Dissecting the HLA contribution to Rheumatoid Arthritis

剖析 HLA 对类风湿关节炎的贡献

基本信息

批准号：
8094154
负责人：
Lindsey Ann Criswell
金额：
$ 23.32万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-06-28 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8094154
关键词：
6p21 Affect Alleles Arts Autoimmune Diseases Autoimmune Process Breast Feeding Caucasians Caucasoid Race Cells Characteristics Chromosomes Classification Clinical Complex DNA Sequence Disease Epigenetic Process Epitopes Family Fetus Genes Genetic Genetic Heterogeneity Genetic Screening Genetic Variation Genomic Imprinting Genomics Genotype Goals HLA-DRB1 Haplotypes Immune system Individual Inherited Investigation Knowledge Linkage Disequilibrium Logistic Regressions Major Histocompatibility Complex Methodology Microchimerism Modeling Modification Molecular Mothers NIMA Outcome Parents Pathogenesis Phenotype Postpartum Period Predisposition Pregnancy Pregnancy Histories Reporting Research Design Research Personnel Research Support Rheumatoid Arthritis Rheumatoid Factor Risk Role Screening procedure Testing Time Trees Variant base disease transmission disorder risk fetal imprint maternal imprint non-genetic novel programs reproductive secondary outcome trafficking transmission process

项目摘要

We propose to define the complex role of genes within the major histocompatability complex (MHC) region on chromosome 6p21 in rheumatoid arthritis (RA) pathogenesis. Our study design is based on the overall hypothesis that complex genetic and non-genetic MHC related mechanisms, including effects conferred by classical HLA loci, contribute to disease risk and clinical outcome. It is clear that the genetic contribution of the MHC to RA is substantial, with HLA-DRB1 alleles encoding the RA "shared epitope" demonstrating the most prominent association. However, previous research supports the presence of additional, possibly interacting, susceptibility loci within the MHC. Further, the extensive linkage disequilibrium in the region and incomplete knowledge of allelic variation in surrounding genes has been a major limiting factor in attempts to further define the genetic contribution of the MHC to RA. Through the recent efforts of the MHC Haplotype Project, all genes encoded within the -4.5 Mb MHC region have been identified and localized, and are now publicly available, providing an unparalleled molecular guide for deciphering the MHC contribution to RA. It is also evident that additional mechanisms such as genomic imprinting and non-inherited or environmental influences are likely to be involved in susceptibility to complex diseases such as RA. Using 1,000 stringently ascertained and clinically characterized RA families, state of the art genotyping methodologies, and novel analytical approaches we propose for the first time a comprehensive study of all genes residing within the MHC. In addition, we will investigate potential imprinting and maternal-fetal relationships in these families to determine whether MHC encoded loci and specific HLA alleles or haplotypes influence the risk of RA. These studies will unequivocally identify the genes and allelic variants residing in the MHC region involved in susceptibility to RA. Finally, due to the clinical and apparent genetic heterogeneity of RA, we will study specific RA phenotypes as secondary outcomes.

我们建议定义基因在主要的组织兼容性复合物（MHC）区域中的复杂作用。在类风湿关节炎（RA）发病机理中6p21染色体上。我们的研究设计基于整体假设复杂的遗传和非遗传MHC相关机制，包括由经典的HLA基因座，有助于疾病的风险和临床结果。显然，遗传贡献到RA的MHC很大，HLA-DRB1等位基因编码RA“共享表位”，证明了最杰出的关联。但是，以前的研究支持了其他，可能 MHC内的相互作用，敏感性基因座。此外，该地区的广泛连锁不平衡对周围基因的等位基因变异的不完整知识是试图尝试的主要限制因素进一步定义了MHC对RA的遗传贡献。通过MHC单倍型的最新努力项目，所有在-4.5 MB MHC区域内编码的基因均已鉴定和局部，现在已公开可用，提供了无与伦比的分子指南，以破译MHC对RA的贡献。它同样明显的是，基因组印记和非植产或环境等其他机制影响可能与对RA等复杂疾病的敏感性有关。严格使用1,000 确定和临床表征的RA家族，最先进的基因分型方法和新颖我们首次提出的分析方法是对所有基因的全面研究 MHC。此外，我们将调查这些家庭中潜在的烙印和孕产妇关系确定MHC编码基因座和特定的HLA等位基因或单倍型是否会影响RA的风险。这些研究将明确地识别属于与MHC区域的基因和等位基因变体对RA的敏感性。最后，由于RA的临床和明显的遗传异质性，我们将研究特定的RA表型作为次要结果。