Identification of a gender-specific rat arthritis locus

描述(申请人提供)：大鼠胶原性关节炎(CIA) 是一种成熟的实验动物模型，已经被用来获得 洞察类风湿性关节炎(RA)的发病机制 常见致残性疾病，在大多数人群中的患病率为1%。两者都有 CIA和RA是由MHC和非MHC基因调控的复杂性状疾病， 两者在女性中的易感性都增加了，类风湿关节炎女性对男性的易感性增加 3：1的比例。女性优势增加的原因 对类风湿性关节炎的认识较少。性腺激素，尤其是性腺激素 它们的水平与疾病的发病机制有关，但这并不是 说明了疾病表现的所有性别差异。潜在的 这一建议的假设是，控制易感性的非MHC基因座 而大鼠CIA的严重程度与RA的发病机制高度相关， 而且至少一部分CIA的遗传易感性是不同的 在雌性和雄性之间，有特定的基因在一个性别中控制疾病 但不是在另一个地方。这些性别特异基因的鉴定，以及 调节他们外向的性别因素将与 对女性增长因素的认识 易感性，并可能产生更多发展的新目标 用于预防、诊断和预后的特殊疗法。在对……的研究中 MHC完全相同的近交系CIA易感DA大鼠F2杂交的CIA 和CIA耐药的ACI大鼠，性别在易感性和在 关节炎的严重性。对女性和男性分别进行的全基因组扫描 导致在12号染色体上发现了一个新的非MHC基因座Cia12， 这规范了女性的CIA，占遗传贡献的24% 与关节炎严重程度的差异有关，但在男性中不是。《老鼠城》12 间隔，其在小鼠和人类基因组中的同线区域包含基因座 调节几种形式的自身免疫性疾病，包括关节炎， 这表明该基因可能与不同的疾病有关，强调 这项研究的更广泛的相关性。为了鉴定这个基因，并确认和 为了确定其特定性别的影响，计划采取一种综合方法。论AIM 1，将生成速度等值线，从 ACI大鼠进入DA背景，反之亦然，将对两性进行研究 单独为中情局工作。在……上面 目标2，性腺激素和神经内分泌操作预计将 确定调节Cia12的特定性别的机制。在AIM 3上，Subs- 可能更直接地参与自身免疫反应的表型 由CIA12调控的复合型关节炎表型，将被鉴定 并用于缩小感兴趣的区间。这一目标还将 提供对Cia12基因功能的更多了解。在目标4上 特定的基因将根据候选基因分析或 位置克隆和致病等位基因变异。

DESCRIPTION (provided by applicant): Collagen-induced arthritis (CIA) in rats is a well-established experimental animal model that has been used to gain insight into the pathogenesis of rheumatoid arthritis (RA), a chronic and commonly disabling disease with a prevalence of 1% in most populations. Both CIA and RA are complex trait diseases regulated by MHC and non-MHC genes, and both have an increased susceptibility among females, with a RA female to male ratio of 3:1. The factors that account for the increase female preponderance of RA are poorly understood. Gonadal hormones, particularly a reduction in their levels, have been implicated in disease pathogenesis, but that does not account for all the gender differences in disease expression. The underlying hypotheses of this proposal are that the non-MHC loci governing susceptibility and severity of CIA in rats will be highly relevant to the pathogenesis of RA, and also that at least part of the genetic susceptibility to CIA differs between females and males, with certain genes regulating disease in one gender but not in the other. The identification of these sex-specific genes, and the sex factors regulating their penetrance will be of great relevance to the understanding of the factors accounting for the increased female susceptibility, and could generate new targets for the development of more specific therapies, for prevention, diagnosis and prognosis. In a study of CIA in a F2 intercross between MHC identical inbred CIA-susceptible DA rats and CIA-resistant ACI rats, gender had a major effect in susceptibility and in arthritis severity. A genome-wide scan done separately for females and males led to the identification of a new non-MHC locus, Cia12, on chromosome 12, that regulates CIA in females, accounting for 24% of the genetic contribution to the variance in arthritis severity, but not in males. The rat Cia12 interval, and its syntenic regions in the mouse and human genomes contain loci regulating several forms of autoimmune diseases, including arthritis, suggesting that this gene may be relevant to different diseases, underscoring the broader relevance of this study. To identify this gene and to confirm and characterize its sex-specific effect a combined approach was planned. On Aim 1, speed-congenic lines will be generated, introducing the Cia12 interval from ACI rats into DA background, and vice-versa, and both genders will be studied separately for CIA. On Aim 2, gonadal hormones and neuro-endocrine manipulation are anticipated to determine the sex-specific mechanisms regulating Cia12. On Aim 3, sub- phenotypes involved in the autoimmune response, perhaps more directly regulated by Cia12 than the complex arthritic phenotype, will be identified and used in the narrowing of the interval of interest. This aim will also provide additional insight into the Cia12 gene function. On Aim 4 the specific gene will be identified based on candidate gene analysis or positional cloning, and disease-causing allelic variations characterized.