Genotypic and phenotypic insights into an Irish axial spondyloarthritis cohort
Citation:
Kenyon, Marcus, Genotypic and phenotypic insights into an Irish axial spondyloarthritis cohort, Trinity College Dublin, School of Medicine, Clinical Medicine, 2024Download Item:
Abstract:
Axial spondyloarthritis (AxSpA) encompasses a group of closely related chronic inflammatory conditions which primarily affect the lumbar spine. The prototypic presentation of the disease is ankylosing spondylitis, which comprises more than half of AxSpA cases. AxSpA presentation is highly heterogenous, with a wide range of axial disease severity and concomitant peripheral manifestations, such as uveitis, peripheral arthritis, psoriasis and IBD.
AxSpA is a highly heritable disease, with strong generational recurrence and robust evidence of genetic association. The strongest of these is the MHC class I type, HLA-B27, which was first reported in 1973 and is present in over 80% of AxSpA patients. 50 years since this discovery, over 100 independent genetic loci have been linked with the disease. Genetic risk points to the involvement of aberrant antigen presentation by HLA-B27 and dysregulation of the IL-17 pathway as key factors in AxSpA aetiology. However, only a small proportion of genetically susceptible individuals ever develop the disease. The specific event which triggers onset of the disease in genetically susceptible individuals remains elusive, but is generally considered to be a ubiquitous environmental influence. However, a significant proportion of AxSpA patients present with sub-clinical gut inflammation and gut dysbiosis has also been reported. This may point to an altered relationship between the immune system and gut microbiome in disease susceptible individuals.
Here, we provide a comprehensive account of the clinical presentation of AxSpA within a unique Irish registry cohort while investigating the role of genetic traits in shaping disease characteristics. Our study employed a range of genetic techniques, including genome-wide and gene-specific approaches, to identify key genetic variants associated with disease onset and severity. Additionally, we utilised polygenic risk scores to explore how composite genetic risk, both within and beyond the HLA complex, might influence disease presentation. Furthermore, I performed a meta-analysis of genetic risk, incorporating findings from our study cohort with a previous genome-wide association study to identify novel risk variants. Lastly, we investigated how the regulation of specific genes and bio-molecular pathways differ between AxSpA patients and healthy controls using single-cell RNA sequencing.
We found that some peripheral manifestations associated with AxSpA occur at a steady rate over time, while others appear to either precede or occur early in AxSpA disease. In particular, dactylitis seemed to occur early in AxSpA disease and was strongly associated with other peripheral manifestations, especially uveitis and was also inversely associated with HLA-B27 and spinal radiographic involvement. Our results suggest that patients presenting with dactylitis represent a distinct subset of AxSpA. Disease presentation was also found to be influenced by genetic risk variants. We revealed that multiple genetic variants within the ERAP1 gene were associated with the age at which AxSpA disease developed and the likelihood of concomitant uveitis episodes within patients. This was supported by polygenic risk scores, which demonstrated that genetic variants, both within and outside of the HLA region are associated with earlier AxSpA disease onset. We found further evidence for lymphocyte involvement through the identification of several disease risk variants located near to genes relevant to the differentiation and function of these cells. This was supported using single cell RNA expression analysis, which revealed increased expression of IL-17 pathway genes in multiple cell subtypes and a strong signature of immune cell activation in patient relative to control samples. Several genes associated genetically with AxSpA were found to be differentially regulated in immune cells. Finally, molecular pathways differentially expressed between AxSpA patients and healthy controls support the hypothesis that gut dysbiosis is involved in AxSpA pathogenesis.
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Author: Kenyon, Marcus
Advisor:
McManus, O.Publisher:
Trinity College Dublin. School of Medicine. Discipline of Clinical MedicineType of material:
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