| Background：Bullous pemphigoid （BP） is a chronic autoimmune blistering diseasecharacterized by subepidermal blistering. BP mainly affects older people and rare inchildren, typically presents with tense, mostly clear, blisters with a negative Nikolskysign and frequently scattered in limbs flexor side, leg and waist. The incidence of BP isvery low, which has been estimated between10and70new cases per1million per yearin central Europe. In Chinese people, it is also quite low, accounting for about0.02%ofoutpatients in a survey. Incidence rises substantially to150–330per1million peopleper year in people older than80years.1-year mortality for patients with BP ranges from20%to40%, which is about two times higher than that mortality rate （12%） in ChineseHan population.So far, the etiology and pathogenesis of BP is unclear. The mechanism by which BPautoantibodies are thought to be pathogenic may be summarized in these steps,including complement activation, recruitment of inflammatory cells, release ofproteolytic enzymes, and direct interference with the adhesion function of theautoantigens. The humoral and cellular immune-mediated process in BP pathogenesisrequires the cooperation between B cells and CD4+Th cells. In patients with BP,self-antigens are caught by antigen-presenting cells, processed, bound to majorhistocompatibility complex class （MHC） II and displayed on the cell surface. Thereceptor-mediated recognition of these epitopes by T cells, triggers the release ofvarious cytokines and, consequently, B cells are stimulated to produce autoantibodies.HLA genes are probably the most significant genetic predisposition factor, due to theirrole in the antigen presentation process. Using the candidate genes approach, it has found the correction among the HLA class IIgene in MHC region, non-MHC genes and BP. Especially, the findings ofHLA-DQB1*0301has a significant correlation with BP. However, the geneticbackground of different ethnic and geographic may be the main factor to result inheterogeneity genetic. The HLA-DQB1*0301allele is also associated with Indianpopulation, but different in Chinese and Japanese populations. In addition, it is also toexplore the genetic susceptibility of BP from the pathogenesis, screening the possiblecandidate genes, such as the COL17A1, IGHV and cytokine genes. BP is a complexdisease caused by multiple factors. The strategy, including such as linkage analysisstudy, candidate gene association studies, may have the limitation to explore the geneticof complex disease. Therefore, to conduct the GWAS of BP will be of great importancein promoting understand of the pathogenesis and genetic basis of BP.Object: To explore BP associated SNPs in whole genome and identify susceptibilitygenes/loci for BP by using GWAS approach and to build the GWAS database of BPcases and controls in Chinese Han population.Method: All subjects in this study were recruited from the collaboration with multiplehospitals in China, which were divided into two separate groups in southern andnorthern Chinese population. Samples in the GWAS stage were genotyped by IlluminaHumanOmniZhongHua-8BeadChips. A total of1795subjects,91BP patients and575normal controls from north of China,138BP cases and991normal controls form southof China, respectively, were genotyped by this BeadChips. After strict quality control，two genotyping data from different groups were combined for Meta-analysis andhaplotype analysis.Results：1)It was the first GWAS study of bullous pemphigoid and had built theGWAS database of801,392autosomal SNPs, including total229BP cases and1566controls in Chinese Han population.2) Through Meta-analysis of the GWAS data from northern and southern Chinese population, we found a new susceptibility loci at1q43（rs72766895，P=6.38×10-9，OR=3.14） significantly associated with BP. In thisLD region, the PLD5gene prompt to be the susceptibility gene of BP, according to thefunctional study on published researches.3) We also Found two suggestivesusceptibility loci associated with BP, which located in18q21.31(SNP rs117788424, P=1.38×10-7, OR=2.51) and2p25.3(SNP rs12988270, P=1.96×10-7, OR=2.52).Based on the evidence of genes function study in this LD block, it indicated that18q21.31and2p25.3might be the susceptibility loci associated with BP.4) Replicatedthe previous reports of association between BP and HLA genes, we further confirmedthe correlation between HLA and BP and also found a risk haplotype in the HLA-IIgene region associated with BP.Conclusion：It is the first GWAS of bullous pemphigoid research in Chinese Hanpopulation. We found a new susceptibility locus and two suggestive loci associated withBP at non-MHC region. Through the haplotype analysis, we found a risk haplotype inHLA-II gene region associated with BP, and further confirmed the correlation betweenHLA and BP. We had built the GWAS database of bullous pemphigoid in Chinesedatabase. Not only emphasized the importance of immune factors in the pathogenesis ofBP in this study, but also pay attention to genetic variations associated with pathogenicpathways. This study will be promote us to understand the genetic bases of BP deeply,and also provided new evidence for the pathogenesis research of BP. |
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