The Pleiotropic Effect Study Among Psoriasis And Multiple Chronic Inflammatory Diseases

Background: Psoriasis(PS), Rheumatoid arthritis(RA) and Inflammatory Bowel Disease(IBD) are a group of chronic inflammatory disease which have been shown to be epidemiologically, pathogenesis and therapeutically connected. Several previous Genome-wide association studies(GWAS) have shown that many susceptibility genes associated with PS were also shared with other chronic inflammatory disease. For example, IL23 R gene shared with PS, IBD and Ankylosing spondylitis(AS); TYK2 gene shared with PS,IBD, RA, AS, T1 D and multiple sclerosis(MS); TNFAIP3 gene shared with PS and IBD, RA, system lupus lupus(SLE), celiac disease(Ce D); REL gene shared with PS and IBD, RA, Ce D; IL12 B gene shared with PS and IBD, AS, MS; NFKB1 and STAT3 gene shared with PS, IBD, MS; PTPN22 gene shared with PS, IBD,RA, and SLE. Thereby providing further evidence that these diseases are genetic overlap, and these shared genes with multiple traits also have pleiotropic effects. Thus, it would be effectively improve the efficiency of identified susceptibility genes with pleiotropic characteristics of genes. Integrate and dig existing GWAS data of various chronic inflammatory diseases, it is important to further discover new susceptibility genes of psoriasis, understanding pathogenesis of chronic inflammatory diseases,and it also important for future therapeutic drugs development.Objective: to indentify new susceptibility genes of chronic inflammatory diseases, such as PS, RA, IBD, by using the gene-based method(GBAT). And perform a joint meta-analysis with the single GBAT results, and further carry out pathway-analysis, protein-protein interaction network analysis.Increase the statistics efficiency to identify psoriasis susceptibility genes, and explore gene pleiotropy of shared psoriasis genes, and further discover the potential common biological pathogenesis.Methods: In this study, we first analyzed three GWAS results summary data by versatile gene-based test for genome-wide association studies(VEGAS),respectively. Including GWAS results data of psoriasis, which was derived from Chinese populations, and rheumatoid arthritis data was derived from European populations, chronic inflammatory bowel disease data were derived from European and multi-ethnic populations GWAS results. In order to test gene pleiotropy of three diseases, we combined the results of PS/RA, PS/IBD, RA/IBD, and PS/RA/IBD to meta-analysis using fisher method,respectively. In addition, we performed pathway-analysis, gene expression analysis, protein-protein interaction network analysis subsequently to validation genes pleiotropic of shared genes, and to explore shared pathways and pathogenesis mechanisms of chronic inflammatory diseases.Results: Using VEGAS method. We indentified 169 PS gene, which 9 lying outside the HLA region; 187 RA gene, which 13 lying outside the HLA region;IBD 197 genes, which 149 lying outside the HLA region. Combined with PS,RA, IBD results by meta-analysis. We found In line with the significant standard PS, RA with 183 genes, which are all located in the HLA region;with PS, IBD significant standard of 124 genes, 32 genes in the HLA region with RA, IBD significantly standards 157, the 72 genes in the HLA region with 111 PS, RA, IBD significantly standard, 19 genes in the HLA region.The pathway analysis of shared-gene showed that 40 pathways were significant, such as, IL23-mediated signaling events. Gene expression analysis revealed 9 of 12 shared genes, 5 of 7 PS genes(ORAI3, UBLCP1,SETD1 A, BCL7 C, STX1B) in normal skin psoriasis, psoriatic lesions and normal skin expression were significantly different. Protein interactions showed that in 30 genes shared PS and IBD, there are 27 that can be mapped to the corresponding proteins, including 11 proteins exist 27 interaction;shared in 12 genes PS 、 RA and IBD, 10 genes can be mapped to the corresponding protein, of which two proteins exists an interaction.Conclusion: 1. Our study further confirmed that multiple PS susceptibility genes has pleiotropic effects, especially with IBD is more significant,whether in non HLA region and HLA region has many shared genes, and the RA gene pleiotropy only focus in the HLA region. PS, RA, IBD there is a certain degree of genetic and biological pathways overlap, in the pathogenesis of the disease may be there is some overlap, and may have some enlightenment on the PS, RA, a deeper understanding of IBD and future treatment strategies. 3. Through GBAT analysis can increase the statistical efficiency, make full use of existing GWAS data, and further found that the new PS susceptibility gene.