Page 95 - Recognizing axial spondyloarthritis - Janneke de Winter

INTRODUCTION
Axial spondyloarthritis (axSpA) is a common form of chronic inflammatory arthritis affecting the axial skeleton, including the sacroiliac joints and the spine, as well as peripheral joints and extra-articular sites. The disease has a strong genetic predisposition with ankylosing spondylitis (AS), the most homogenous and well-studied clinical phenotype within the axSpA disease spectrum, having a recurrence risk of 8% in first-degree relatives (1). Human leukocyte antigen (HLA)-B*27, part of the major histocompatibility complex (MHC), is the major susceptibility gene for AS. However, it accounts for only 25% of the overall AS heritability (2). Moreover, the concordance rate of AS in monozygotic twins (63%) is higher than in dizygotic twins (12.5%), even when dizygotic twins are concordant for HLA-B*27 (27%) (3,4). These and other observations suggest that AS is a multigenic disease and that other susceptibility genes should contribute beyond HLA-B*27. This concept has been well validated by large Genome Wide Association Studies (GWAS), identifying a whole series of additional genes in AS (5). Albeit the GWAS analyses have contributed significantly to the identification of disease-relevant pathways, the relative contribution of individual susceptibility genes remains modest, indicating that many other genes contributing to the disease may be difficult to identify by this approach. This may include rare variants as well as non-HLA-B*27 genes in the MHC region on chromosome 6p (6). Although most of the genetic association of this locus is driven by the association of AS with HLA-B*27, there is strong evidence for the involvement of other MHC genes.
An alternative approach to identify disease-relevant pathways in axSpA is to perform large-scale expression analysis using microarray or RNA sequencing technology. We have previously performed unbiased pan-genomic microarray analysis of inflamed synovial tissue (7); this approach, however, can also be used to focus on potential pathways of interest. As the expression of beta-2 microglobulin has been demonstrated to modify the disease phenotype induced by HLA-B*27 in transgenic rats (8), firstly we aimed to assess the level of mRNA expression of MHC and related genes in AS versus peripheral blood mononuclear cells of healthy controls. Since this screening experiment revealed low mRNA expression of a particular HLA-C gene product in AS, secondly the study aimed to assess if this particular MHC gene, HLA-C*07, is associated with susceptibility to AS and axSpA.
METHODS
Cohorts
HLA-C*07 was assessed in a) an exploratory cohort of 24 AS patients versus 40 healthy controls, b) a confirmatory cohort of 113 AS patients and 83 non- radiographic axspa patients from the GErman SPondyloarthritis Inception Cohort
HLA-C*07 IN AXIAL SPA
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