MOLECULAR GENETICS OF PSORIASIS AND PSORIATIC ARTHRITIS

这项建议旨在促进对遗传学的理解。 确定的免疫识别事件似乎是银屑病的基础 和银屑病关节炎。HLA基因，尤其是I类基因 基因座，已被确定为易感性的主要标志物， 很可能参与了潜在的不适当的免疫反应 银屑病和银屑病关节炎。HLA基因的精确身份 赋予易感性及其遗传作用机制， 相互作用仍然很模糊。此外，还有一个悖论， 尽管有很强的HLA等位基因关联， 在系谱研究中已经确定了复合体。其总体目标是 项目是使用最近开发的方法， HLA等位基因鉴定和先进的遗传分析， HLA关联的基础，从而确定性质， 许多基因提供了相互关联的分子基础， 易患银屑病和银屑病关节炎。 利用与临床研究者的合作， 已经积累了93个与银屑病关节炎无关的个体， 他们的家人。34个多功能家庭已经 识别日期。主要目标是（1）使用基于序列的 I类和II类MHC等位基因分型以进行关联研究 93例具有银屑病关节炎的种族同质个体， 单倍型相对风险法。重点将放在 明确定义HLA-A、B、C和DRB 1基因座等位基因， 识别可能存在的共同基序， 在这个分析中，敏感性更好。其他候选等位基因 在初步研究中似乎有希望的MHC基因座也将被 研究了(2)将研究范围扩大到下列人员的一级和二级亲属： 多发性银屑病关节炎家系， MHC单倍型遗传及其与受影响 兄妹(3)检查两种单倍型的等位基因对 使用单倍型相对风险和受影响同胞对的易感性 单倍型共享方法。确定MHC基因的组合 通过使用联系方法负责易感性 能够识别两个基因的贡献。

This proposal is directed to advancing understanding of the genetically determined immune recognition event that appears to underlie psoriasis and psoriatic arthritis. HLA genes, especially those of the class I loci, have been identified as major markers of susceptibility and very likely participate in the inappropriate immune response underlying psoriasis and psoriatic arthritis. The precise identity of the HLA genes that confer susceptibility and the mechanism of their genetic action and interaction remains quite obscure. Moreover there is a paradox in that despite strong HLA allelic associations only a weak linkage to the HLA complex has been identified in pedigree studies. The overall aim of this project is to use recently developed methods for the precise identification of HLA alleles and advanced genetic analyses to formalize the basis of the HLA association and thereby identify the nature and number of genes that provide the interrelated molecular basis of susceptibility to the development of psoriasis and psoriatic arthritis. Advantage is taken of a collaboration with clinical investigators who have accumulated 93 unrelated individuals with psoriatic arthritis and their family members. Thirty-four multiplex families have been identified to date. The primary objectives are to (1) use sequence-based typing of the class I and II MHC alleles to perform an association study of 93 ethnically homogenous individuals with psoriatic arthritis using the haplotype relative risk method. Emphasis will be placed on explicitly defining the HLA-A, B, C and DRB1 locus alleles with the goal of identifying the possible presence of shared motifs that correlate better with susceptibility in this analysis. Candidate alleles of other MHC loci that appear promising in preliminary studies will also be studied. (2) Extend the studies to first and second degree relatives of multiplex families with psoriatic arthritis propositi to define the inheritance of MHC haplotypes and their association with affected siblings. (3) Examine the contribution of alleles of both haplotypes to susceptibility using haplotype relative risk and affected sib pair haplotype sharing methods. Identify the combinations of MHC genes responsible for susceptibility through the use of linkage methodology capable of identifying the contribution of two genes.