# Allostatic load elevates the risk and adverse prognosis of immune-mediated inflammatory diseases: modulatory effects of lifestyle interventions and genetic susceptibility

## TL;DR

High stress levels increase the risk and worsen outcomes of immune diseases, but lifestyle changes and genetics play a role in this relationship.

## Contribution

This study identifies a stress-gene synergy and shows lifestyle factors can partially offset stress-related immune disease risks.

## Key findings

- High allostatic load significantly increases the risk of multiple immune-mediated diseases.
- Physical activity and ω-3 intake reduce some risks linked to high stress levels.
- Genetic susceptibility amplifies the effects of stress on specific immune diseases.

## Abstract

•Allostatic load (AL) elevates immune‑mediated inflammatory disease (IMID) risk.•Physical activity and ω‑3 intake partially offset AL‑linked immune disease risks.•Stress‑gene synergy identified: polygenic scores amplify AL effects on IMIDs.

Allostatic load (AL) elevates immune‑mediated inflammatory disease (IMID) risk.

Physical activity and ω‑3 intake partially offset AL‑linked immune disease risks.

Stress‑gene synergy identified: polygenic scores amplify AL effects on IMIDs.

Allostatic load (AL)—the cumulative biological cost of lifelong stress—can disrupt immune homeostasis via hypothalamic–pituitary–adrenal-axis dysregulation and persistent sympathetic activation. Immune-mediated inflammatory diseases (IMIDs) are organ-specific chronic inflammatory disorders imposing a major public-health burden, yet their causal link with AL remains unclear.

In this prospective study of 186 310 UK Biobank participants, Cox proportional-hazards models quantified dose-response associations between AL and the incidence of ten IMIDs plus all-cause mortality. Interaction models evaluated the modifying effects of physical activity, ω-3 polyunsaturated fatty acids (ω-3 PUFAs) and other lifestyle variables, and assessed gene–environment interplay using polygenic risk scores (PRS).

Compared with the lowest AL quartile, the highest quartile showed significantly greater incidence of rheumatoid arthritis (hazard ratios (HR) = 1.52), spondyloarthritis (HR = 2.50), asthma (HR = 1.38), inflammatory bowel disease (IBD) (HR = 1.19), type 1 diabetes (T1DM) (HR = 5.16), psoriasis (HR = 1.87), autoimmune retinopathy (HR = 1.77) and composite IMIDs (HR = 1.55) (all p < 0.05). Elevated AL also predicted dose-dependent increases in all-cause mortality among patients with rheumatoid arthritis (HR = 6.59), asthma (HR = 1.87), IBD (HR = 2.00), T1DM (HR = 2.72) and composite IMIDs (HR = 2.01). Sufficient physical activity and higher ω-3 PUFA intake partially attenuated AL-related risks, whereas high PRS synergistically amplified AL effects for spondyloarthritis (attributable proportion (AP) = 7.6%), T1DM (AP = 4.7%) and psoriasis (AP = 4.9%).

AL is causally linked to both the development and prognosis of IMIDs, with its impact jointly modifiable by lifestyle factors and genetic susceptibility. Building AL-centred psychoneuroimmunological biomarker networks may enable refined risk stratification and precision interventions for IMIDs.