Researchers identify key proteins and pathways that link social relationships to cardiovascular disease, stroke and mortality, paving the way for targeted interventions.
Study: Plasma proteomic signatures of social isolation and loneliness associated with morbidity and mortality. Image credits: David Michael Bellis/Shutterstock.com
From a recent study published in Nature Human behaviora group of researchers examined the proteomic signatures that link social relationships, specifically social isolation and loneliness, to health outcomes and mortality.
Background
Social relationships are essential for well-being and survival, but social isolation and loneliness are associated with significant health risks, including morbidity and mortality, similar to smoking and obesity.
These effects are mediated by mechanisms such as inflammation, antiviral responses, and dysregulation of the sympathetic nervous and hypothalamic-pituitary-adrenal systems.
Proteins, as functional components of biological processes and important drug targets, hold promise in explaining these links. Emerging evidence suggests that proteomic changes may mediate the health effects of social relationships.
Further research is needed to identify specific proteins and pathways to improve disease prediction, prevention and intervention strategies.
About the study
The United Kingdom (UK) Biobank cohort consists of over 500,000 participants aged 40-69 years, recruited from 22 centers in Great Britain between 2006 and 2010. Participants provided comprehensive data including genome-wide genotyping, magnetic resonance imaging , electronic medical records, and blood and urine biomarkers.
Ethical approval was obtained from the National Information Governance Board for Health and Social Care and the North West Multi-Centre Research Ethics Committee. Social isolation and loneliness were assessed using validated scales.
Social isolation was defined based on living situation, frequency of social contacts and participation in activities, while loneliness was assessed by feelings of loneliness and frequency of confiding in close others.
Proteomic profiling was performed on plasma samples from 53,026 participants using Olink Explore assays, yielding data on 2,920 proteins after stringent quality control. Genotyping was performed on 487,409 participants using rigorous methods to ensure high quality data, with 9,910,057 Single-Nucleotide Polymorphisms (SNPs) and 337,138 participants retained after quality control.
Structural Magnetic Resonance Imaging (MRI) data and blood biomarkers provided additional phenotypic endpoints.
Health outcomes were assessed through linked health records, focusing on cardiovascular disease (CVD), dementia, type 2 diabetes (T2D), depression and stroke. Covariates included demographic, behavioral, and physiological factors.
Statistical analyzes included proteomic and genomic data, where associations, co-expression networks and potential causal relationships were identified using Mendelian randomization and mediation models.
Study results
The primary study population consisted of 42,062 participants from the UK Biobank, with a mean age of 56.4 years (±8.2), and 52.3% were female. These individuals had quality-controlled proteomic data and extensive behavioral data, including measures of social isolation, loneliness, and all relevant covariates.
Among them, 9.3% (3,905 participants) reported being socially isolated, while 6.4% (2,689 participants) felt lonely.
During a median follow-up of 13.7 years (±2.1), ending November 2022, there were 2,695 cases of CVD, 892 cases of dementia, 1,703 cases of T2D, 1,521 cases of depression, 983 cases of stroke and 4,255 deaths.
Proteome-wide association studies (PWASs) of 2,920 plasma proteins revealed that 776 proteins are significantly associated with social isolation and 519 proteins related to loneliness in models adjusted for age, gender, location, technical factors, and principal genetic components.
After additional adjustments for ethnicity, education level, household income, smoking, alcohol consumption and body mass index, 175 proteins remained significantly associated with social isolation and 26 proteins with loneliness at the Bonferroni-corrected threshold.
Key findings included the strong association of growth differentiation factor 15 (GDF15) with social isolation and proprotein convertase subtilisin/kexin type 9 (PCSK9) with loneliness.
Notably, most identified proteins were positively associated with social isolation and loneliness, while a few, such as CXC motif chemokine ligand-14 (CXCL14), emerged as protective factors.
Shared proteomic patterns were observed, with 22 proteins common to both social isolation and loneliness. Protein-protein interaction networks revealed significant interactions between identified proteins, especially in immune pathways and complement systems.
Further analyzes highlighted the causal links between loneliness and five proteins, including adrenomedullin (ADM) and asialoglycoprotein receptor 1 (ASGR1), supported by Mendelian randomization and colocalization analyses.
These proteins were significantly associated with several health outcomes, including cardiovascular disease, stroke and mortality. Mediation analyzes have shown that ADM specifically mediates the relationship between loneliness and multiple diseases, including cardiovascular disease, dementia and mortality.
Conclusions
In summary, using data from 2,920 plasma proteins from over 40,000 UK Biobank participants, this study identified proteins and networks associated with these social constructs.
Many proteins were associated with inflammation, antiviral responses and complement systems, with more than half prospectively associated with CVD, T2D, stroke and mortality over 14 years of follow-up.
Mendelian randomization analyzes suggested that loneliness had a causal influence on five proteins, with ADM and ASGR1 further validated by colocalization. These proteins also mediated the relationships between loneliness and important health outcomes, underscoring their biological relevance.