(513) Plasma PKD2 regulates immune cell phenotypes in age-related hearing loss

Introduction: Age-related hearing loss (ARHL) is a highly prevalent degenerative condition with emerging evidence implicating immune dysregulation in cochlear pathology. This study investigated whether genetically regulated plasma proteins causally influence ARHL risk through modulation of immune cell phenotypes.

Methods: We conducted a multi-cohort genetic causal analysis using publicly available genome-wide association study (GWAS) data for plasma proteins, immune cell phenotypes, and ARHL in approximately 200,000 individuals. Robust Mendelian randomization and mediation frameworks were applied to estimate causal relationships and pathway effects. Associations between PKD2 expression and immune cell infiltration were further evaluated using established computational tools.

Results: Eight plasma proteins and nine immune cell phenotypes showed significant associations with ARHL. PKD2 emerged as the only plasma protein that passed reverse-causality testing, demonstrating a significant inverse total effect on ARHL risk (α_total = −2.4800).
Mediation analysis indicated that monocytic myeloid-derived suppressor cells (M-MDSCs) partially mediated the PKD2–ARHL relationship (α_mediated = −0.0347, 95% CI: −0.203 to 0.134), accounting for approximately 10.2% of the total causal effect. TIMER analyses revealed a significant negative correlation between PKD2 expression and monocyte infiltration in ARHL cases (p < 0.05). Moreover, individuals harboring functional PKD2 variants exhibited significantly increased M-MDSC infiltration (p < 0.05), suggesting that PKD2 deficiency may promote an immunosuppressive microenvironment

Conclusions: Plasma PKD2 identifies a genetically supported immunomodulatory target for age-related hearing loss. Using multi-source human genetic data, we demonstrate that PKD2 exerts a protective effect on ARHL, partially mediated by suppression of M-MDSC infiltration and maintenance of inner-ear immune homeostasis. These findings provide genetic evidence supporting PKD2 as a candidate target for immune- and protein-based therapeutic strategies in ARHL.