Impact of Infection-Related Immune Responses on ANCA-Associated Vasculitis in Finns: A Mendelian Randomization Study.

BACKGROUND: ANCA-associated vasculitis (AAV) includes microscopic polyarteritis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA). Studies have revealed that infection-related immune responses could trigger vasculitis. This study aims to investigate the relationship between infection-related immune responses and AAV in Finns. METHODS: We used multiple Mendelian randomization (MR) methods and bioinformatics to examine how infection-related immune responses affect AAV, also investigating the mediation effects of neutrophil extracellular traps (NETs) and aging phenotypes. Bioinformatics data were from the Gene Expression Omnibus (GEO) database. Serum-specific antibodies were from the U.K. Biobank. AAV subtypes were from FinnGen. Single-cell sequencing data of immune cells were from the OneK1K database. NETs and aging phenotypes were from the genome-wide association studies (GWAS). RESULTS: This study found a preliminary negative correlation between anti-IgG of HSV1 and the risk of MPA (OR: 0.499, 95% CI: 0.361-0.692, p = 3.05E-05). The SCeQTL analysis revealed that several genes in immune cells were linked to anti-IgG of HSV1 and MPA, while mediation analysis highlighted DNA methylation Hannum age acceleration (DNAmAA) as a key mediator between gene expression and MPA. HLA-C expression in CD8nc T cells (Z = -2.921, p = 0.003, mediation effect = 82.2%) and MDC1 in dendritic cells (Z = -3.310, p = 0.001, mediation effect = 81.5%) lowered the risk of MPA by downregulating DNAmAA. Conversely, MICA expression in NKR NK cells (Z = 3.702, p < 0.001, mediation effect = 72.1%) was associated with an increased risk of MPA by upregulating DNAmAA. CONCLUSIONS: This study demonstrated potential correlations between infection-related immune responses and MPA. The SCeQTL analysis revealed that HLA-C expression in CD8nc T cells, MDC1 in dendritic cells, and MICA expression in NKR cells were related to the risk of MPA. Furthermore, mediation analysis indicated that DNAmAA exerted a strong mediation effect on the relationship between gene expression and MPA.