Background/Purpose: Although sinonasal involvement is common in ANCA-associated vasculitis (AAV), the mechanisms underlying this higher burden of sinonasal inflammation remain unclear. Whether genetic susceptibility to sinonasal disease contributes to risk of AAV is unknown. We hypothesized that higher polygenic risk for nasal polyps would be associated with increased risk of AAV.

Methods: Using FinnGen genome-wide association summary statistics, we calculated a polygenic risk score for nasal polyps (NP-PRS) in two independent cohorts: the United Kingdom Biobank (UKB) and the All of Us Research Program (AoU). AAV was defined via diagnostic codes (ICD-9: 446.4; ICD-10: M30.1, M31.3, M31.7) or self-report in UKB. Individuals with other vasculitis phenotypes were excluded from the control group.

The association between the NP-PRS and AAV was evaluated using logistic regression for prevalent AAV and Cox proportional hazards models (time-to-event for incident AAV, excluding prevalent baseline cases, from the date of enrollment in UKB or AoU). All models were adjusted for age, sex, the first five genetic principal components, and genotyping array in UKB. Predictive discrimination was assessed using the area under the receiver-operating characteristic curve (AUC) and C-index with 100-iteration bootstrap optimism correction.

Results: The study compared 214 AAV cases (102 incident; mean age 59, 45% female) with 374,601 controls (mean age 57, 54% female) in UKB. Similarly, 320 AAV cases (63 incident; mean age 57, 66% female) were compared with 309,358 controls (mean age 52, 61% female) in AoU. In both cohorts, NP-PRS distributions were shifted upward among AAV cases relative to controls (Fig. 1). A 1-standard deviation (SD) increase in the NP-PRS was associated with higher odds of AAV in UKB (Fig. 2, OR 1.21, 95% CI 1.06-1.39) and AoU (Fig. 2, OR 1.18, 95% CI 1.05-1.32). In time-to-event analysis, a 1-SD increase in the NP-PRS was associated with an increased hazard of incident AAV in UKB (Figs. 2 & 3, HR 1.38, 95% CI 1.14-1.67) and AoU (Figs. 2 & 3, HR 1.47, 95% CI 1.14-1.90). After applying bootstrap optimism correction, discrimination was modest for prevalent AAV, yielding AUCs of 0.60 in UKB and 0.63 in AoU. For incident AAV, optimism-corrected C-indices were 0.62 and 0.64, respectively.

Conclusion: Higher polygenic risk for nasal polyps associated with AAV in two independent population-based biobanks. These findings suggest a shared genetic susceptibility between localized sinonasal inflammatory disease and AAV. Although predictive performance was modest, this study provides preliminary evidence that upper airway inflammatory biology may partially overlap with the pathways involved in systemic autoimmunity and AAV pathogenesis.

Figure 1. Distribution of the Nasal Polyps-Polygenic Risk Score in the United Kingdom Biobank and All of Us Research Program. Nasal polyps polygenic risk score distributions were shifted upward among ANCA-associated vasculitis cases relative to controls in both cohorts. Black diamonds denote the mean.

Figure 2. Association of the Nasal-Polyps Polygenic Risk Score (NP-PRS) with ANCA-Associated Vasculitis. In both the United Kingdom Biobank and All of Us Program, a 1-SD increase in the NP-PRS was associated with increased odds of prevalent AAV and an increased hazard of incident AAV.

Figure 3. Time-to-Diagnosis of Incident ANCA-Associated Vasculitis (AAV) by Nasal Polyps-Polygenic Risk Score (NP-PRS). A higher NP-PRS was associated with an increased hazard of incident AAV in both the United Kingdom Biobank and All of Us Program. High and low NP-PRS groups were dichotomized at the median score.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/polygenic-risk-for-nasal-polyps-in-anca-associated-vasculitis/