination in the U.S., and while racism may be a particularly detrimental form of unfair treatment, recent evidence suggests that unfair treatment of any type may predict poorer health outcomes in minority and non-minority populations alike. While unfair treatment was associated with greater coronary artery calcification among African American women in the Study of Women’s Health Across the Nation (SWAN), racial discrimination was not more detrimental than other forms of discrimination (Lewis et al., 2006). Similarly, carotid intima media thickness in the SWAN study was significantly greater among African American women with greater exposure to unfair treatment, but racism specifically was only marginally associated with artery thickness (Troxel et al., 2003). Results from the Chicago Health and Aging Project showed that perceived discrimination was associated with a significantly increased risk of mortality, and this was true for both African American and Caucasian participants (Barnes et al., 2008). In the Survey of MidLife in the United States (MIDUS), perceived discrimination was associated with higher rates of depression in Caucasians than in African Americans (Kessler et al., 1999). In the Whitehall study, perceived unfairness has been related to incident coronary events (De Vogli et al., 2007), incident psychiatric morbidity (Ferrie, 2006), and metabolic syndrome (De Vogli et al., 2007). These studies are not framed within the context of discrimination but unfairness is operationalized with measures similar to those used in the discrimination literature. Indeed, perceived discrimination is linked to adverse health outcomes in many diverse groups in a broad range of national contexts (Williams and Mohammed, In Press). Collectively, these results suggest that any form of unfair treatment may increase disease risk, and that diverse groups may be vulnerable to consequent adverse health outcomes. The measures used in the current study were designed to distinguish between perceptions of kinds of unfair treatment (e.g. being denied a promotion; receiving inferior service) and the perceived reasons for receiving such unfair treatment (e.g. race/ethnicity, age, gender; (Williams et al., 1997)). Thus, it was possible to test the hypothesis that unfair treatment in general (i.e., for any reason) rather than racism, in particular, would be positively associated with circulating concentrations of E-selectin.

Approximately 35% of the male participants reported at least one instance of major lifetime discrimination with 19% reporting more than 3 instances. The most common forms of discrimination reported were not being hired for a job (19.1%), not being given a job promotion (16.4%), and being denied service or given inferior service (14.7%). The most common reasons given for discrimination were age (48.4% of those reporting discrimination) and race (31.2%; data not shown). Thirty-one percent of men reported never experiencing everyday discrimination, while almost 39% reported chronic experiences of everyday discrimination (Table 2).

Almost half of the female participants reported at least one instance of major lifetime discrimination while nearly 30% reported 3 or more instances (Table 2). As was the case for men, among those reporting discrimination not being hired for a job (20%), not being promoted (16.4%), and being denied service or given inferior service (14.7%) were the most common forms of discrimination, while gender (72%) and height/weight (28.2%) were the principal reasons for discrimination reported (data not shown). Finally, only 20% of women reported no experiences of everyday discrimination while more than half reported chronic everyday discrimination (Table 2).

Discrimination has been shown to have an impact on the mental and physical health of stigmatized groups (Krieger, 2001; Ahmed et al., 2007) as well as individuals exposed to unfair treatment (Kessler et al., 1999; Williams et al., 2003; Ferdinand, 2006; Barnes et al., 2008), and cardiovascular disease (CVD), the leading cause of death in the US (Rosamond et al., 2008), provides a compelling nexus for research on the health consequences of discrimination as well as the mechanisms involved. For example, rates of cardiovascular disease are higher in populations who have traditionally experienced discriminatory treatment (Ferdinand, 2006; Rosamond et al., 2008), and indices of risk for CVD, such as vascular pathology, are positively linked to perceived exposure to unfair treatment (Troxel et al., 2003; Lewis et al., 2006). Perceived discriminatory treatment, particularly for reasons of race, has also been linked to greater blood pressure responses to laboratory stressors among African American women (Guyll et al., 2001; Harrell et al., 2003), and greater cardiovascular reactivity may constitute a risk factor for cardiovascular disease (Treiber et al., 2003). Importantly, chronic elevations in blood pressure are associated with greater endothelial dysfunction generally (Ross, 1999) and elevated serum concentrations of E-selectin specifically (Miller et al., 2004). Given these associations, the current results suggest that endothelial dysfunction may be an important mechanism by which discrimination may increase the risk of cardiovascular disease in particular.

Health status and health behaviors represent potential rival explanations for the observed associations. For example, health status, including obesity, may simultaneously explain perceived exposure to discrimination (Andreyeva et al., 2008) and higher circulating levels of E-selectin (Bonora, 2006). Indeed, BMI was a significant predictor of E-selectin levels in all statistical models (data not shown), and women in particular reported height/weight as the basis of unfair treatment almost 30% of the time. Moreover, discrimination is also thought to result in poorer health behavior and consequently greater likelihood of adverse health outcomes (Ahmed et al., 2007). A number of health behaviors, including smoking, have also been positively linked with endothelial dysfunction and higher levels of soluble E-selectin (Blann and McCollum, 1993; Sacanella et al., 1999; Papamichael et al., 2005). For these reasons, statistical models in the current study adjusted for health status and health behaviors, and the association between perceived discrimination and E-selectin levels remained significant among men. Thus, while health status and health behavior are clearly linked to endothelial dysfunction, they do not constitute rival explanations for the relationship between unfair treatment and E-selectin. That said, it may be fruitful to examine the extent to which the strength of the links between discrimination and adhesion molecules (or other biological markers of disease risk) varies among individuals distinguished by differences in health status, health behaviors, or other characteristics. Such analyses of the interplay among multiple variables will help to identify groups of individuals for whom the association of discrimination and biological risk is particularly strong (or weak).

