AKT1 but not AKT2 single nucleotide polymorphisms are associated with the risk of microscopic polyangiitis

Microscopic polyangiitis (MPA), a severe antineutrophil cytoplasmic antibody associated vasculitis (ANCA-associated vasculitis, AAV), demonstrates strong clinical association with myeloperoxidase/perinuclear anti-neutrophilic cytoplasmic antibodies (MPO/P-ANCA). While genetic factors are known to contribute to MPA susceptibility, the potential roles of AKT signaling components remain incompletely characterized, with limited data available for AKT1 and even less for its homologous gene AKT2 in this specific disease context.

This case-control analysis included 798 participants (202 MPA patients and 596 controls, the latter comprising 387 individuals from the 1,000 Genomes Project), with control groups pooled after confirmation of genetic homogeneity. Genotypes of seven single-nucleotidepolymorphisms (SNPs) (four in AKT1, three in AKT2) with divergent allele frequencies across populations were analyzed. Association analyses were conducted under multiple genetic models, with gene-level and set-based approaches employed to evaluate aggregate effects. Secondary analyses included haplotype reconstruction, SNP-SNP interaction testing, and functional characterization through expression quantitative trait locus (eQTL) mapping.

Specific AKT1 variants (rs2498786 and rs1130233) demonstrated significant associations with reduced MPA risk, particularly in P-ANCA-positive patients. Gene-level analyses revealed a strong association for the AKT1 gene set (OR = 0.884, P = 0.002) but not for AKT2. Haplotype analysis identified protective AKT1 haplotypes, while interaction testing revealed high-risk genotype combinations. eQTL analysis indicated that protective alleles correlate with enhanced AKT1 expression in immune-relevant tissues, suggesting a potential regulatory mechanism.

AKT1 emerges from this study as a likely genetic contributor to MPA, with its influence potentially involving neutrophil regulatory functions and vascular maintenance. The consistent absence of association signals for AKT2 across all analytical approaches could be viewed as reinforcing the specificity of AKT1's involvement. These insights help refine the genetic architecture of MPA and position AKT1 signaling as a candidate pathway for future therapeutic exploration.