Immune Cells and Polymyalgia Rheumatica: Insights from a Bidirectional Mendelian Randomization Analysis.

INTRODUCTION: Polymyalgia Rheumatica (PMR) is an inflammatory disease of older adults in which immune dysregulation is thought to play a central role. However, the specific circulating immune cell phenotypes linked to PMR remain incompletely defined. METHODS: We performed a two-sample, bidirectional Mendelian Randomization (MR) study using Genome-Wide Association Study (GWAS) summary statistics from European- ancestry cohorts. In total, 731 immune cell traits were analyzed. Forward MR assessed associations between genetic liability to PMR and immune phenotypes, and reverse MR tested whether genetically proxied immune traits were associated with PMR liability. Multiple MR estimators and sensitivity analyses were used to explore heterogeneity and horizontal pleiotropy. RESULTS: Forward MR identified ten immune cell traits consistently associated with PMR genetic liability, mainly involving B cells, plasmacytoid dendritic cells, monocytes, and T/NK-cell subsets. These findings suggest a heterogeneous pattern of immune perturbations linked to PMR susceptibility. In contrast, reverse MR did not provide robust evidence that genetically proxied immune traits were associated with PMR liability, likely reflecting limited statistical power for modest effects. DISCUSSION: These results suggest that immune cell diversity plays a key role in PMR susceptibility. Understanding these distinct genetic associations may facilitate future biomarker discovery and personalized therapeutic strategies. CONCLUSION: Our research enriches the genetic insights into the intricate interactions between ten immune cell traits and PMR, thus shaping the course of forthcoming clinical and foundational research endeavors.