When grief makes you sick: Bereavement induced systemic inflammation is a question of genotype
Open accessAbstract
Although bereavement is associated with increased morbidity and mortality in the surviving spouse, some widow(er)s remain healthy. Genetic variability in expression of inflammatory markers in response to stress may be the key to this observation. The present study compares bereaved vs. married/partnered older adults, investigating the impact of bereavement status, pro-inflammatory cytokine single nucleotide polymorphisms (SNPs) on circulating markers of inflammation and hypothesizing a gene by environment (GxE) effect. The study sample included 64 older adults, of which 36 were widow(er)s. Circulating levels of inflammatory markers IL-6, IL-1RA and sTNFRII were measured. Participants were genotyped for SNPs in the IL-6 gene (IL-6 -174 and -572), the IL-1β gene (IL-1β -511), and TNF-α gene (TNF-α -308). Grief severity was assessed with the Inventory of Complicated Grief. Bereaved participants had higher circulating levels of IL-1RA and IL-6. This increase could not be explained by pro-inflammatory genotype frequency differences, or Complicated Grief diagnosis. However, a GxE effect with the IL-6 -174 SNP moderated individual vulnerability to higher circulating levels of inflammation resulting from bereavement exposure. These results suggest a possible mechanism for the increase in morbidity and mortality in the surviving spouse. Genetic variability interacts with an environmental stressor, leading to increased inflammatory markers in genetically susceptible subjects only. For these patients, clinical interventions for bereavement-related stressor reduction might be crucial for overall health.
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The effect of bereavement on inflammation was moderated by a variant in the IL-6 gene (IL6 -174), such that SNS activation caused by bereavement-related distress led to GATA1 transcription factor activation that mediates up-regulation of IL-6 production but only for individuals with two GATA1-sensitive -174G alleles.
“This effect was moderated by a variant in the IL-6 gene ( IL6 -174), which modified individuals' likelihood of exhibiting high levels of inflammation following bereavement. Specifically, SNS activation caused by bereavement-related distress led to GATA1 transcription factor activation that mediates up-regulation of IL-6 production but only for individuals with two GATA1-sensitive-174G alleles”
From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as Schultze-Florey et al., 2012
The Results (§3.3) report higher IL-6 levels in bereaved –174G homozygotes than in non-bereaved homozygotes, while –174C carriers had similar levels across groups. The Discussion (§4) proposes that bereavement-related sympathetic activation may lead to GATA1-mediated IL-6 upregulation in –174G homozygotes. The claim overstates that proposed mechanism as an established causal sequence; the reported genotype-by-bereavement interaction only approached statistical significance (p = 0.09). (LLM, conf=0.88)
Experimental — accuracy not yet measuredOlder adults who experienced the recent death of their spouse had higher IL-1 and IL-6 activity than nonbereaved older adults.
“older adults who experienced the recent death of their spouse had higher IL-1 and IL-6 activity than nonbereaved older adults”
From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as Schultze-Florey et al., 2012
The death of a spouse increases IL-1β and IL-6 activity in older adults.
“Schultze-Florey et al (2012) reported that the death of a spouse increased IL-1β and IL-6 activity in older adults.”
From Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders (2017) · cites this paper as Schultze-Florey et al, 2012
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- Authors
- Schultze-Florey, C. R., Martínez-Maza, O., Magpantay, L., Breen, E. C., Irwin, M. R., Gündel, H., & O’Connor, M.-F.
- Affiliations
- University of California, Los Angeles (US)
- Universität Ulm (DE)
- ORCID
- Venue
- Brain, Behavior, and Immunity
- Publisher
- Elsevier BV
- Published
- 2012-10
- Volume
- 26
- Issue
- 7
- Pages
- 1066-1071
- ISSN
- 0889-1591 (ISSN-L)
- PMC
- PMC3601554
- OpenAlex
- W2025704206
- Cited by
- 92
- References
- 39
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 1 · 2023: 2 · 2022: 6 · 2021: 8 · 2020: 6 · 2019: 11 · 2018: 6 · 2017: 6 · 2016: 8 · 2015: 6 · 2014: 10 · 2013: 3 · 2012: 1
- FWCI
- 7.24
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Brain Behavior and Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000124)
- National Institute on Aging (R01AG026364, R01AG034588, P30AG028748, K01AG028404)
- National Cancer Institute (R01CA160245)
- National Center for Advancing Translational Sciences
- Topics
- Social Sciences › Psychology › Clinical Psychology › Grief, Bereavement, and Mental Health
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Social Sciences › Anthropology › Death, Funerary Practices, and Mourning
- Keywords
- bereavement, grief, complicated grief, systemic inflammation, inflammatory cytokines, gene-environment interaction, single nucleotide polymorphisms, interleukin-6, IL-1β, TNF-α, interleukin-1 receptor antagonist, soluble TNF receptor 2, older adults, widowhood
- MeSH terms
- Aged, Aged, 80 and over, Demography, DNA, Female, Genotype, Grief, Humans, Inflammation, Male, Middle Aged, Tumor Necrosis Factor-alpha, Interleukin-6, Body Mass Index, DNA Primers, Polymorphism, Single Nucleotide, Receptors, Tumor Necrosis Factor, Type II, Receptors, Interleukin-1 Type I, Interleukin-1beta, Gene-Environment Interaction
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