Genome-wide SNP association in psoriasis

描述(申请人提供)：牛皮癣是一种常见的慢性炎症性皮肤病，影响大约2%的北欧人口。10-40%的时间会伴有牛皮癣关节炎。牛皮癣是一种复杂的疾病，有许多诱因和环境因素。全面了解银屑病的遗传学对于了解其发病机制很重要，不太可能通过分析单一候选基因来揭示。一个主要的决定因素是HLAI类区域内的一个基因座(PSORS1)，在全基因组连锁扫描后，已有超过19个非人类白细胞抗原基因座被报道。人类白细胞抗原中相关等位基因的外显率约为10%，部分非人类白细胞抗原等位基因的上位性被认为是疾病发生所必需的。也可能有完全依赖于人类白细胞抗原的基因座。连锁分析在确定牛皮癣的易感基因方面取得的成功有限，常见的变异-常见疾病假说表明，全球基因组关联筛查在识别易感变异方面可能要成功得多。我们打算开发一种高吞吐量的全球筛选，以寻找从HapMap项目中识别的相关SNP。来自Illumina Hap300K阵列的317,000个SNP将在500个病例和欧洲来源的匹配对照中进行分型，先前对潜在亚结构进行了评估。将在1000个新确诊的病例和对照中对3840个SNPs进行跟踪研究。250个关联度最高的SNPs将被输入750个新确定的三个SNP。5-15个含有潜在牛皮癣易感基因的区域将被作为疾病基因/变异识别的目标。一旦确定了变异，它们及其易感基因将在我们完整的1250个病例/对照和1250个三联体中进行评估，这些病例代表了我们收集的所有病例，而不考虑种族。这将使对基因-基因和基因-环境相互作用的初步分析成为可能。

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.