| Background:Bullous pemphigoid（BP）is an autoimmune bullous skin disease characterized by tense blisters or bullae,which is found in the chest and abdomen of the trunk,The extremities near the trunk and the extremities of the hands and feet.This disease often occurs in the elderly over 60 years old,patients with different degrees of itching symptoms.The statistics of incidence and fatality rate of this disease are still to be improved.Based on epidemiological findings,patients with neurological diseases such as multiple sclerosis,Parkinson’s disease and dementia have been found to have a significantly increased risk of BP.Dermatomyositis（DM）is an autoimmune connective tissue disease mainly targeting skin and striated muscle.Clinically,the main symptoms are skin and muscle involvement,including but not limited to the skin symptoms of purple macules,Gottron papule,and poikiloderma,and myositis manifestations of weakness of the extremities muscles near the trunk.Major histocompatibility complex（MHC）is the most polymorphic allele complex in human genome.Its polymorphism is significantly associated with genetic susceptibility to diseases,and has been proved to be a genetic factor involved in the pathogenesis of many autoimmune diseases,including BP and DM.Previous Genome-wide association studies（GWAS）have identified numerous variants associated with diseases.However,due to the complexity of MHC region,traditional GWAS studies are unable to meet the needs of more detailed localization of variants.MHC imputation is a technique for fine-location studies based on GWAS data in conjunction with other databases,enabling more efficient and in-depth exploration of genetic variation in diseases.Objective:This study plans to performed MHC imputation using the MHC region data of BP and DM patients in a Han Chinese cohort obtained from GWAS study,conduct fine localization study,find more variation sites,and conduct corresponding research and discussion on the correlation between the two diseases,conduct fine localization study,find more variants,and conduct corresponding research and discussion on the correlation between the two diseases.Methods:Based on data for 312 BP patients,128 DM patients,and 6793 healthy control subjects,we used 1KGP phase 3 dataset as the reference database for imputing SNP,INDEL,and CNV in the MHC region and the Han-MHC database as the reference database for performingHLA gene AA and SNP imputation and MHC region type.Beagle 4.1 was used as the inference software for the above analysis.Then,the association and stepwise regression analysis were carried out for the loci after quality control.Finally,the genetic correlation of MHC region data of the two diseases was analyzed.Results:Association study revealed the most significant SNP associated with BP,namely,rs580921(p=1.06×10-8,odds ratio=1.61,95%confidence interval=1.37–1.90),which is located in the C6orf10 gene,and the most significant classic human leukocyte antigen（HLA）allele asso-ciated with DM,namely,HLA-DPB1*1701(p=6.56×10-10,OR=3.61,95%CI=2.40–5.42).Further stepwise regression analyses with rs580921 identified a threonine at position 163 of the HLA-B gene as a new independent disease-associated AA,and HLA-DPB1*1701 indicated that no loci were significant.Three-dimensional ribbon models revealed that the HLA-B AA position 163(p=3.93×10-7,OR=1.64,95%CI=1.35–1.98)located in theα2 domain of the HLA-B molecule was involved in the process of specific antigen presentation.The calculations showed that there was no significant genetic correlation between BP and DM.Conclusion:Our study identified two BP-related susceptibility sites in the MHC region,among which the C6orf10 gene,where the SNP site is located,has never been found to be associated with BP before and proved that the HLA-DPB1*1701 alleles were associated with DM.The results were consistent with previous researches. |
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