Mapping of Arthritis Susceptibility Genes

关节炎易感性基因图谱

基本信息

批准号：
8248343
负责人：
TIBOR T. GLANT
金额：
$ 43.91万
依托单位：
RUSH UNIVERSITY MEDICAL CENTER
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：
2010-04-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8248343
关键词：
Affect Age Alleles Animals Antibodies Arthritis Autoimmune Diseases Autoimmune Process B-Lymphocytes Candidate Disease Gene Cartilage Characteristics Chromosomes Chromosomes, Human, Pair 1 Chromosomes, Human, Pair 3 Clinical assessments Collagen Arthritis Complex Congenic Mice Congenic Strain Development Disease Disease susceptibility Event Experimental Arthritis Future Gender Gene Order Genes Genetic Genetic Recombination Genomics Goals Grant Histopathology Human Human Chromosomes Human Genome Hybrids Immune Immune response Immunization In Vitro Inbred BALB C Mice Inbred C3H Mice Individual Joints Knock-out Laboratories Major Histocompatibility Complex Maps Mediating Meiosis Modeling Mouse Strains Mus PTPN22 gene Phenotype Physical Map of the Human Genome Polyarthritides Polymorphic Microsatellite Marker Population Positioning Attribute Predictive Factor Predisposition Process Proteoglycan Quantitative Trait Loci Rattus Recording of previous events Regulatory Pathway Research Rheumatoid Arthritis Severities Severity of illness Susceptibility Gene T-Lymphocyte Testing abstracting aggrecan arthropathies autoimmune arthritis base congenic density disease phenotype gene cloning genome wide association study human disease in vivo lymph nodes mouse genome mouse model public health relevance resistant strain tool trait

项目摘要

DESCRIPTION (provided by applicant): Systemic immunization of BALB/c mice with human cartilage proteoglycan (PG) aggrecan induces progressive polyarthritis. This murine model (PG-induced arthritis; PGIA) shares similarities with rheumatoid arthritis (RA) as indicated by clinical assessments, laboratory tests, x-ray and histopathology of diarthrodial joints. Similar to RA, PGIA is a T cell-dependent and antibody/B cell-mediated autoimmune disease. Association of age and gender with disease development and severity, and recessive inheritance of disease susceptibility, dictated by both the major histocompatibility complex (MHC)- and non-MHC-associated genes are additional characteristics that make this model an ideal tool for genetic studies. While the MHC is a critical predictive factor both in RA and PGIA, the MHC alone is insufficient for the induction of autoimmune disease. Although large-scale genome-wide association (GVA) studies repeatedly showed linkage between certain chromosome regions and RA, not a single gene has been identified in the heterogeneous human population as a disease-inducing gene. During the past 10 years, we tested over 3,200 F2 hybrid (including 1,292 arthritic) mice of six different genetic intercrosses. A total of 29 genomic loci (Pgia1-Pgia29 ) controlling PGIA were identified. Many of these quantitative trait loci (QTLs) correlated with those identified in collagen-induced arthritis (CIA) in mice (mCia) and rats, colocalized with QTLs of other autoimmune models, and corresponded with human genomic regions identified in GWA studies of RA. Our hypothesis is that if a genomic locus is shared among different autoimmune or arthritis models, it is likely involved in similar immune regulatory pathways, which also operate in RA and perhaps in autoimmune diseases in general. We intentionally excluded the MHC effect using two murine strains carrying an identical H2d MHC allele, and we have generated five congenic strains containing DBA/2 (PGIA-resistant strain) alleles in chromosomes 3, 7, 8, 15 and 19 in BALB/c (PGIA-susceptible strain) background. The major QTLs were selected to correspond with syntenic regions of the human genome, where several RA-associated QTLs have been identified. After initial testing of these congenic and then subcongenic mouse strains, we selected Pgia26 on chromosome 3 (chr3) for subsequent studies to narrow the chromosome interval to a manageable size, and identify disease-suppressive (within the Pgia26a locus) and disease-promoting (in Pgia26b locus) genes. We selected Pgia26, because it appears to possess one of the most complex loci (after the MHC) regulating arthritis susceptibility and severity in PGIA, and the corresponding (syntenic) region on human chr1 (Chr1:95.2-151.7 Mbp region, including PTPN22) shows the most prominent linkage with RA, after the MHC. In the genomic research history of experimental arthritis, we have identified probably the smallest size of arthritis-associated genomic regions, and now we are in the process of selecting interval-specific congenic (IVSC) strains to reduce further the size of these critical loci. We propose two specific aims to select IVSC strains in both disease-suppressing Pgia26a (chr3:90.4/92.7-96.4/99.9 Mbp) and arthritis-promoting Pgia26b (chr3:108.1/109.2-115.8/121.1 Mbp position) to reduce the chromosome region to a manageable size (Aims 1A and 2A), and then prepare detailed physical maps and introduce positional candidate gene cloning (Aims 1B and 2B). Selected genes will be tested for their expression in arthritic joints and joint-draining lymph nodes, sequenced, and their in vivo (arthritis-affecting) function will be tested in either knockout or IVSC mice, carrying structurally and/or functionally altered gene(s) and altered disease phenotype. PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis (RA) is a complex joint disease affecting approximately 1 % of the human population. Large scale human familial genome-wide association studies have localized chromosome regions associated with RA, but no individual "causative" genes had been identified in the heterogeneous human population within these chromosome regions. We have developed a mouse model of RA, which shows many similarities to the human disease. We narrowed the genomic (chromosome) regions of a number of disease-associated regions, and selected a segment of mouse chromosome 3, which is highly associated with disease phenotype in our arthritis model. This chromosome region (Pgia26) contains both arthritis-promoting and -suppressing genes, and corresponds to a region of human chromosome 1, that shows the highest association with RA after the major histocompatibility complex (MHC). We propose to reduce the size of these regions in the mouse genome, which cannot be done in human population, and select candidate genes that may be involved in arthritis susceptibility and disease severity.

