| Background:Vitiligo is a common depigmentation dermatosis characterized by well-defined porcelain white hypopigmentation patches on the skin,mucosa and hair.The global incidence is 0.5%-1%,and the incidence varies greatly among regions.Although lesions are usually not accompanied by other conscious symptoms,but its disfigurement and the characteristics of prolonged illness,serious patients’mental health and social interaction.Epidemiological studies have shown that patients with vitiligo and their first-degree relatives are significantly more likely to suffer from autoimmune diseases（such as autoimmune hypothyroidism,pernicious anemia,systemic lupus erythematosus,Addison’s disease and inflammatory bowel disease）.Systemic lupus erythematosus（SLE）is a connective tissue disease characterized by the presence of multiple autoantibodies in the circulatory system.It may affect multiple organs and systems such as skin,heart,kidney and nerves.Persistent apoptotic fragments containing nucleic acids can stimulate inflammatory responses by activating nucleic acid recognition receptors,leading to immune disorders and body damage in SLE patients.Major histocompatibility complex（MHC）is one of the most polymorphic genes in the human genome,which plays an important role in both innate and adaptive immunity and has been proved to be involved in the pathogenesis of various autoimmune diseases.The variants identified by GWAS are mostly located in non-coding regions,which cannot meet the needs of studying the pathogenesis of complex diseases.Imputation of classical HLA alleles and amino acid polymorphisms makes it possible to fine mapping the association signals of MHC region,which can effectively explore the genetic variation of complex diseases.Objective:Chinese population-specific HAN-MHC reference panel and 1000 Genomes Project phase 3 were used to impute MHC region data of vitiligo and SLE obtained by GWAS and then fine mapping analysis was conducted to explore the role of MHC region variation in the pathogenesis of vitiligo and SLE.Furthermore,the genetic relationship between vitiligo and SLE was discussed.Methods:SNP genotyping was performed on 1117 vitiligo cases,1046 SLE cases,and1693 healthy control samples using Illumina 610-Quad Bead Chip,followed by imputed the MHC region data obtained from GWAS.Correlation analysis and stepwise regression analysis were used to explore the genetic variation related to disease.Subsequently,the obtained vitiligo and SLE data were analyzed for complex trait association to explore the correlation between the two diseases in MHC region.Results:A total of 1776 mutations in the vitiligo population reached the significance threshold(P=1.32×10-6),including 1725 SNPs,2 CNVs,11 HLA alleles（5 two-digit and 6 four-digit）,and 38 AA polymorphisms.A total of 1266 variants reached significance(P<1.25×10-6),including 1217 SNPs,5 CNVs,5 HLA alleles（2 two-digit and 3 four-digit）,and 39 AA polymorphisms.rs113465897(P=1.03×10-13,OR=1.64,95%CI=1.44–1.87)and rs3129898(P=4.21×10-17,OR=1.93,95%CI=1.66–2.25)were identified as being most strongly associated with vitiligo and SLE,respectively.Stepwise conditional analysis revealed additional independent signals at rs3130969(p=1.48×10-7,OR=0.69,95%CI=0.60–0.79),HLA-DPB1*03:01(p=1.07×10-6,OR=1.94,95%CI=1.49–2.53)being linked to vitiligo and HLA-DQB1*0301(P=4.53×10-7,OR=0.62,95%CI=0.52-0.75)to SLE.Correlation analysis of complex traits showed that the correlation between the two diseases in MHC region was 0.79(P=5.99×10-10,SE=0.07),showing a positive correlation.Conclusion:In this study,we identified new susceptibility signals associated with risks of vitiligo（rs113465897,rs3130969,HLA-DPB1*03:01）and SLE（rs3129898）and confirmed a reported allele,HLA-DQB1*0301,to be associated with SLE.We revealed new genetic predispositions for vitiligo and SLE,advancing research into the functional mechanisms of the disease and demonstrating the correlation of vitiligo and SLE from a population genetics perspective. |
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