| Background: Psoriasis is a chronic inflammatory skin disease, which is hard to be cured and easy to recurrence. The pathogenesis of psoriasis was not clear yet. A number of researches have demonstrated that psoriasis was a complex genetic disease, and multiple genes with environment factors would play importment roles in the development and progression of this diseases.About 12 psoriasis genetic susceptible loci,named as PSOSR1-PSOSR12, respectively,have been found mainly by the family-based genome-wide linkage analysis. Among all these loci, PSOSR1 is located at 6p21.3 region. Along with the era of genome wide association study(GWAS), researchers have carried out several GWAS and subsequent validation studies on psoriasis. A large number of susceptibility genes or loci in nonhuman leucocyte antigen(HLA) region for psoriasis have been found. More than that,HLA region has been demonstrated to have a pivotal role in psoriasis.HLA, located at 6p21.3 region with a length of about 3,600 kb, has a close correlation with human immunity. HLA can be divided into three classes according to the distribution of genes and different functions of the encoded molecules. Classic HLA-I genes, containing HLA-A, HLA-B and HLA-C gene, are expressed at the surfaces of all karyocytes and their physiological function is presenting endogenous antigens to the CD8+ cells. Classic HLA-II genes, including-DP,-DQ and-DR gene, are expressed at the surface of mononuclear macrophage, B lymphocyte, dendritic cell as well as other antigen presenting cell types and its physiological function is presenting exogenous antigens to the CD4+ cells. It was first found that HLA played a role in the graft rejection, and with the studies progressed, HLA was found to be closely associated with various diseases, such as psoriasis, ankylosing spondylitis, Behcet’s disease, leprosy and so on. The genetic characteristic of HLA region is complex and features linkage disequilibrium and highly genetic polymorphism. It was a big challenge to elucidate the genetic factors of HLA region with diseases.Imputation could predict the ungenotyped or missed genotypes based on existing data..It could reduce the experiment cost and increase the coverage of genetic marker of whole genome or a specific location and thereby improve the study efficiency. In addition, various genotype data from different genotyping platforms could be merged by this approach. Imputation is now the most common approach for fine mapping.Additionally, imputation of HLA region can obtain the data of single nucleotide polymorphisms(SNPs), classic HLA alleles and amino acid polymorphisms simultaneously and have be successfully applied in genetic researches of HLA related complex diseases, such as achalasia cardia, systemic lupus erythematosus, drug-induced acute pancreatitis, ulcerative colitis, crohn disease and so on.Objective:(i) Imputation of HLA region based on the data from the genome-wide exome array study.(ii) Exploration of independent signals in HLA region with psoriasis.(iii) Genotype-phenotype analysis based on the independent signals and clinical characteristics of samples.Method:(i) Whole Exome Beadchip was used for genotype the SNPs located in the whole exome of 11,245 psoriasis patients and 11,177 healthy controls. The genotyped data in HLA region was collected.(ii) Based on the SNP2 HLA imputation strategy,SNPs, classic alleles and amino acid polymorphisms were imputed into the HLA region.(iii) We further explored more independent signals, classic alleles or amino acid polymorphisms according to the imputation result by stepwise regression analysis.(iv)We summarized and analyzed the independent signals of HLA region by e QTL to explore the influence of gene expressions by the different variants.(v) We gathered the clinical characteristics of the tested samples, such as age of onset, family history,severity of disease and type of skin lesion, and further performed genotype-phenotype analysis accordingly.Results: The imputation analysis of SNP2 HLA showed that there were 636 amino acid residue or position polymorphisms, 141 two or four-digit classic HLA alleles and 3,756 SNPs in the data.The most significant SNP, amino acid polymorphism and HLA classic allele were rs1265181(χ2= 4,404,OR = 4.77, 95%CI = 4.54-5.00), of HLA-C amino acid residue156Trp(χ2= 3654,OR = 3.68, 95%CI = 3.53-3.84) and HLA-C*06:02(χ2= 3,448,OR = 4.19, 95%CI = 3.98-4.40), respectively. The three loci have been explored previously by other researches.The subsequent stepwise regression analysis showed the 7 independent signals:HLA-B*15:18(P = 7.66×10-67,OR = 3.25,95% CI = 2.84 – 3.72)、rs6457710(P= 6.45×10-43,OR = 0.77,95% CI = 0.74 – 0.79)、rs9267487(P = 4.44×10-27,OR =1.72,95% CI = 1.56 – 1.90)、rs2523619(P = 6.33×10-17,OR = 1.34,95% CI = 1.25– 1.43)、rs3807031(P = 3.17×10-14,OR = 1.24,95% CI = 1.17 – 1.31)、rs887468(P = 9.89×10-12,OR = 1.32,95% CI = 1.22 – 1.42)and rs2523535(P = 2.20×10-9,OR = 0.82,95% CI = 0.77 – 0.88). We found that the SNPs had correlations with the expression of MICB, HLA-DPB1, HLA-G and other genes.Genotype-phenotype analysis identified the association between age of onset and rs1265181(P = 5.36×10-14,OR = 1.36,95% CI = 1.26- 1.47),rs2523619(P = 2.29×10-12,OR = 0.76,95% CI = 0.70-0.82) and rs887468(P = 1.67×10-8,OR = 1.28,95% CI =1.17-1.39); the severity and rs6457710(P = 4.07×10-2,OR = 1.14, 95% CI = 1.01 –1.30); the lesion type and rs6457710(P =3.69×10-30,OR = 1.65,95% CI = 1.51 – 1.80)as well as rs887468(P = 1.48×10-5,OR = 0.83,95% CI = 0.76 – 0.90), family history and rs887468(P = 1.91×10-3,OR = 1.12,95% CI = 1.04 – 1.21) as well as rs1265181(P= 3.25×10-3,OR = 1.11,95% CI = 1.04 – 1.19).Conclusion : Our study has identified 8 independent signals in the HLA region of Chinese Han population by fine mapping study of HLA region, and furthermore we have demostrated these signals had correlation with clinical phenotypes, such as age,disease severity, family history and skin lesion. The results indicated the important effect of HLA region on the development and progression of psoriasis and partially illustrated the pathogenesis of psoriasis. It would provide a potential theoretical evidence for clinic prediction, diagnosis and therapy. |
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