In patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), sex-dependent, genetically distinct subgroups have been identified, according to a study published in the journal Rheumatology.
AAV comprises 3 rare disorders: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic GPA. AAVs, which are clinically heterogeneous, present with a myriad of symptoms that can vary from mild to life-threatening organ failure. Based on large-scale genetic analyses, disease susceptibility loci linked to the presence of 1 of 2 autoantibodies in patients with GPA and MPA have been identified: (1) proteinase 3 (PR3)-ANCA (HLA-DP, SERPINA1, PRTN3) and (2) myeloperoxidase (MPO)-ANCA (HLA-DQ, BACH2).
The researchers sought to genetically describe subgroups of patients with GPA and MPA in terms of their ANCA subtype and sex. They used a previously established single nucleotide polymorphism genotyping data set of 1088 Scandinavian patients with AAV and 1589 controls, merging their key findings with clinical data regarding disease manifestations.
All patients who had been clinically diagnosed with GPA or MPA were recruited from rheumatology or nephrology units at hospitals in 10 cities located in Denmark, Norway, or Sweden. Healthy controls included blood donors or population controls from Norway or Sweden.
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In terms of genetic analyses, DNA samples of cases in the discovery cohort, as well as controls from both the discovery and the replication cohorts, underwent liquid capture and the sequencing of exons/conserved regions of 1853 immune-related genes. Following quality control, 588 ANCA-positive cases and 999 controls were available for analysis in the discovery cohort, whereas 500 ANCA-positive cases and 590 controls were available for analysis in the replication cohort.
All cases and controls were evaluated for an association with 5 key AAV single nucleotide polymorphisms. In fact, rs9274619—a lead variant at the HLA-DQB1/HLA-DQA2 locus that had been previously linked with being AAV positive for MPO-ANCA—was examined for its association with cumulative disease involvement of 10 distinct organ systems.
Results of the study demonstrated that the rs9274619 variant exhibited a statistically significantly stronger association to MPO-ANCA-positive females than males (odds ratio [OR], 2.3; 95% CI, 1.5-3.5; P =2.0 x 10–4). In contrast, PR3-ANCA-associated variants rs1042335, rs9277341 (HLA-DPB1/A1), and rs28929474 (SERPINA1) were distributed equally among both males and females with PR3-ANCA.
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Among participants with MPO-ANCA-positive AAV, carriers of the rs9274619 risk allele were significantly more susceptible to disease of the eyes (OR, 11; 95% CI, 2.2-205; P =.021) and significantly less predisposed to lung involvement (OR, 0.52; 95% CI, 0.30-0.92; P =.026).
Further, AAV that exhibited both MPO-ANCA and PR3-ANCA was significantly associated with the PR3-ANCA lead single nucleotide polymorphism rs1042335 (OR, 0.091; 95% CI, 0.0022-0.55; P =.0015) but not with rs9274619.
“Specifically, our results suggest sex-dependent genetically distinct subgroups of patients within MPO-ANCA+AAV,” the authors indicated. “In addition, patients positive for both PR3- and MPO-ANCA are more likely to share characteristics with PR3-ANCA+ patients,” they concluded.
Ekman D, Sennblad B, Knight A, et al. Stratified genetic analysis reveals sex differences in MPO-ANCA-associated vasculitis. Rheumatology. Published online April 2, 2023. doi:10.1093/rheumatology/kead152