Gene-Environment Interactions in RA Autoimmunity and Disease Severity

描述（由申请人提供）： 风湿性关节炎（RA）是一种全身性炎症性疾病，导致进行性关节破坏， 残疾和加速死亡。影响RA自身抗体产生和疾病严重性的因素尚未完全确定。然而，越来越多的数据表明，吸烟， 与疾病易感性相关，也与RA结果相关，其作用可能受到多种遗传因素的影响，包括编码共享表位（SE）和药物代谢酶（DME）多态性的HLA-DRB 1等位基因。检查RA严重程度的研究集中在 吸烟与单基因多态性的相互作用几乎完全包括 白种女人这是一个重要的区别，因为就类风湿关节炎风险（特别是自身抗体阳性疾病）而言，吸烟对男性的影响最大，而其他与吸烟相关的疾病 对非白种人的影响不成比例。我们将在来自退伍军人事务部RA（VARA）队列的800名受试者（包括600名白人男性）和来自NIH资助的非裔美国人早期RA纵向评估联盟（CLEAR）登记处的400名非裔美国人中检查自身抗体产生和疾病严重程度的决定因素。这项研究的总体假设是，吸烟与更大的自身抗体产生和更严重的RA相关，这种环境暴露的影响被多种基因吸烟相互作用所改变。本研究的目的是检查：1）吸烟与自身抗体水平和放射学指标的相关性，2）DME多态性与这些结果的相关性，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，待研究的遗传因素还包括DME多态性（编码N-乙酰转移酶[NAT]1、NAT 2、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（PTPN 22）。将检查的RA特异性结局包括放射学指标（改良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，将使用一种新的递归分区技术，将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扩展到其他RA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.