Differential associations between relationship stressors and natural killer cell gene expression by race/ethnicity and sex among older U.S. adults

Abstract

Close interpersonal relationships can shape health, in part, through immune-related biological pathways. While chronic relational stress has been linked to inflammation and immune dysregulation, little is known about how such stressors relate to transcriptional markers of innate immune activity. As such, we investigated whether multiple forms of relationship stress were associated with altered expression of two genes related to natural killer cell function, FCGR3A and NCAM1, and whether these associations varied by sex or race/ethnicity. Data were drawn from the Midlife in the United States study, a population-based sample of midlife adults (n = 1,215) who provided whole-transcriptome RNA sequencing data and completed validated relationship stress measures. Covariate-adjusted linear mixed effects models, which included random intercepts for study site, quantified the associations of each stress domain z-score with log2(FCGR3A) and log2(NCAM1), and tested for moderation by sex and race/ethnicity. While males maintained relatively stable expression across stress domains, females showed significant positive associations between FCGR3A expression and both marital risk and spouse/partner strain. For participants in the non-Hispanic Other group, higher friend and cumulative strain was significantly associated with elevated FCGR3A expression. This group also exhibited significant NCAM1 upregulation in response to family, friend, and cumulative strain. In contrast, Hispanic participants showed a non-significant trend toward NCAM1 downregulation under relationship strain, but not significant changes in FCGR3A. These findings suggest that relationship stress may be differentially biologically embedded through changes in innate immune gene expression across demographic groups, highlighting the importance of social context in shaping transcriptional markers of immune function. Further research is needed to clarify whether these patterns confer adaptive immune readiness or contribute to long-term immune dysregulation.

Keywords: Biological dysregulation; Biological stress; CTRA; Epigenetics; Internalizing; Lifestyle genomics; Middle-aged; Psychoneuroimmunology; Psychosocial stressors; Social genomics.