Mapping of Arthritis Susceptibility Genes

关节炎易感性基因图谱

基本信息

批准号：
7879181
负责人：
TIBOR T. GLANT
金额：
$ 40.72万
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/7879181
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 Figs - dietary 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）：用人软骨蛋白聚糖（PG）聚集蛋白聚糖对BALB/c小鼠进行全身免疫可诱导进行性多关节炎。临床评估、实验室测试、X 射线和关节关节的组织病理学表明，这种小鼠模型（PG 诱导的关节炎；PGIA）与类风湿性关节炎（RA）有相似之处。与 RA 类似，PGIA 是一种 T 细胞依赖性、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，以及由主要组织相容性复合体 (MHC) 和非 MHC 相关基因决定的疾病易感性的隐性遗传，是使该模型成为遗传研究理想工具的附加特征。虽然 MHC 是 RA 和 PGIA 的关键预测因素，但单独的 MHC 不足以诱导自身免疫性疾病。尽管大规模全基因组关联（GVA）研究反复显示某些染色体区域与 RA 之间的联系，但在异质人群中没有一个基因被鉴定为疾病诱导基因。在过去 10 年中，我们测试了超过 3,200 只具有 6 种不同基因杂交的 F2 杂交小鼠（包括 1,292 只关节炎小鼠）。总共鉴定了 29 个控制 PGIA 的基因组位点 (Pgia1-Pgia29)。其中许多数量性状基因座 (QTL) 与小鼠 (mCia) 和大鼠胶原诱导性关节炎 (CIA) 中鉴定的基因座相关，与其他自身免疫模型的 QTL 共定位，并与 RA GWA 研究中鉴定的人类基因组区域相对应。我们的假设是，如果不同的自身免疫或关节炎模型共享一个基因组位点，那么它很可能参与类似的免疫调节途径，这些途径也在 RA 中起作用，并且可能在一般的自身免疫性疾病中起作用。我们故意使用携带相同 H2d MHC 等位基因的两个鼠品系排除 MHC 效应，并在 BALB/c 中的 3、7、8、15 和 19 号染色体上生成了五个含有 DBA/2（PGIA 抗性品系）等位基因的同源品系（PGIA-敏感菌株）背景。选择的主要 QTL 与人类基因组的同线性区域相对应，其中已经鉴定了几个与 RA 相关的 QTL。在对这些同源和亚同源小鼠品系进行初步测试后，我们选择了 3 号染色体 (chr3) 上的 Pgia26 进行后续研究，以将染色体间隔缩小到可管理的大小，并确定抑制疾病（在 Pgia26a 位点内）和促进疾病（在 Pgia26b 位点）基因中。我们选择 Pgia26，因为它似乎拥有最复杂的位点之一（仅次于 MHC），调节 PGIA 中的关节炎易感性和严重程度，以及人类 chr1 上的相应（同线）区域（Chr1：95.2-151.7 Mbp 区域，包括 PTPN22）显示出与 RA 的最显着的联系，仅次于 MHC。在实验性关节炎的基因组研究历史中，我们已经确定了可能是最小尺寸的关节炎相关基因组区域，现在我们正在选择间隔特异性同源（IVSC）菌株以进一步减小这些关键基因座的大小。我们提出了两个具体目标，即在抑制疾病的 Pgia26a（chr3：90.4/92.7-96.4/99.9 Mbp）和促进关节炎的 Pgia26b（chr3：108.1/109.2-115.8/121.1 Mbp 位置）中选择 IVSC 菌株，以减少染色体区域达到可管理的规模（目标 1A 和 2A），然后准备详细的物理图谱并引入位置候选基因克隆（目标1B和2B）。将测试选定的基因在关节炎关节和关节引流淋巴结中的表达、测序，并在携带结构和/或功能改变基因的敲除小鼠或 IVSC 小鼠中测试它们的体内（影响关节炎的）功能。）和改变的疾病表型。公众健康相关性：类风湿性关节炎 (RA) 是一种复杂的关节疾病，影响约 1% 的人口。大规模人类家族全基因组关联研究已经定位了与 RA 相关的染色体区域，但在这些染色体区域内的异质人群中尚未发现个体“致病”基因。我们开发了一种 RA 小鼠模型，它与人类疾病有许多相似之处。我们缩小了许多疾病相关区域的基因组（染色体）区域，并选择了小鼠 3 号染色体的一段，它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) 包含促进关节炎和抑制关节炎的基因，对应于人类 1 号染色体的一个区域，该区域与 RA 的关联性仅次于主要组织相容性复合体 (MHC)。我们建议减少小鼠基因组中这些区域的大小，这在人类中是不可能做到的，并选择可能与关节炎易感性和疾病严重程度有关的候选基因。