Integrated Genomics Identifies Convergence of Ankylosing Spondylitis with Global Immune Mediated Disease Pathways

Abstract

Ankylosing spondylitis(AS), a highly heritable complex inflammatory arthritis. Although, a handful of non-HLA risk loci have been identified, capturing the unexplained genetic contribution to AS pathogenesis remains a challenge attributed to additive, pleiotropic and epistatic-interactions at the molecular level. Here, we developed multiple integrated genomic approaches to quantify molecular convergence of non-HLA loci with global immune mediated diseases. We show that non-HLA genes are significantly sensitive to deleterious mutation accumulation in the general population compared with tolerant genes. Human developmental proteomics (prenatal to adult) analysis revealed that proteins encoded by non-HLA AS risk loci are 2-fold more expressed in adult hematopoietic cells.Enrichment analysis revealed AS risk genes overlap with a significant number of immune related pathways (p < 0.0001 to 9.8 × 10-12). Protein-protein interaction analysis revealed non-shared AS risk genes are highly clustered seeds that significantly converge (empirical; p < 0.01 to 1.6 × 10-4) into networks of global immune mediated disease risk loci. We have also provided initial evidence for the involvement of STAT2/3 in AS pathogenesis. Collectively, these findings highlight molecular insight on non-HLA AS risk loci that are not exclusively connected with overlapping immune mediated diseases; rather a component of common pathophysiological pathways with other immune mediated diseases. This information will be pivotal to fully explain AS pathogenesis and identify new therapeutic targets.

Ankylosing Spondylitis and Axial Spondyloarthritis

“…50,62 The majority of these loci also confer susceptibility to other immune-mediated diseases, particularly inflammatory bowel disease and, to a lesser degree, psoriasis. 63,64 Genes that affect the interleukin-23interleukin-17 pathway are prominently represented in this group. CARD9, IL12B, and PTGER4 can promote the production of interleukin-23, whereas IL23R, TYK2, and STAT3 can affect the production of interleukin-17 and other cytokines in response to interleukin-23 stimulation.…”

Progress of genome‐wide association studies of ankylosing spondylitis

“…These findings are consistent with a previous study which performed a similar epigenetic analysis with predicted causal AS SNPs. 96, 97 In addition, AS-associated variants were shown to be enriched in regulatory elements, especially in enhancer regions, in related immune cells. Moreover, the AS upregulated genes show different enrichment bias in both gene and protein expression compared with AS downregulated genes.…”

Targeting the interleukin-23/17 axis in axial spondyloarthritis

“…Many other IL-23/IL-17 pathway related genes such as IL-6R, IL-12B, IL-27, CARD9, STAT3 and TYK2, also have been implicated in AS [15] indicating the potential importance of the IL-I7/IL-23 pathway in the axSpA. Uddin et al applied an integrative genomics approach to show that AS risk alleles overlap with global immune related pathways and Th17 related genes in AS pathogenesis [16]**. Integration of genetic and epigenetic fine mapping of causal variants related to autoimmune diseases further revealed the relatedness of AS, psoriasis and inflammatory bowel disease; all three disorders demonstrated a Th17 cell specific epigenetic signature for the known variants [17]**.…”