Immunological and Lipid Metabolic Markers of Aggression
Abstract
Background: Aggression and violence are complex behavioral phenomena with substantial biological underpinnings involving immune activation and lipid metabolism. Previous evidence has linked inflammatory signaling and altered cholesterol homeostasis to impulsive and antisocial behaviors. The present exploratory study investigated differential gene expression patterns associated with severe violent offending and their relationship with aggression-related phenotypes. Methods: Whole-blood samples from 19 male severe violent offenders and 11 healthy controls were analyzed using Clariom S gene expression arrays followed by qPCR validation. Participants additionally completed psychometric assessments including the State Trait Anger Expression Inventory-II (STAXI-II), the Psychopathic Personality Inventory-Revised (PPI-R), and the Appetitive and Facilitative Aggression Scale (AFAS). Results: Differential expression analysis identified 833 significantly dysregulated genes (FDR < 0.1; fold change ≥ 1.5) in violent offenders relative to controls. Among the most strongly altered genes were IL1B, TLR4, PTGS2 (COX-2), ABCA1, IL6R, PRF1, and MMP9. qPCR validation confirmed significant upregulation of MMP9, PTGS2, IL6R, and PRF1. Gene x behavior analyses demonstrated significant associations between PTGS2 expression and reactive as well as outwardly directed aggression, while MMP9 expression correlated with psychopathy-related traits. Furthermore, several lipid metabolism-related genes, including ABCA1, ABCG1, NPC1, DGAT2, and TLR4, showed expression patterns suggestive of altered intracellular lipid trafficking and lysosomal lipid accumulation. ABCA1 expression correlated positively with outward anger expression (STAXI-II), whereas ABCG1 and TLR4 were negatively associated with inwardly expressed anger (STAXI-II). Conclusions: These findings support a model in which innate immune activation and dysregulated lipid metabolism contribute to aggression-related phenotypes and severe violent behavior. Although exploratory and limited by sample size, the results highlight potential molecular pathways underlying pathological aggression and warrant further investigation in larger cohorts.