The death of a spouse is one of the most distressing life events, and is associated with an increase in morbidity and mortality risk, independent of a host of covariates (Boyle et al., 2011
). Stressful life events are linked to dysregulation of the immune system and increased cellular inflammatory signaling (Irwin and Cole, 2011
). Because it is our long-term goal to determine the mechanism linking bereavement and morbidity/mortality, and because substantial evidence shows that increases in inflammatory markers such as interleukin (IL)-6 are associated with mortality risk (Ershler and Keller, 2000
), we investigated whether responses to spousal bereavement are impacted by markers of inflammation.
Chronic stress as a result of caregiving (i.e., those taking care of a severely ill family member) or social isolation is associated with the up-regulated gene expression and production of systemic markers of inflammation (Kiecolt-Glaser et al., 2003
; McDade et al., 2006
), especially of IL-6, IL-1 and TNF-alpha (Dantzer, 2001
). Further data indicate genetic variability in the expression of inflammatory markers in response to stress (Cole et al., 2010
). For example, the presence of the guanine/cytosine (G/C) single nucleotide polymorphism (SNP) in the promoter of the IL-6
gene (IL-6) –174 bp upstream of the transcription start site affects the binding of a β-adrenergic-sensitive transcription factor, GATA-1 (Cole et al., 2010
). Following an in vitro
β-adrenergic stimulus, the IL-6
–174G SNP leads to increased IL-6 production, while the IL-6
– 174C SNP does not. In vivo
, an association between depression and increased mortality risk was found only in IL-6
174GG homozygous patients (Cole et al., 2010
), but levels of inflammatory markers were not characterized. Thus, it is not known whether genetic variability in cytokine gene polymorphisms alters the influence of life stress on the production of inflammatory markers in humans.
Given evidence that some widow(er)s show an increase in morbidity and mortality, but others remain healthy and thus appear to be protected from this “widowhood effect” (Buckley et al., 2011
), the present study hypothesizes that bereavement may be a socio-environmental stress that interacts with pro-inflammatory genetic variation to produce modulated levels of inflammation. This gene by environment (GxE) interaction predicts that among widow(er)s, those with genotypes that are associated with higher expression of inflammatory markers would exhibit greater systemic signs of inflammation, e.g. higher circulating levels of inflammatory markers. Conversely, widow(er)s with low pro-inflammatory genotypes are hypothesized to have similar circulating levels as non-bereaved individuals.
The work reported here compares bereaved and healthy married/partnered older adults, first investigating the impact of bereavement status on circulating levels of inflammatory markers IL-6, IL-1RA as a marker of IL-1 activity (Arend et al., 1998
) and soluble tumor necrosis factor receptor II (sTNFRII) as a surrogate marker of TNF-α levels (Diez-Ruiz et al., 1995
; Schuld et al., 1999
). Second, corresponding to our circulating measures, we investigated the impact of pro-inflammatory cytokine SNPs in the IL-6
, and tumor necrosis factor alpha (TNF-α
genes on the mentioned inflammatory markers and a possible interaction with bereavement status. Given evidence of in vitro
data for the GxE pathway for the IL-6
–174 SNP, we primarily focused on the interaction between bereavement stress and this polymorphism.