Artikel
Proteinase 3 gene polymorphisms associated with risk for the autoimmune disease GPA (granulomatosis with polyangiitis)
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Veröffentlicht: | 29. August 2016 |
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Gliederung
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Background: Granulomatosis with polyangiitis (GPA) belongs to the so-called ANCA-related vaskulitides and is a systemic autoimmune disorder of the small blood vessels, which can expand in principle to almost all organs. Pathognostic sign of this life-threatening illness is the appearance of antineutrophil cytoplasmic autoantibodies (c-ANCA), which are directed against the neutrophilic enzyme proteinase 3 (PR3). A direct role of the PRTN3 gene in the progression of the disease could be assigned in a genomewide association study (GWAS). Therefore, the aim of our investigation is the capture of those polymorphisms of the PRTN3 gene which cause a higher risk for PGA. It would be an important breakthrough in vasculitis research, if significant accumulations of certain alleles or mutations could be proved in the PRTN3 gene of GPA patients.
Methods: Our initial investigations enclose the promoter region, the coding sequences (exons) and the intron areas directly surrounding the exons. For this purpose, blood was taken from the patients as well as the controls and genomic DNA from leucocytes was isolated. Samples of lymphocytic DNA were amplified with PCR, directly sequenced and analyses of the coding exons including the flanking intron/UTR-sequences of the PRTN3 gene were performed. Single nucleotide polymorphisms (SNPs) were ascertained, evaluated statistically and compared to the SNP data bank of the „National Center for Biotechnology Information“ (NCBI).
Results: First results show a remarkable accumulation and coupling of certain SNP variations at 5' ends of the Introns 1 and 2. These variations are inherited as haplotypes and are associated with GPA patients. However, the significance of these results must be still secured by a higher case number. Regardless of the illness we have succeeded in characterizing gene variants of the PRTN3 gene which may also be used for phylogenetic studies of human populations.
Conclusion: The results generated by us will help to understand the importance of the PR3 in the pathogenesis of ANCA-related vaskulitides and can also serve to better describe the critical role of the enzyme as an autoantigen. Furthermore, the genetic PR3 variations described by us can also be used as a tool to improve the diagnostics of this serious autoimmune disease.