Functional Characterization and Association of Erap-1 Gene Loci Genetic Variations in Taiwanese Spondyloarthropathy (Spa) and Immune Mediated Disease

Endoplasmic reticulum aminopeptidase 1 (ERAP-1) alters protein functions influence on the antigen processing pathway that expression levels changes of ERAP1 suggests to play as an important mechanism in promoting several immune mediated diseases and cancers. Ankylosing spondylitis (AS) is the best characterized subset of AxSpA demonstrates insidiously progressive and debilitating form of arthritis involving the axial skeleton (spine and sacroiliac joint) but also peripheral joint inflammation, enthesitis. The extensive osteoproliferation leading to syndesmophyte formation and spine fusion. The strong evidence genetic predisposition suggested from the observations twin and family studies but the precise mechanisms remain unclear. We sought to investigate genetic variations predict disease severity leading to advanced stage with spinal ankylosis and early onset AS. AS strongly associated with genetic variation within the major histocompatibility complex (MHC) so called Human Leukocyte Antigen (HLA) region due to the critical antigen possession B27 heavy chain structures misfold to form cell-surface heavy chain homodimers (B27)2 can also be expressed at the cell surface and (B27)2 bind to innate immune receptors on T, NK, and myeloid cells to induce pro-inflammatory responses. Non-HLA-B27 MHC class I alleles and the importance of T cells recognition in AS and SpA also contribute to pathogenesis and disease susceptibility. ERAP1 variants may change the enzyme activity and interact with HLA-B27 lead to significant changes in MHC-I peptidome. ERAP-1 protective polymorphism resulted in diminished ERAP-1 activity, less efficient trimming, suboptimal HLA-B27 peptidomes, and decreased molecular stability. This functional and positional genetic approach aims to:Specific Aim 1: To identify novel genetic variations of ERAP1 through the extended deep sequencing Specific Aim 2: To investigate the association of distinct ERAP-1 genetic variations (SNPs) and haplotypes with Taiwanese AS susceptibility and clinical phenotypesSpecific Aim 3: Functionally characterization of distinct ERAP-1 alleles affect MHC folding and assembly, cytokines productions and different gene and protein expressionsSpecific Aim 4: Investigate the functional effects of gene interaction between distinct ERAP 1 haplotypes and MHC class I (HLA-ABC) alleles in Taiwanese ASSpecific Aim 5: To investigate the association of distinct ERAP-1 SNPs and haplotypes with Psoriasis, chronic HCV infection susceptibility, clinical phenotypes and response to therapy

Project ID:PC10907-1121
External Project ID:MOST109-2314-B182-065-MY3