Gender was a significant determinant of both E-selectin levels and of the relationship between E-selectin and experiences of unfair treatment. A number of previous studies have reported higher E-selectin levels in men compared to women (Blann et al., 1996; Jilma et al., 1996; Bannan et al., 1998; Demerath et al., 2001), although others have observed no such differences (Ponthieux et al., 2004). One potential explanation for this difference may be sex hormones. Pre-menopausal women are at considerably reduced risk of endothelial dysfunction than postmenopausal women (Virdis et al., 2002), and hormone replacement therapies have been shown to improve endothelial function in postmenopausal women (Guzic-Salobir et al., 2001; Colacurci et al., 2003; Prestwood et al., 2004; Salpeter et al., 2006). In additional analyses for the current study, we examined differences in E-selectin levels in pre- and postmenopausal women, and observed no significant group differences between women who reported having a menstrual cycle in the prior 12 months and those who reported none (data not shown). While this analysis suggests that sex hormones did not appear to explain the sex differences observed here, MIDUS does not include the types of data needed for precise classification of menopausal status (Weinstein et al., 2003). For this reason we cannot confidently rule out the possibility that menopausal status may have contributed to sex differences in E-selectin levels in the current study. A second possible source of the sex difference is BMI, which was higher for men than for women. Although BMI strongly predicted E-selectin levels in both men and women, the effect size was almost 30% larger for men (η_p² = .07 – .08) than for women (η_p² = .05 – .06), suggesting that BMI may be more strongly related to endothelial dysfunction in men than in women.

We found no associations between discrimination and E-selectin levels in women, even though women reported higher rates of both lifetime and everyday discrimination. These results differ from those of prior studies documenting vascular pathology (Troxel et al., 2003; Lewis et al., 2006) and increased cardiovascular reactivity (Guyll et al., 2001) in women reporting greater exposure to discrimination, although links between perceived everyday discrimination and mortality were observed for men and women alike (Barnes et al., 2008). One important difference between this current study and prior ones is the composition of the sample. Data for each of the studies cited above were taken from the SWAN, a national longitudinal study of mid-life Caucasian and African American women. In contrast, as previously noted the MIDUS biomarker sample was predominantly Caucasian. In addition, the age range for the current sample was much broader (35–84 years old) than for the SWAN (42–52 years old). Although like others (Miles et al., 2001) we observed no robust relationship between age and E-selectin levels in the current study (data not shown), it is possible that age-related variables (e.g. health, body habitus) may affect how discrimination and E-selectin are associated over such a large age range in women; future efforts will examine this possibility more closely. Men and women in this sample differed in several ways that could have influenced the link between perceived unfair treatment and E-selectin. A larger percentage of women were taking steroid and antidepressant medication, although additional analyses showed that medication use was not associated with differences in E-selectin (data not shown). Female sex hormones have also hypothesized to preserve endothelial function, but as mentioned above menopausal status was unrelated to E-selectin levels and thus are unlikely to explain the observed sex differences. Finally, men had higher average BMI and the relationship between BMI and E-selectin was stronger in men than in women; it is possible that obesity may accentuate the relationship between discrimination and E-selectin, even though obesity was not reported as a principle reason for discrimination.

As noted above, psychosocial stressors have been linked to endothelial dysfunction (Rozanski et al., 1999; Harris and Matthews, 2004; Das and O’Keefe, 2006), and while subjective experiences of stress were not examined in the current study, future efforts will examine the extent to which such perceptions are associated with both perceived discrimination and adhesion molecule concentrations. In addition, personality attributes, such as the tendency to view events in a negative light (e.g. neuroticism), have been linked to increased risk of mortality (Almada et al., 1991; Mroczek and Spiro, 2007), particularly from cardiovascular disease (Shipley et al., 2007), and may also increase the likelihood of perceiving unfair treatment (Williams et al., 2003). In the current analyses, neuroticism was higher in those reporting greater perceived discrimination, but it was not associated with E-selectin nor did it mediate or moderate the link between discrimination and E-selectin. These results suggest that the biological signatures of unfair treatment may be independent of the tendency to view the world negatively.

Another way in which the current results differ from prior examinations of discrimination and health is that the MIDUS biomarker sample was almost exclusively Caucasian; only 7% of the sample was non-White. The demographic composition of the sample makes it impossible to extend these results to minority populations or to determine the extent to which racism is unique in its biological signature compared to unfair treatment in general; we intend to pursue these issues in future research using data from an oversample of African Americans in the MIDUS study. As the biomarker sample was also slightly more educated than the full MIDUS sample (23.5% with post-secondary education vs. 17.4% for the full sample), these results may also not extend to those with lower socioeconomic standing. Nonetheless, high proportions of both men and women reported experiences of unfair treatment. This result underscores the value of measuring exposure to discrimination independently of perceived reasons for discrimination. Conflating discrimination and racism, for example, may have masked the association of unfair treatment broadly construed and E-selectin levels. These results also highlight the importance of broadening the consideration of the health impacts of unfair treatment to include populations that are not typically considered stigmatized (e.g. women, obese individuals, the aged). Perceptions of unfair treatment, even among members of privileged racial or ethnic groups, may have significant health consequences. Interestingly, men in the current study cited race/ethnicity as the reason for discriminatory treatment more than 30% of the time, and the most common form of discrimination reported was not being hired. These responses may constitute perceptions of “reverse discrimination” whereby Caucasian men take a negative view of social policies designed to address racial inequities (Fraser and Kick, 2000) and may feel personally disadvantaged by such policies or practices.