Mapping of Arthritis Susceptibility Genes

关节炎易感性基因图谱

• 批准号: 8639963
• 负责人: TIBOR T. GLANT
• 金额: $ 43.44万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8639963
• 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; 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; 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.

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 等位基因的两个小鼠品系排除 MHC 效应，并在 BALB/c（PGIA 敏感品系）背景下的 3、7、8、15 和 19 号染色体上生成了 5 个含有 DBA/2（PGIA 抗性品系）等位基因的同源品系。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，并鉴定疾病抑制基因（Pgia26a 位点内）和疾病促进基因（Pgia26b 位点内）。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，并且人类 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，以将染色体区域减少到可管理的大小（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/或功能改变的基因和改变的疾病表型的敲除小鼠或 IVSC 小鼠中测试它们的体内（影响关节炎的）功能。

项目成果

Disease-promoting and -protective genomic loci on mouse chromosomes 3 and 19 control the incidence and severity of autoimmune arthritis.

小鼠 3 号和 19 号染色体上的疾病促进和保护性基因组位点控制自身免疫性关节炎的发病率和严重程度。

• DOI: 10.1038/gene.2012.2
• 发表时间: 2012
• 期刊: Genes and immunity
• 影响因子: 5
• 作者: Glant,TT;Adarichev,VA;Boldizsar,F;Besenyei,T;Laszlo,A;Mikecz,K;Rauch,TA
• 通讯作者: Rauch,TA

Differentially expressed epigenome modifiers, including aurora kinases A and B, in immune cells in rheumatoid arthritis in humans and mouse models.

在人类和小鼠模型中，在类风湿关节炎中的免疫细胞中，差异表达的表观基因组修饰剂，包括Aurora激酶A和B。

• DOI: 10.1002/art.37986
• 发表时间: 2013-07
• 期刊: ARTHRITIS AND RHEUMATISM
• 作者: Glant, Tibor T.;Besenyei, Timea;Kadar, Andras;Kurko, Julia;Tryniszewska, Beata;Gal, Janos;Soos, Gyoergyi;Szekanecz, Zoltan;Hoffmann, Gyula;Block, Joel A.;Katz, Robert S.;Mikecz, Katalin;Rauch, Tibor A.
• 通讯作者: Rauch, Tibor A.

Transcription factor Zbtb38 downregulates the expression of anti-inflammatory IL1r2 in mouse model of rheumatoid arthritis.

• DOI: 10.1016/j.bbagrm.2018.09.007
• 发表时间: 2018-11
• 期刊: Biochimica et biophysica acta. Gene regulatory mechanisms
• 作者: T. Ocskó;D. Tóth;Gyula Hoffmann;Vilmos Tubak;T. Glant;T. Rauch

Genetics of rheumatoid arthritis - a comprehensive review.

• DOI: 10.1007/s12016-012-8346-7
• 发表时间: 2013-10
• 期刊: CLINICAL REVIEWS IN ALLERGY & IMMUNOLOGY
• 影响因子: 9.1
• 作者: Kurko, Julia;Besenyei, Timea;Laki, Judit;Glant, Tibor T.;Mikecz, Katalin;Szekanecz, Zoltan
• 通讯作者: Szekanecz, Zoltan

An Arthritis-Suppressive and Treg Cell-Inducing CD4+ T Cell Epitope Is Functional in the Context of HLA-Restricted T Cell Responses.

抑制关节炎和诱导 Treg 细胞的 CD4 T 细胞表位在 HLA 限制性 T 细胞反应中发挥作用。

• DOI: 10.1002/art.39444
• 发表时间: 2016
• 期刊: Arthritis & rheumatology (Hoboken, N.J.)
• 作者: deWolf,Charlotte;vanderZee,Ruurd;denBraber,Ineke;Glant,Tibor;Maillère,Bernard;Favry,Emmanuel;vanLummel,Menno;Koning,Frits;Hoek,Aad;Ludwig,Irene;vanEden,Willem;Broere,Femke
• 通讯作者: Broere,Femke