Background/Purpose: The complement alternative pathway (AP) plays an important role in ANCA-associated vasculitis (AAV), but the role of complement genetic risk in AAV is incompletely understood. Multiple genetic variants encoding a range of protein functional activities in complement pathways lead to different set points for complement activation and influence the risk of complement-mediated tissue damage in other inflammatory conditions. This study sought to determine if co-inherited genetic variation in three complement factors, C3, complement factor B (CFB), and complement factor H (CFH), with two forms of AAV: granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). In the AP, C3 and CFB are activation proteins, while CFH is a negative regulator. The hypothesis was that higher genetically-defined complement activity, based on combinations of three genetic variants (“complotypes”), would be associated with an increased risk for AAV.

Methods: This was a retrospective case-control study utilizing data from a large, international genome wide association study of patients with AAV and healthy controls. Genotyping was performed using Affymetrix Axiom Biobank 1 Genotyping Array, which measures rs2230199 (C3 R102G) directly and passed quality control measures. Imputation was performed using the TOPMed imputation server for rs641153 (CFB R32Q) and rs800292 (CFH V62I). To determine the associations between inherited variants in complement and AAV, cases were categorized based on established patterns of complement activity (Table 1). The C3-CFB-CFH complotype was modeled as a continuous variable with an additive effect, which assumes each change in category leads to a stepwise increase in complement activity. A secondary analysis modeled the effect categorically, comparing each group to the lowest activity complotype. Also assessed were the associations between complotype and AAV, AAV disease subtypes (GPA, MPA), and ANCA specificity (anti-PR3+, anti-MPO+) as compared to disease-free controls. For AAV, associations between complotype and lung or kidney disease were also evaluated. Logistic regression models adjusted for age, sex, and genetic similarity.

Results: Data from 2038 patients with AAV and 3814 controls were available (Table 1). A higher-activity complotype increased risk for AAV with an 8% increase in odds of AAV for each step-wise increase in complement activity (Figure 1, p = 0.006). Comparing across complotype activity categories, a possible dose response was observed. The highest activity complotype had a 61% higher odds of AAV compared to the lowest activity complotype (p = 0.008). A similar magnitude of association was seen across AAV subtypes and antibody-positive disease; this was statistically significant for GPA, PR3+ AAV, and MPO+ AAV (Figure 2). There was no association of complotype with prevalent lung involvement or renal involvement using the additive models (Figure 2).

Conclusion: Genetic variation in C3, CFB, and CFH that increases complement activity is associated with higher risk for AAV, emphasizing a potential pathophysiologic role of this complotype in AAV.

Table 1. Demographics, Disease Characteristics, and Complotype for Patients in the Study Cohort

Figure 1. Association of C3-CFB-CFH Complotype with ANCA-Associated Vasculitis.

Increased complement activity in the C3-CFB-CFH complotype was associated with increased odds of ANCA-associated vasculitis. By complotype activity, this effect was statistically significant comparing the lowest activity complotype to the two highest activity complotypes, where those with the highest activity complotype had 61% higher odds of vasculitis compared to those with the lowest activity complotype. Associations were tested using logistic regression, adjusted for age, sex, and 10 principal components of population structure.

Figure 2. Association of C3-CFB-CFH Complotype with Disease Subtypes, ANCA Types, and Clinical Manifestations of ANCA-Associated Vasculitis.

Increasing complement activity in the C3-CFB-CFH complotype was associated with increased odds for granulomatosis with polyangiitis (GPA), anti-proteinase-positivity (PR3+), and anti-myeloperoxidase-positivity (MPO+) compared to healthy controls, but was not associated with microscopic polyangiitis (MPA). Among those with ANCA-associated vasculitis, there were no associations with prevalent lung or renal involvement. Associations were tested using logistic regression, adjusted for age, sex, and 10 principal components of population structure.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/association-of-increasing-genetically-mediated-complement-activity-with-anca-associated-vasculitis/