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Sci Rep. 2015 May 18;5:10314. doi: 10.1038/srep10314.

Integrated genomics identifies convergence of ankylosing spondylitis with global immune mediated disease pathways.

Author information

1
Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
2
Faculty of Medicine, Memorial University, Newfoundland, St. John's, Canada.
3
1] Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada [2] McLaughlin Centre, University of Toronto, Toronto, Ontario, Canada [3] Department of Molecular Genetics, University of Toronto, Ontario, Canada.

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 × 0(-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.

PMID:
25980808
PMCID:
PMC4434845
DOI:
10.1038/srep10314
[Indexed for MEDLINE]
Free PMC Article

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