Department of Family Medicine, Internal and Metabolic Diseases, Warsaw Medical University, Warsaw, Poland.
Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland.
Adv Exp Med Biol. 2018;1070:9-18. doi: 10.1007/5584_2018_156.
Alpha-1 antitrypsin (A1AT) deficiency is one of the most common genetic disorders in Caucasian population. There is a link between granulomatosis with polyangiitis (GPA) and most frequent variants of SERPINA1 gene encoding severe alpha-1 antitripsin deficiency. However, the potential effect of PiZ, PiS as well as other SERPINA1 variants on clinical course of vasculitis are not well understood. The aim of the study was to analyze the potential effect of A1AT protein phenotype representing the SERPINA1 gene variants on the clinical course of GPA. The study group consisted of 64 subjects with GPA, stratified according to the disease severity: patients in active phase (group I, n = 12), patients during remission on treatment (group II, n = 40) or untreated (group III, n = 12). Normal PiMM SERPINA1 genotype was detected by means of real-time polymerase chain reaction (PCR) or direct sequencing in 59 patients, PiMZ genotype in 2, and PiIM, PiMS or PiSZ in 1 patient respectively. The patients with abnormal PiZ, PiS, or PiI allele constituted 17% in group I, 5% in group II, and 8% in group III. The serum content of A1AT and high sensitivity C-reactive protein (hsCRP) assessed by nephelometry did not differ between the groups. Interestingly, the mean serum antiPR3-antibodies level detected by Elisa method was significantly greater in the GPA patients with PiZ, PiS, or PiI SERPINA1 variants than in the PiMM homozygotes. In summary, heterozygous PiMZ, PiMS, and PiSZ genotype was detected in 7.8% of total group of GPA patients, and in 10.5% of those with lung lesions. The abnormal alleles of PiS and Pi*Z may affect the clinical course of the disease.
α-1 抗胰蛋白酶（A1AT）缺乏症是白种人群中最常见的遗传疾病之一。肉芽肿性多血管炎（GPA）与编码严重 A1AT 缺乏症的 SERPINA1 基因的最常见变异体之间存在关联。然而，PiZ、PiS 以及其他 SERPINA1 变异体对血管炎临床病程的潜在影响尚不清楚。本研究旨在分析代表 SERPINA1 基因变异体的 A1AT 蛋白表型对 GPA 临床病程的潜在影响。研究组包括 64 名 GPA 患者，根据疾病严重程度分层：活动期患者（I 组，n=12）、治疗缓解期患者（II 组，n=40）或未治疗患者（III 组，n=12）。通过实时聚合酶链反应（PCR）或直接测序在 59 名患者中检测到正常的 PiMM SERPINA1 基因型，在 2 名患者中检测到 PiMZ 基因型，在 1 名患者中检测到 PiIM、PiMS 或 PiSZ 基因型。I 组、II 组和 III 组中异常 PiZ、PiS 或 PiI 等位基因的患者分别占 17%、5%和 8%。通过散射比浊法评估的 A1AT 和高敏 C 反应蛋白（hsCRP）血清含量在各组之间无差异。有趣的是，通过 ELISA 法检测到的 GPA 患者中 PiZ、PiS 或 PiI SERPINA1 变异体的平均血清抗 PR3 抗体水平明显高于 PiMM 纯合子。总之，在总 GPA 患者组中检测到杂合子 PiMZ、PiMS 和 PiSZ 基因型，在有肺部病变的患者中占 10.5%。PiS 和 Pi*Z 的异常等位基因可能影响疾病的临床病程。
