SERPINA1 Gene Variants in Granulomatosis with Polyangiitis

Abstract

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 Pi*Z, Pi*S 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 Pi*MM SERPINA1 genotype was detected by means of real-time polymerase chain reaction (PCR) or direct sequencing in 59 patients, Pi*MZ genotype in 2, and Pi*IM, Pi*MS or Pi*SZ in 1 patient respectively. The patients with abnormal Pi*Z, Pi*S, or Pi*I 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 Pi*Z, Pi*S, or Pi*I SERPINA1 variants than in the Pi*MM homozygotes. In summary, heterozygous Pi*MZ, Pi*MS, and Pi*SZ 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 Pi*S and Pi*Z may affect the clinical course of the disease.

Pleiotropic effects of heterozygosity for theSERPINA1Z allele in the UK Biobank

“…Individuals heterozygous for the Z allele exhibited higher FEV 1 (β = 9.26 ml, P = 0.041) but no association with FEV 1 /FVC or FVC compared to wild-type ( Table 2 ). However, in stratified analyses of UK Biobank never- and ever-smokers, we found that heterozygosity for the Z allele was associated with a large increase in FEV 1 (β = 19.36 ml, P = 9.21×10 - 4 ) and increased FEV 1 /FVC (β = 0.0031, P = 1.22×10 -5 ) in never-smokers, but not in ever-smokers (Table 2). Statistical tests of Z allele*ever-smoking interactions showed interactions for FEV 1 (P = 0.022) and FEV 1 /FVC (P = 1.06×10 -4 ) ( Supplementary Table 4 ).…”

“…Some previous studies have sought to characterise the effect of Z allele heterozygosity and homozygosity on non-respiratory traits, particular liver diseases 2, 3, 4, 5, 6 . However, these have often been carried out in small sample sizes and/or clinical subgroups.…”

Gene variants and treatment outcomes in antineutrophil cytoplasmic antibody-associated vasculitis

“…Several other genetic variants, not related to a specific treatment, have been associated with clinical outcomes of AAV. Examples include gene polymorphisms of monocyte chemoattractant protein-1 [73], alpha-1 antitrypsin [74], and human leukocyte antigen (HLA)-DPB1 [75].…”

Ocular Manifestations of Granulomatosis with Polyangiitis: A Review of the Literature

“…Other responsible gene pathways include alpha-1 antitrypsin deficiency and polymorphisms of CTLA-4 (which is involved in T-cell activation) and Fcγ receptor IIIb on the surfaces of neutrophils and monocytes/macrophages. Furthermore, the presence of the PTPN22 R620W allele (associated with T-cell activation) and SERPINA1 gene variants has also been implicated in GPA [7, 8].…”