Genome-wide SNP association in psoriasis

描述（由申请人提供）：银屑病是一种常见的慢性炎症性皮肤病，影响约2%的N。欧洲人口。10-40%的时间，它是伴随着银屑病关节炎。银屑病是一种复杂的疾病，有许多诱发变异和环境触发因素。全面了解银屑病的遗传学对于了解其发病机制非常重要，并且不太可能通过分析单个候选基因来揭示。一个主要的决定因素是HLA I类区域（PSORS 1）内的基因座，并且在全基因组连锁扫描后已经报道了超过19个非HLA基因座。HLA内相关等位基因的等位率约为10%，据信疾病发展需要与这些非HLA等位基因中的一些上位性。也可能存在完全HLA依赖性的基因座。连锁分析在确定银屑病易感基因位点方面取得的成功有限，而常见变异-常见疾病假说表明，全球基因组关联筛选在确定易感变异方面可能更为成功。我们打算利用一个高通量的全球屏幕相关的SNPs，确定从人类基因组单体型图项目。来自Illumina Hap 300 K阵列的317，000个SNP将在500个病例中进行分型，并匹配欧洲起源的对照，先前评估了潜在的子结构。将在1,000例新确定的病例和对照中进行3840个SNPs的随访研究。250个最高度相关的SNP将在750个新确定的三重中进行分型。5-15携带潜在银屑病易感基因的区域将被靶向用于疾病基因/变体鉴定。一旦鉴定出变异体，将在我们完整的>1250例病例/对照和1250个三人组中评估它们及其易感基因，这些病例/对照和三人组代表我们收集的所有病例，而不考虑种族。这将允许基因-基因和基因-环境相互作用的初步分析。

DESCRIPTION (provided by applicant): Psoriasis is a common, chronic inflammatory skin disease that affects approximately 2% of the N. European population. 10-40% of the time it is accompanied by psoriatic arthritis. Psoriasis is a complex disease with a number of predisposing variants and environmental triggers. A comprehensive understanding of the genetics of psoriasis is important for understanding its pathogenesis and is unlikely to be revealed by an analysis of single candidate genes. One major determinant is a locus within the HLA class I region (PSORS1) and over nineteen non-HLA loci have been reported following genome-wide linkage scans. The penetrance of associated alleles within HLA is ~10% and it is believed that epistasis with some of these non HLA alleles is required for disease development. There may also be loci that are entirely HLA-dependent. Linkage analyses have had limited success in identifying susceptibility loci for psoriasis, and the common variant-common disease hypothesis suggests that a global genome association screen may be far more successful at identifying susceptibility variants. We intend to exploit a high throughput global screen for associated SNPs, identified from the HapMap project. 317,000 SNPs from the Illumina Hap300K array will be typed in 500 cases and matched controls of European origin, previously evaluated for underlying substructure. Follow-up studies of 3840 SNPs will be performed in 1,000 newly ascertained cases and controls. 250 of the most highly associated SNPs will be typed in 750 newly ascertained trios. 5-15 regions harboring potential psoriasis susceptibility genes will be targeted for disease gene/variant identification. Once variants are identified they, and their predisposing genes will be evaluated in our complete set of >1250 cases/controls and 1250 trios, representative of all cases in our collection, regardless of ethnicity. This will permit a preliminary analysis of gene-gene and gene-environment interactions.