# Proteomics signature of moderate-to-vigorous physical activity and risk of multimorbidity of cancer and cardiometabolic diseases

## TL;DR

This study finds blood proteins linked to physical activity that are associated with lower risks of cancer, heart disease, diabetes, and having multiple chronic diseases.

## Contribution

Identifies a proteomic signature of physical activity and links it to reduced disease risks through specific proteins.

## Key findings

- 220 proteins are associated with moderate-to-vigorous physical activity after multiple testing corrections.
- Proteins related to metabolism and immune function are linked to disease risks and physical activity.
- The proteomic signature score is inversely associated with cancer and T2D risks but not multimorbidity.

## Abstract

Moderate-to-vigorous physical activity (MVPA) is inversely associated with risks of cancer, cardiovascular diseases (CVD), type 2 diabetes (T2D), and their co-occurrence, defined as multimorbidity; however, the underlying biological pathways remain unclear.

In 33,806 UK Biobank participants with 2911 measured blood proteins, a proteomic signature of MVPA was derived with linear and LASSO regressions. Multivariable Cox models, adjusted for MVPA, estimated prospective associations with cancer, CVD, T2D, and multimorbidity.

We show that after multiple testing corrections, 220 proteins are retained in the MVPA signature. Proteins related to food intake, metabolism, and cell growth (e.g., LEP, MSTN) are inversely associated, while those involved in immune cell migration and musculoskeletal integrity (e.g., integrins, COMP) are positively associated with MVPA. Several proteins positively associated with MVPA are inversely associated with disease risk (e.g., integrins, CLEC4A for cancer; LPL, LEP for T2D), while proteins negatively associated with MVPA are positively associated with disease risk (e.g., CD38, TGFA for CVD). The proteomic signature score is inversely associated with cancer risk (hazard ratio per interquartile range: 0.87; 95% confidence interval: 0.78, 0.96) and T2D (0.66; 0.60, 0.72). For multimorbidity, proteins inversely related to MVPA align with expected risk patterns (e.g., GGT1, HR: 1.32; 95% CI: 1.12, 1.57), but the proteomic signature score is not associated.

This study identifies several proteins associated with MVPA that are also associated with cancer, CVD, T2D, and the multimorbidity of these conditions. Further studies investigating the causal nature of these associations are welcome.

Many people develop more than one long-term disease, such as cancer, heart disease, or diabetes, a condition known as multimorbidity. While regular physical activity is known to reduce the risk of these diseases, the underlying biological pathways remain poorly understood. In this study, we analyzed thousands of proteins in the blood of over 33,000 adults participating in UK Biobank, a large health study, to identify proteins linked with higher levels of physical activity. We discovered several proteins that were either more or less common in active individuals – and these same proteins were also associated with a lower risk of developing cancer, heart disease, diabetes, and multimorbidity. These findings suggest that physically activity may help prevent multiple diseases by influencing proteins in the blood. This opens new possibilities for research into how physical activity supports long-term health.

Stein et al. identify circulating blood proteins linked to regular moderate-to-vigorous physical activity in over 33,000 UK Biobank participants. Many of these proteins are associated with lower risk of cancer, cardiovascular disease, type 2 diabetes, and multimorbidity, highlighting molecular links between activity and health.