Introdução: Polimorfismos do gene SERPINA1, que codifica a enzima alfa-1- antitripsina (A1AT), e do gene PRTN3, que codifica a enzima proteinase-3 (PR3), foram associados às vasculites ANCA-associadas (VAA) em estudos de Genomewide association (GWAS) de pacientes brancos. Entretanto, a relação entre estes polimorfismos e as VAA na população multiétnica brasileira ainda é desconhecida. Objetivos: Avaliar a associação entre single nucleotide polymorphisms (SNPs) dos genes SERPINA1 e PRTN3 com as VAA em uma coorte multiétnica de pacientes brasileiros, e avaliar também a associação entre esses SNPs e classificação da doença, positividade do ANCA, concentrações séricas de A1AT, manifestações clínicas, dano e mortalidade. Métodos: Trata-se um estudo de caso-controle e coorte prospectivo que incluiu 115 pacientes com VAA (2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides e 2007 European Medicines Agency Algorithm for Classification of Vasculitis) e 608 controles saudáveis, no período de junho de 2018 a julho de 2020. Os SNPs rs7151526 e rs28929474 do gene SERPINA1 e rs62132295 do gene PRTN3 foram identificados utilizando a técnica de real time PCR. A presença dos ANCA foi avaliada pelos métodos de imunofluorescência indireta e ELISA (anti-PR3 vs. anti-MPO). As concentrações séricas de A1AT foram avaliadas pelo método imunoturbidimétrico. Resultados: Avaliamos 115 pacientes (65,2% granulomatose com poliangiite, 17,4% granulomatose eosinofílica com poliangiite, 17,4% poliangiite microscópica) e 608 controles. O rs7151526 foi mais frequente em pacientes em homozigose (1,7% vs. 0,2%, p=0,045) e o rs28929474 foi mais frequente em pacientes tanto em heterozigose (6,1% vs. 1,3%, p<0,0001) quanto em homozigose (1,7% vs. 0%, p<0,0001) do que nos controles. Na subanálise de indivíduos pretos, os rs7151526 e rs28929454 foram mais frequentes em pacientes em heterozigose (9,6% vs. 3,8%, p=0,0035; 7,7% vs. 0,5%, p<0,0001, respectivamente) e homozigose (3,8% vs. 0,0%, p=0,0035; 3,8% vs. 0%, p<0,0001, respectivamente) do que nos controles. Os portadores desses SNPs tiveram uma sobrevida média menor [rs28929474: 54,9 (40,9-68,9) anos; rs7151526: 57,4 (42,7-72,1) anos] do que não portadores [68,0 (67,2-69,0) anos, p<0,0001]. A associação entre esses SNPs foi o principal preditor de mortalidade (HR=6,2, IC95%=1,4-27,1, p=0,015). Não foi possível verificar associação entre o rs62132295 e o diagnóstico de VAA em nossa coorte. Conclusões: Nosso estudo é o primeiro a demonstrar a associação entre SNPs do gene SERPINA1 e o diagnóstico de VAA em uma coorte multiétnica brasileira. A presença destes SNPs também se associou a uma menor sobrevida entre os pacientes com VAA nesta coorte

Introduction: Polymorphisms of the SERPINA1 gene, which encodes the alpha-1- antitrypsin enzyme (A1AT), and the PRTN3 gene, which encodes the proteinase-3 enzyme (PR3), have been associated with ANCA-associated vasculitis (AAV) in Genome-wide association studies (GWAS) of white patients. However, the relationship between these polymorphisms and AAV in the Brazilian multiethnic population remains unknown. Objectives: To evaluate the association between single nucleotide polymorphisms (SNPs) of the SERPINA1 and PRTN3 genes and the diagnosis of AAV in a multiethnic cohort of Brazilian patients and to evaluate the association between these SNPs and disease classification, ANCA positivity, serum A1AT levels, clinical manifestations, damage, and mortality. Methods: This was a case-control and prospective cohort study that included 115 patients with AAV (2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides and 2007 European Medicines Agency Algorithm for Classification of Vasculitis) and 608 healthy controls, from June 2018 to July 2020. The SERPINA1 SNPs rs7151526 and rs28929474 and PRTN3 SNP rs62132295 were identified using real-time PCR. The presence of ANCAs was evaluated using the indirect immunofluorescence and ELISA (anti-PR3 vs. anti-MPO) methods. Serum A1AT levels were evaluated using an immunoturbidimetric method. Results: We evaluated 115 patients (65.2% granulomatosis with polyangiitis, 17.4% eosinophilic granulomatosis with polyangiitis, 17.4% microscopic polyangiitis) and 608 controls. The rs7151526 was more frequent in patients in homozygosis (1.7% vs. 0.2%, p=0.045) and rs28929474 was more frequent patients in heterozygosis (6.1% vs. 1.3%, p<0.0001) and homozygosis (1.7% vs. 0%, p<0.0001) than in controls. In the sub-analysis of black individuals, rs7151526 and rs28929454 were more frequent in patients in heterozygosis (9.6% vs. 3.8%, p=0.0035; 7.7% vs. 0.5%, p<0.0001, respectively) and homozygosis (3.8% vs. 0%, p=0.0035; 3.8% vs. 0%, p<0.0001, respectively) than in controls. Carriers of these SNPs had a lower mean survival [rs28929474: 54.9 (40.9-68.9) years; rs7151526: 57.4 (42.7-72.1) years] than non-carriers [68.0 (67.2-69.0) years, p<0.0001]. The association between these SNPs was the main predictor of mortality (HR=6.2, 95%CI=1.4-27.1, p=0.015). We were unable to verify an association between rs62132295 and AAV diagnosis in our cohort. Conclusions: Our study is the first to demonstrate an association between SERPINA1 SNPs and the AAV diagnosis in a Brazilian multiethnic sample. The presence of these SNPs was also associated with shorter survival among patients with AAV in this cohort