MOLECULAR GENETICS OF PSORIASIS AND PSORIATIC ARTHRITIS

这项提议是为了促进对遗传基因的理解 确定的免疫识别事件似乎是银屑病的基础 和牛皮癣关节炎。人类白细胞抗原基因，特别是I类基因 基因座，已被确定为主要的易感和非常 可能参与潜在的不适当的免疫反应 牛皮癣和牛皮癣关节炎。人类白细胞抗原基因的精确识别 它们的易感性和遗传作用的机制以及 互动仍然相当模糊。此外，这其中存在着一个悖论 尽管与人类白细胞抗原有很强的等位基因关联，但与人类白细胞抗原的关联很弱 在系谱研究中已经发现了这种复合体。这样做的总体目标是 项目是使用最新开发的方法来精确地 人类白细胞抗原等位基因鉴定和先进的遗传分析正规化 人类白细胞抗原关联的基础，从而确定其性质和 提供相互关联的分子基础的基因数量 易患牛皮癣和牛皮癣关节炎。 利用与临床研究人员的合作 已经积累了93名患有银屑病关节炎和 他们的家人。34个多用途家庭已经被 到目前为止已经确定了。主要目标是(1)使用基于序列的 对I类和II类MHC等位基因进行分型以进行关联研究 93名患有银屑病关节炎的种族相同的人使用 单倍型相对风险法。重点将放在 明确定义人类白细胞抗原-A、B、C和DRB1等位基因的目的 识别可能存在的相关共享基序 在这项分析中，敏感度更好。其他的候选等位基因 在初步研究中看似有希望的MHC基因座也将是 学习。(2)将研究范围扩大到一级和二级亲属 银屑病关节炎先证者多个家系的定义 MHC单倍型的遗传及其与发病的关系 兄弟姐妹。(3)检验两种单倍型的等位基因对 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 通过使用连锁方法负责敏感度 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.