| Background Psoriasis is a common inflammatory hyperproliferative skin disease, characterized by thick, silvery scale patches. It affects up 2–5% of the population in Caucasians and 0.1–0.3% in Asians with considerable ethnic variation. A combination of genetic and environmental agents is implicated in its pathogenesis. Numerous family studies have provided compelling evidence of a genetic predisposition to psoriasis. Psoriasis can be classified into two types: type I with age of onset before 40 years associated with HLA and type II with age of onset after 40 years lacking HLA association. Within the past decade, several genome-wide linkage studies have reported many susceptibility loci for psoriasis, few of which have been confirmed, except for the MHC locus. Nowadays, genome-wide association study (GWAS) have been proven to be a powerful approach for screening the susceptibility genes (loci) of complex diseases. Taking advantage of these developments, ten GWAS on psoriasis have identified more than 20 susceptibility loci/genes, such as MHC, IL12B, IL23R, LCE, TNIP1, TRAF3IP2 and so on. These results provide us with many novel clues on disease pathogenesis, in both immune and non-immune pathways. Recently, we have identified 7 novel susceptibility loci associated with psoriasis in the Chinese Han population containing the candidate genes LCE, ERAP1, PTTG1, CSMD1, GJB2, SERPINB8 and ZNF816A and replicated 3 genes/loci, MHC, IL12B and 5q33.1 (TNIP1-ANXA6), previously reported in the European studies. However, these genetic signals do not fully account for the observed variation in genetic susceptibility to psoriasis, suggesting that additional genetic factors remain to be discovered.Objective (1) To explore additional susceptibility factors for psoriasis by extending our previous GWAS data. (2) To test whether genetic heterogeneity of psoriasis between the European and Chinese Han population by comparison between the results of our GWAS and previous GWAS in Europeans. (3) To explore the relationship of the SNPs with the psoriasis subphenotype by genotype-phenotype analysis in Chinese Han population.Methods (1) We collected all the cases and controls from the Chinese Han population through collaboration with multiple hospitals, which were matched by gender and geographic region. After quality controls, 8,339 cases and 12,185 controls were selected and separated into three independent stages in our study. Initial stage: To maximize the power of the study, we included data from our previously published GWAS of psoriasis, as well as data from 467 newly genotyped controls (in total, 1,139 psoriasis cases and 1,694 healthy controls), Replication 1: 2202 cases and 2206 controls and Replication 2: 4998 cases and 8285 controls. (2) The newly 467 controls in the initial stage were genotyped by Illumina Human 610-Quard BeadChips, and the genotyping data were combined with the previous GWAS data. After quality controls, we conducted genome wide association analysis, and selected several potentially associated SNPs for follow-up replication study in two independent cohorts (Replication 1 and Replication 2) using Sequenom MassArray. A joint association analysis using samples from the GWAS, Replication 1 and Replication 2 was performed to seach for the susceptibility SNPs associated with psoriasis in Chinese Han population. (3) In an attempt to uncover susceptibility genes underlying each of the association signals, we investigated the patterns of recombination and LD around the associated SNPs. (4) The psoriasis associated SNPs previously reported in Europeans were investigated in Chinese Han population. Combined with GWAS data, a comparison analysis was performed to explore the genetic heterogeneity of psoriasis within the two ethnic populations. (5) The association of the SNPs with psoriasis was analyzed by subphonotype (classified by age of onset and family history) stratification in Chinese Han population.Results (1) In extend of our previous genome-wide association study for psoriasis, we conducted a replication study by genotyping 58 SNPs from GWAS dataset in an independent sample of 2,202 cases and 2,206 controls from Chinese Han population (Replication 1), 4 SNPs showed evidence for association with psoriasis. We then selected these 4 SNPs to be genotyped in another independent cohort of 4,998 cases and 8,285 controls (Replication 2) and found consistent association evidence for 3 SNPs in each stage (GWAS, Replication 1 and Relication 2). (2) In the joint association analysis of all combined samples from the GWAS, replication 1 and replication 2, the SNP rs2303138 reached genome-wide significance with Pcombined=1.87×10-12. (3) After investigating the patterns of recombination and LD around the SNP rs2303138, we identified two genes (ERAP2 and LNPEP) located within same region of LD with SNP rs2303138. (4) We investigated 5 SNPs from 5 loci in Replication 2 that were previously reported to be associated with psoriasis in European populations. Combined with the GWAS data, we found significant association for 2 SNPs in Chinese Han population (rs4649203, Pcombined=2.29×10-12, OR=1.18, and rs8016947, Pcombined=5.26×10-7, OR=1.12, respectively), of which rs4649203 (IL28RA) have surpassed the genome-wide significance (P<5×10-8). (5) Five SNPs which have consistent association evidence in all three stages or show consistent significant association with psoriasis in both European and Chinese population were selected to be given a genotype-phenotype analysis to explore the relationships of these 5 SNPs and psoriasis subphenotypes in Chinese Han population. Two SNPs (rs2303138 and rs4649203) were preferentially associated with type 1 psoriasis in the combined Chinese Han datasets (rs2303238, P = 3.91×10-3, OR = 1.15; rs4649203, P=1.91×10-2, OR = 0.87). No nominal heterogeneity was observed between the odds ratios for the different subphenotypes stratified by family history.Conclusion This study was designed to maximize statistical power in a cost-effective manner by adopting a multistage analysis strategy in Chinese Han population, resulting in the identification of one new susceptibility loci (ERAP2/LNPEP) and replication of one gene IL28RA previously reported in the European studies. ERAP2/LNPEP and IL28RA were shown to be preferentially associated with Type I psoriasis in Chinese Han population. Our findings increase the number of genetic risk factors for psoriasis, which have also been implicated in biological pathway in development of psoriasis. Our results also suggest additional genetic factors that may contribute to its age of onset, and provide insight into the genetic heterogeneity of psoriasis between Chinese and European populations.
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