IgD‐CD38‐B Cell Partially Mediates the Protective Effect of Higher Serum Triacylglycerol (53:4) Levels Against Parkinson's Disease

ABSTRACT Emerging evidence suggests that dysregulated lipid metabolism contributes to Parkinson's disease (PD) risk, with chronic inflammation in the central nervous system (CNS) also playing a pivotal role. Although correlations between inflammatory responses, serum lipid metabolism, and PD risk are established, a causal relationship remains unclear. Building on previous findings linking higher serum triacylglycerol (51:4) levels to reduced PD risk, this study explores the potential causal associations between 38 triacylglycerol isoforms and PD risk using Mendelian randomization (MR). We utilized summary‐level data from genome‐wide association studies (GWAS) on PD, circulating immune cells, inflammatory proteins, and serum lipidomes—including 38 triacylglycerol isoforms, 15 sterol ester isoforms, and 46 phosphatidylcholine isoforms—to assess the relationship between serum lipid profiles and PD. Our analysis revealed that higher levels of serum triacylglycerol (51:4) and triacylglycerol (53:4) were associated with a reduced PD risk, whereas lower levels of phosphatidylcholine (17:0_18:1) and sterol ester (27:1/20:2) were linked to higher PD risk. Notably, multivariable MR analysis confirmed a robust causal association between increased serum triacylglycerol (53:4) and a 24% reduction in PD risk (1 SD higher triacylglycerol (53:4) leading to a 24% [95% CI, 0.54–0.97] risk reduction, p = 0.005). Mediation analysis suggested that circulating immune cells, rather than inflammatory proteins, may mediate the relationship between triacylglycerol (53:4) levels and PD risk. These findings establish a causal link between triacylglycerol (53:4) and PD risk, highlighting the potential role of immune modulation in PD pathogenesis. image