描述（由申请人提供）：使用人软骨蛋白聚糖（PG）Aggrecan对BALB/C小鼠进行全身免疫，可引起进行性多重关节炎。这种鼠模型（PG诱导的关节炎； PGIA）与临床评估，实验室测试，X射线和恐惧关节的组织病理学相似。与RA相似，PGIA是T细胞依赖性和抗体/B细胞介导的自身免疫性疾病。年龄和性别与疾病发展和严重程度的关联，以及疾病易感性的隐性遗传，这是由主要的组织相容性复合物（MHC）和非MHC相关基因决定的，这是使该模型成为遗传研究的理想工具的其他特征。尽管MHC是RA和PGIA中的关键预测因素，但仅MHC就不足以诱导自身免疫性疾病。尽管大规模基因组的关联（GVA）的研究反复显示某些染色体区域与RA之间的联系，但在异质人口中并未发现单个基因是诱发疾病的基因。在过去的10年中，我们测试了3,200多种F2杂种（包括1,292只关节炎）小鼠，这些小鼠的六种不同的基因间交联。总共确定了控制PGIA的29个基因组基因局（PGIA1-PGIA29）。这些定量性状基因座（QTL）中的许多与在胶原蛋白诱导的关节炎（CIA）（MCIA）和大鼠中与其他自身免疫模型的QTL共定位的小鼠（CIA）相关，并与RA的GWA研究中鉴定出的人类基因组区域相对应。我们的假设是，如果在不同的自身免疫性或关节炎模型中共享基因组基因座，则可能参与类似的免疫调节途径，该途径也可能在RA中起作用，也许是在自身免疫性疾病中。我们使用两种带有相同H2D MHC等位基因的鼠菌株有意排除MHC效应，并且我们在染色体3、7、8、15和19中产生了五个含有DBA/2（PGIA抗性菌株）等位基因的先天性菌株（PGIA usbalb/c（pGia usiblible敏感）。选择了主要的QTL与人类基因组的同步区域相对应，在该区域中已经鉴定出了几个与RA相关的QTL。在对这些先天性小鼠菌株进行初步测试后，我们在3染色体3（CHR3）上选择了PGIA26，以便随后的研究将染色体间隔缩小到可管理的大小，并鉴定出疾病抑制（在PGIA26A基因座中）（在PGIA26B Locus中）。我们选择了PGIA26，因为它似乎具有调节PGIA的关节炎易感性和严重程度的最复杂的基因座之一，以及人类CHR1的相应（同步）区域（CHR1：95.2-151.7 MBP区域，包括PTPN22），包括最突出的MHC与RAC互联。在实验性关节炎的基因组研究史上，我们已经确定了与关节炎相关的基因组区域的最小大小，现在我们正在选择间隔特异性的异基因（IVSC）菌株，以进一步减少这些关键基因座的大小。我们提出了两个具体目的，旨在在疾病抑制的PGIA26A（Chr3：90.4/92.7-96.4/99.9 MBP）和关节炎促进PGIA26B（CHR3：108.1/108.1/109.2-115.8/121.1.1 MBP位置）中，以降低CHROMOSOMOS的尺寸，以下是2A，准备详细的物理图并引入位置候选基因克隆（目标1B和2B）。选定的基因将在关节关节和淋巴结淋巴结（测序）中测试其表达，并将在敲除或IVSC小鼠中测试其体内（影响关节炎）功能，并在结构上和/或功能上改变的基因（S）和/或功能上改变的基因和疾病疾病现象型。公共卫生相关性：类风湿关节炎（RA）是一种复杂的关节疾病，影响了大约1％的人口。大规模的人类家族基因组的关联研究已经定位了与RA相关的染色体区域，但是在这些染色体区域内的异质人群中尚未鉴定出任何个体的“病因”基因。我们已经开发了RA的小鼠模型，该模型与人类疾病显示了许多相似之处。我们缩小了许多与疾病相关区域的基因组（染色体）区域，并选择了小鼠3染色体的一部分，这与我们的关节炎模型中的疾病表型高度相关。该染色体区域（PGIA26）既包含促进性关节炎和抑制基因），并且对应于人类1的一个区域，该区域显示出在主要的组织相容性复合物（MHC）之后与RA的最高关联。我们建议减少小鼠基因组中这些区域的大小，而小鼠基因组不能在人群中进行，并选择可能涉及关节炎敏感性和疾病严重程度的候选基因。