| Background Psoriasis is a common inflammatory hyper-proliferative skin disease,characterized by thick, silvery scale patches. It affects up2–5%of the population inCaucasians and0.1–0.3%in Asians with considerable ethnic variation.A combination ofgenetic and environmental agents is implicated in its pathogenesis. Psoriasis can beclassified into two types: type I with age of onset before40years associated with HLA-Cand type II with age of onset after40years lacking HLA-C association，while HLA-B27has been implicated in type2psoriasis.Within the past decade, several genome-widelinkage studies have reported many susceptibility loci for psoriasis, few of which havebeen confirmed, except for the MHC locus. Thus, a number of susceptibility loci forpsoriasis and PsA have been discovered. Although these loci explain only a fraction ofthe heritability estimates, a model of important pathways in psoriasis pathogenesis isemerging that combines skin barrier function （LCE3B, LCE3C）, TH17pathway （IL12B,IL23A, IL23R, TRAF3IP2, TYK2）, innate immunity [NFκB and IFN signaling pathway（TNFAIP3, TNIP1, NFKBIA, REL, TYK2, IFIH1, IL23RA） and β-defensin], TH2pathway （IL4, IL13）, and adaptive immunity involving CD8+T cells （ERAP1, ZAP70）.However, these genetic signals identified so far can not fully account for the pathogenesisof psoriasis, suggesting that additional genetic factors may exist. Furthermore,differences in the results of similarly-powered GWAS of psoriasis in Chinese and Caucasian populations suggest the existence of allelic and/or locus heterogeneitybetween different populations.Objective①To detect the association of risk loci for psoriasis identified in the previousGWAS study in Caucasian population with Chinese Uygur population in Xinjiang.②Toexplore the relationship of the SNPs with the psoriasis subphenotype bygenotype-phenotype analysis in Uygur population.③To explore the difference ofexpression of ERAP1gene between psoriasis lesion and normal skin。Methods①We collected all the cases and controls from the Chinese Uygur populationthrough collaboration with multiple hospitals, which were matched by gender andgeographic region. After quality controls,539cases and749controls were selected.②To maximize the power of the study, we included data from previously publishedGWAS of in Caucasian psoriasis population. After quality controls, we selected20potentially associated SNPs （especially SNP in loci of Il23R and L23A） for follow-upreplication study in our cohorts.③The genotyping analysis of the20SNPs wasperformed in539psoriasis patients and749controls of Chinese Uygur using theSequenom MassArray system （Sequenom iPLEX assay）.④The association of theSNPs with psoriasis was analyzed by PLINK Software.⑤Subphonotype （classified byage of onset and family history） stratification in Chinese Uygur population by SPSS13.0.⑥Analyzed the expression of ERAP1mRNA and protein level in the paired lesion andnon-psoriasis skins using quantitative real-time PCR and Western-blot analysis,respectively.⑦ERAP1protein qualitative expression in normal skin and psoriasisleison by Immunohistochemistry.Results①Among8SNPs, two were confirmed to be associated with Chinese Uygurpsoriatic group (SNP rs495337at ZNF313: P=4.0*10-3, OR=0.7917; SNP rs20541atIL13: P=2.1*10-3, OR=0.82).②Subgroup analysis showed that MAF of the two SNPssignificantly associated with type I psoriasis patients （p<0.05）. Rs20541might preferentially associated with psoriasis in early age of onset negative family historywhereas rs495337ass positive showed statistically difference between positive familyhistory of psoriasis patients and controls.③a significant2-locus interaction wasobserved by MDR between SNP rs495337and rs20541with a cross-validationconsistency of4/5and average balanced prediction （accuracy=55.5%, p<0.001）.④ourstudy failed to find any evidence in support of the association of IL23R and IL23A withpsoriasis in Xinjiang Uygur population.⑤ERAP1mRNA expressed in both normal skinand psoriasis skin lesion. Our study showed no statistical difference in two groups（P＞0.05）⑥ERAP1protein had not been detected in normal skin and psoriasis lesion bywestern-blot.⑦ERAP1protein expressed in basal cell and DC in both psoriasis andnormal skin. The expression of ERAP1is higher in serious inflammatory response ofpsoriasis than in long-lasting or steady lesions.Conclusion①Our study not only replicate the association of ZNF313and IL13previously reported in the European studies with psoriasis in the Chinese Uygurpopulation. ZNF313and IL13were shown to be preferentially associated with Type Ipsoriasis in Chinese Uygur population. Our results abundunt the number of genetic riskfactors for psoriasis, which have also been implicated in biological pathway indevelopment of psoriasis. Our findings also provide insight into the genetic heterogeneityof psoriasis between Chinese and European populations.②ERAP1expressed in KC andDC in skin and may Participate in the Pathogenesis of Psoriasis. |
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