Inflammation-Mediated Lipid Metabolism in Endocrine Autoimmune Diseases: A Genetic Distance-Based PRS Approach Integrating HLA Region

<b>Background</b>: Endocrine autoimmune diseases (AIDs) exhibit special polygenic characteristics in human leucocyte antigen (HLA) region. Current understanding of their association with lipid metabolism remains constrained by imprecise polygenic risk score (PRS) modeling. Advanced analytical approaches are needed to elucidate the association between genetic susceptibility and lipid metabolic dysregulation. <b>Methods</b>: We proposed a genetic distance-based clumping gPRS to account for linkage disequilibrium in the HLA region. gPRS and pathway gPRS were constructed for individuals diagnosed with type I diabetes (T1D), Graves' disease (GD), Hashimoto thyroiditis (HT) and Addison's disease (AD) in the UK Biobank, with sex considered as a stratification factor. Latent correlations between gPRS and phenotypes were explored using Kendall's tau test, two-trait LD score regression (LDSC) and gene annotation. <b>Results</b>: Lipid metabolism served an important function through immune and inflammatory biomarkers across multiple traits. Males with low genetic risk tended to have lower high-density lipoprotein cholesterol level, while the correlation presented the opposite pattern in females. Increased genetic susceptibility to AIDs was associated with elevated levels of low-density lipoprotein cholesterol, triglycerides in low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) across all traits. Moreover, levels of polyunsaturated fatty acids, including omega-3 and omega-6, decreased with higher PRS in males and females, while those of monounsaturated fatty acids exhibited an increasing trend. <b>Conclusion</b>: Our study constructed more precise polygenic risk scores of AIDs, highlighting inflammation-mediated lipid metabolism as a potential pathogenic mechanism in endocrine AIDs, offering valuable insights into shared etiology for future comprehensive investigations.