Mapping of Arthritis Susceptibility Genes

关节炎易感性基因图谱

• 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
• 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

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（由申请方提供）：用人软骨蛋白聚糖（PG）聚集蛋白聚糖全身免疫BALB/c小鼠诱导进行性多关节炎。该鼠模型（PG诱导的关节炎; PGIA）与类风湿性关节炎（RA）具有相似性，如临床评估、实验室检查、X射线和关节炎关节的组织病理学所示。与RA相似，PGIA是一种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的理想工具的额外特征。虽然MHC是RA和PGIA的关键预测因子，但单独的MHC不足以诱导自身免疫性疾病。虽然大规模的全基因组关联（GVA）研究反复表明某些染色体区域和RA之间的联系，没有一个单一的基因已被确定在异质人群作为一个疾病诱导基因。在过去的10年里，我们测试了超过3,200个F2杂交（包括1,292个关节炎）小鼠的6个不同的遗传互交。共鉴定出29个控制PGIA的基因组座位（Pgia 1-Pgia 29）。这些数量性状位点（QTL）中的许多与在小鼠（mCia）和大鼠的胶原诱导性关节炎（CIA）中鉴定的那些相关，与其他自身免疫模型的QTL共定位，并且与RA的GWA研究中鉴定的人类基因组区域相对应。我们的假设是，如果一个基因组位点在不同的自身免疫或关节炎模型中共享，那么它可能参与类似的免疫调节途径，这些途径也在RA中起作用，可能在一般的自身免疫疾病中起作用。我们有意排除了MHC的影响，使用两个鼠株携带相同的H2 d MHC等位基因，我们已经产生了5个同源株含有DBA/2（PGIA耐药株）等位基因在染色体3，7，8，15和19中的BALB/c（PGIA敏感株）的背景。选择的主要QTL与人类基因组的同线区域相对应，其中已经鉴定了几个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（chr 3）上的Pgia 26进行后续研究，以将染色体间隔缩小到可管理的大小，并确定疾病抑制（Pgia 26 a基因座内）和疾病促进（Pgia 26 b基因座内）基因。我们选择了Pgia 26，因为它似乎具有调节PGIA中关节炎易感性和严重性的最复杂的基因座之一（在MHC之后），并且人chr 1上的相应（同线）区域（Chr 1：95.2-151.7 Mbp区域，包括PTPN 22）显示出与RA的最突出的连锁，在MHC之后。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，以进一步减少这些关键位点的大小。我们提出了两个具体的目标，以选择IVSC菌株在疾病抑制Pgia 26 a（chr 3：90.4/92.7-96.4/99.9 Mbp）和关节炎促进Pgia 26 b（chr 3：108.1/109.2-115.8/121.1 Mbp位置），以减少染色体区域到可管理的大小（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）。将检测选定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/或功能改变的基因和改变的疾病表型的敲除或IVSC小鼠中检测其体内（关节炎影响）功能。 公共卫生相关性：风湿性关节炎（RA）是一种复杂的关节疾病，影响约1%的人口。大规模的人类家族性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单独的“致病”基因。我们已经开发了一种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，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（Pgia 26）包含关节炎促进和抑制基因，并且对应于人类1号染色体的区域，其在主要组织相容性复合体（MHC）之后显示与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，这在人类群体中无法做到，并选择可能参与关节炎易感性和疾病严重程度的候选基因。