| Introduction: Psoriasis is a chronic common hyperproliferative inflammatory disease of the skin, involving scalp, nails and joints that presents in several clinical forms. Family based analyses of psoriasis and numerous population-based epidemiological studies have confirmed the genetic basis of Psoriasis. The ethnic and genetic heterogeneity may contribute to the complexity of its clinical manifestation. Over past two decades, numerous studies were performed and identified multiple genetic factors related to psoriasis by linkage and association study. In particular, the genome-wide association study (GWAS) using affordable high throughput single nucleotide polymorphism (SNP) genotyping technology has become an extensively approach to identify susceptible genes for psoriasis nowadays. A large number of susceptibility genes and/or loci have been found.However, SNP-based association studies fail to fully explain the genetic component of psoriasis. Some studies have switched to increasing recognition of the critical roles of other genetic structural variations, including copy number variations (CNVs). In a recent study, the association of the deletion of two late cornified envelope (LCE) genes, LCE3C and LCE3B (LCE3CLCE3B-del), with psoriasis in 1,426 unrelated psoriatic patients and 1,406 controls from four populations of European ancestry has been reported.Object: The aim of this multicenter meta-analysis with individual patient data was to further investigate the contribution of LCE3CLCE3B-del to psoriasis susceptibility and its possible interaction with the HLA-Cw06 gene in PSORS1 locus in different populations. Meanwhile, the second aims was to investigate the association of haplotype of LCE3CLCE3B-del and the SNPs (rs4112788, rs10888502) in the same linkage disequilibrium (LD) block with psoriasis in Chinese Han population, and investigate whether the haplotype was associated with family history and onset age of paoriasis.Methods: A total of 9,389 psoriatic samples and 9,477 unrelated controls belonging to thirteen different data sets were included in this present study. In all, 13 cohorts from 12 populations, 9 of European ancestry (Finland, France, Germany, Ireland, Italy, Spain, The Netherlands, United Kingdom, and United States (US-California (US-CA) and US-Michigan (US-MI)), and 3 of Asiatic origin (China, Mongolia, and Japan), were included. Genotyping of the LCE3CLCE3B-del copy number variant was performed by multiplex direct PCR using a four-primer or three-primer assay as previously described, allowing the simultaneous detection of intact and deleted alleles. And the related SNPs including rs4112788, a tag SNP for the biallelic LCE3CLCE3B-del, and rs130076, a SNP in linkage disequilibrium with HLA-Cw06 gene were detected using Taqman.Results: 1. Association analyses of the genotyping data confirmed that the LCE3CLCE3B-del is a susceptibility determinant for psoriasis in the European ancestry populations, with a significantly higher frequency of the LCE3CLCE3B-del allele in psoriasis cases compared with controls (POverall=4.58×10-13, OROverall=1.21(1.15–1.27)). At the genotype level, the analysis suggests a potential dosage effect with genotypes having two copies of genes LCE3C and LCE3B being a protective factor against the development of the disease in the European ancestry populations(POverall=1.42×10-13, OROverall=1.20(1.15–1.28)). 2. The deletion is strongly associated with psoriasis in the Chinese and Mongolian populations with regard to both the allelic (P=1.70×10-07, OR=1.27(1.16–1.34); P=8.16×10-05, OR=2.08(1.44–2.99), respectively) and the genotype level (P=1.41×10-07, OR=1.28(1.16–1.41); P=9.38×10-05, OR=2.04 (1.41–2.94), respectively).3. The evidence for interaction between LCE3CLCE3B-del and HLA-Cw06 gene was observed in the Netherlands and the US-MI data set with a corresponding P-value of 0.016 and 0.00028. The interaction between rs4112788 and HLA-Cw06 gene also observed in them with a corresponding P-value of 0.018 and 0.00027.4. The only Chinese data sets haplotype analysis. Risk haplotype"del C"(order of variants: LCE3CLCE3B-del-rs4112788) was significantly associated with psoriasis in cases and controls (62.79% vs 57.19%) with a P-value of 5.85×10-7 which was two orders of magnitude higher in the two-marker haplotype analysis compared with three-marker analysis.5. The frequency of"Non-del C T"(order of variants: LCE3CLCE3B-del -rs10888502-rs4112788) haplotype was the most common one in cases and controls (28.55% vs 34.17%), with a corresponding P-value of 1.48×10-10, indicating it was the protective haplotype for psoriasis. Then,"del G C"haplotype was the second common in cases and controls (30.72% vs 25.84%) with the P-value of 1.95×10-5 indicating it was the risk one.6. The frequency of"Non-del G T"haplotype in controls, all psoriasis cases, type I psoriasis and type II psoriasis was 8.33%, 7.11%, 7.03% and 3.52%, respectively. It was significantly higher in type I psoriasis than in type II psoriasis with a corresponding P-value of 0.02. So it can conclude that this haplotype might play a more important role in onset age for psoriasis.Conclusion: The study confirms that the deletion of LCE3C and LCE3B is a common genetic factor for susceptibility to psoriasis in the European populations and for the first time directly demonstrates the deletion's association with psoriasis in the Chinese and Mongolian populations. The analysis of the HLA-Cw06 locus showed significant differences in the epistatic interaction with the LCE3C and LCE3B deletion in at least some European populations, indicating epistatic effects between these two major genetic contributors to psoriasis. The different haplotypes of LCE locus could play different roles in the pathogenesis of psoriasis at least in Chinese Han population. The study highlights the value of examining genetic risk factors in multiple populations to identify genetic interactions, and indicates the need of further studies to understand the interaction of the skin barrier and the immune system in susceptibility to psoriasis.
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