Gene-Environment Interactions in RA Autoimmunity and Disease Severity

描述(由申请人提供)： 类风湿性关节炎(RA)是一种导致进行性关节破坏的全身性炎症性疾病， 残疾和加速死亡。影响类风湿关节炎自身抗体产生和疾病严重程度的因素尚未完全明确。然而，越来越多的数据表明，吸烟， 与疾病易感性有关，也与类风湿关节炎的预后有关，其影响可能受到多种遗传因素的影响，包括编码共有表位(SE)和药物代谢酶(DME)基因的HLA-DRB1等位基因。检查类风湿关节炎严重性的研究主要集中在 吸烟与单基因多态的交互作用几乎完全包括 高加索女性。这是一个重要的区别，因为就RA风险而言，吸烟(特别是对自身抗体阳性的疾病)对男性的影响最大，而其他与吸烟有关的疾病 对非高加索人的影响不成比例。我们将研究来自退伍军人事务部RA(VARA)队列的800名受试者(包括600名高加索男性)和来自NIH资助的非裔美国人纵向评估非裔美国人早期RA(CLEAR)登记的400名非裔美国人的自身抗体产生和疾病严重性的决定因素。这项研究的总体假设是吸烟与更多的自身抗体产生和更严重的类风湿性关节炎相关，这种环境暴露的影响被多个基因-吸烟相互作用所改变。这项研究的目的是检查：1)吸烟与自身抗体水平和放射学测量的关系，2)二甲基醚基因多态与这些结果的关系，以及3)与这些结果相关的基因-吸烟相互作用的作用。除SE外，将研究的遗传因素包括二甲醚多态(编码N-乙酰转移酶[NAT]1、NAT2、微粒体环氧化物水解酶和谷胱甘肽S转移酶的基因)和蛋白酪氨酸磷酸酶(PTPN22)。将检查的RA特异性结果包括放射学测量(修正的Sharp评分)、结节、类风湿因子(RF)和抗环瓜氨酸肽(CCP)抗体。除了传统的统计方法外，还将使用一种新的递归分割技术，允许检测多个候选基因和吸烟之间的同时相互作用。我们预计，这项研究的结果将推广到其他类风湿性关节炎人群。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a systemic inflammatory disease that leads to progressive joint destruction, disability, and accelerated mortality. Factors that influence autoantibody production and disease everity in RA have not been fully defined. However, there is increasing data showing that cigarette smoking, associated with disease susceptibility, is also associated with RA outcome and its effect is likely modified by multiple genetic factors including HLA-DRB1 alleles encoding the shared epitope (SE) and drug metabolizing enzyme (DME) polymorphisms. Studies examining RA severity have focused on the interaction of smoking with single gene polymorphisms in groups that have almost exclusively included Caucasian women. This is an important distinction because smoking, in terms of RA risk (particularly for autoantibody positive disease), has its greatest impact in men while other smoking related illnesses disproportionately impact non-Caucasians. We will examine determinants of autoantibody production and disease severity in 800 subjects (including 600 Caucasian men) from the Veterans Affairs RA (VARA) cohort and 400 African Americans from the NIH-funded Consortium for the Longitudinal Evaluation of African Americans with Early RA (CLEAR) registry. The overall hypothesis of this study is that smoking is associated with greater autoantibody production and more severe RA and the effect of this environmental exposure is modified by multiple gene-smoking interactions. The aims of this study are to examine: 1) associations of smoking with autoantibody levels and radiographic measures, 2) associations of DME polymorphisms with these outcomes, and 3) the role of gene-smoking interactions relevant to these outcomes. In addition to SE, genetic factors to be studied will include DME polymorphisms (in genes encoding N-acetyltransferase [NAT]1, NAT2, microsomal epoxide hydrolase, and glutathione S-transferase), and protein tyrosine phosphatase (PTPN22). RA-specific outcomes that will be examined include radiographic measures (modified Sharp score), nodules, rheumatoid factor (RF), and anti-cyclic citrullinated peptide (CCP) antibody. In addition to traditional statistical approaches, a novel recursive partitioning technique will be used that will allow for the detection simultaneous interactions among multiple candidate genes and smoking. We anticipate that the results of this study will be extended to other RA populations.