The Relationship of Candidate Gene Polymorphisms with Ankylosing Spondylitis and its Clinical Course. Summary of the Doctoral Thesis

Abstract

Ankylosing spondylitis (AS) is a systemic, chronic, immune system mediated inflammatory arthritis which mainly affects sacroiliac joints, axial skeleton with or without the involvement of extraspinal manifestations such as peripheral arthritis, uveitis etc. An agressive and long-standing disease results in ankylosis of the sacroiliac joints and a bamboo-like spine (bony bridges made from fusion of syndesmophytes and ossification of ligaments) manifested as a significant restriction of spinal mobility and thus causing functional disability. AS is a polygenic disease. Therefore, candidate genes (genes which can be involved in the pathogenesis of the disease) studies are significant to calculate the risk of the development of the disease in order to make a prognosis for the clinical course and thus preventing an irreversible damage. The aim of the study is to investigate the association and its clinical significance between the polymorphisms of candidate genes (ERAP1 rs10050860 G/A, rs30187 G/A, rs26653 G/C, IL23R rs10889677 C/A, rs11209026 G/A, rs2201841 A/G, TNFA rs1800629 G/A, CD40 rs4810485 G/T, IL10 rs1800896 A/G, TGFβ1 rs1800469 C/T, rs1800470 T/C, IRF5 rs10954213 A/G, rs2004640 T/G, rs3757385 G/T, PTPN22 rs2476601 C/T) and the haplotypes of different combinations of these SNPs and AS as well as its clinical course and the treatment efficacy with tumor necrosis factor alpha inhibitors. The association between the seven single nucleotide polymorphisms (SNPs) out of 15 analysed SNPs located in eight genes and the disease (CD40 rs4810485, TNFA rs1800629, PTPN22 rs2476601) and its clinical manifestations, such as uveitis (IRF5 rs3757385, IL10 rs1800496) and peripheral arthritis (ERAP1 rs10050860, TGFβ1 rs1800469), was found based on the differences of the frequencies in the distribution of alleles and/or genotypes in 98 AS patients and 154 healthy controls. Additionally, the association between the polymorphisms of the candidate genes and the chosen biomarkers, such as the spinal structural damage progression dependent on the duration of the disease and the activity changes in the disease during the treatment period with TNFα inhibitors, was found for five SNPs. An analysis of haplotypes showed an association between combinations of SNPs of CD40, TNFA and PTPN22 genes and AS, combinations of IRF5 SNPs and uveitis as well as combinations of IL10/TGFβ1 SNPs and peripheral arthritis. The results of the study offer an additional information for the evaluation of the possible risk of developing AS in patients with inflammatory back pain as well as for the prognosis of the clinical course of AS by analysis of the most frequent extraspinal manifestations, such as uveitis and peripheral arthritis, the risk of progression of radiographic damage in the cervical and lumbar spine and the prognosis of the treatment efficacy with TNFα inhibitors.