Unravelling the role of inflammatory markers in coronary artery disease risk via association, mediation and prediction analyses.

BACKGROUND

Systemic inflammation plays a critical role in coronary artery disease (CAD), yet comprehensive profiling of inflammatory markers and their integration into predictive models remain incompletely characterised. We here sought to identify key CAD-related inflammation markers and construct an integrated inflammatory risk score (IRS) to enhance conventional cardiovascular risk prediction.

METHODS

Associations between 18 complete blood count based inflammatory markers and incident CAD were assessed among 475 134 UK Biobank participants free of CAD at baseline. Weighted quantile sum (WQS) regression evaluated the relative directional contributions of individual markers, and mediation analysis further examined the role of inflammation in linking accelerated aging and unhealthy lifestyle factors to CAD. Predictive performance was assessed by comparing IRS-augmented models in terms of AUC (area under the receiver operating characteristic curve), net reclassification improvement (NRI), and decision curve analysis.

RESULTS

All analysed inflammatory markers showed statistically significant associations with CAD risk, although effect sizes varied. Monocyte-to-HDL-C ratio (MHR), neutrophil-to-HDL-C ratio (NHR), and systemic inflammation response index (SIRI) exhibited the strongest positive associations (21-41% increased risk per SD), while platelet-to-lymphocyte ratio (PLR) and platelet-to-leukocyte ratio (PWR) demonstrated modest inverse associations (5-13% decreased risk). Several markers (e.g. MHR, PLR, PWR) displayed discernible group-level differences over a decade before CAD onset. WQS regression highlighted heterogeneous, direction-specific contributions of these markers to CAD risk. Mediation analysis suggested that a portion of the observed associations may operate through accelerated aging (mediation proportion = 7-43%) or via inflammation in the link between unhealthy lifestyle and CAD. The integrated IRS modestly improved CAD risk prediction, particularly within the short-term window of 0 - 5 years (absolute increase in AUC (ΔAUC) = 2.7%, NRI = 1.6%; net benefit = 5%).

CONCLUSIONS

Inflammatory markers captured by routine test were consistently associated with future CAD, suggesting that part of CAD risk is reflected in low-cost hematologic parameters. An integrated IRS showed modest but statistically significant improvement in risk discrimination, but external validation and clinical impact studies are needed before implementation.