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

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.