Impact of genetic variation TLR/CD14 pathways and smoking in RA

描述(由申请人提供)： 类风湿关节炎(RA)是一种全身性炎症性疾病，可导致进行性关节破坏、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，也与类风湿性关节炎的预后相关，其影响可能被编码共同表位(SE)的HLA-DRB1等位基因改变。检查类风湿关节炎严重性的研究主要集中在吸烟与SE的相互作用上，这些群体中只有高加索女性。这一点很重要，因为就RA风险而言，吸烟对男性的影响最大，而其他与吸烟有关的疾病对非高加索人的影响不成比例。越来越多的数据表明，CD14和Toll样受体(TLRs)(发现于炎症细胞上的模式识别受体)的遗传变异可能解释了其他炎症/自身免疫条件表达的差异，在吸烟的背景下可能特别重要。我们将检查来自VARA队列的1300名受试者(包括约1040名高加索人)和680名非裔美国人(约500名来自Clear，约180名来自VARA)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，编码CD14/TLRs的基因变异将中介吸烟对RA特异性自身抗体产生、疾病严重程度和关节外疾病(最显著的是类风湿结节和肺部受累)的流行的有害影响。本研究的目的是：1)检测CD14/TLR基因变异与疾病特异性自身抗体产生和RA疾病严重程度的关系；2)吸烟与CD14/TLR基因变异之间的相互作用，作为疾病特异性自身抗体产生和RA疾病严重程度的决定因素。除了CD14/TLR基因的遗传多态性外，有待研究的因素还包括SE和蛋白酪氨酸磷酸酶(PTPN22)，这两个基因是RA的典型危险因素。将检查的RA特异性结果包括放射学测量(修正的Sharp评分)、类风湿因子(RF)、抗环瓜氨酸肽(CCP)抗体和关节外疾病(结节和肺部受累)。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。这项工作扩展了这个团队的高效合作，并代表了第一个系统研究CD14/TLR基因多态和吸烟在RA中的双重作用的研究之一。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。 公共卫生相关性： 叙述(与退伍军人健康相关)：关节炎及其相关疾病在退伍军人中比非退伍军人更常见，影响到超过三分之一的退伍军人医疗保健用户(Dominick KL等人)。J Rheumatol。2006)。尽管类风湿性关节炎影响了0.5%到1%的总人口，而且女性比男性更常见，但据估计，它影响了多达2%的退伍军人管理局医疗保健使用者。此外，与女性类风湿性关节炎相比，男性类风湿性关节炎(退伍军人管理局中最常见的人群)会导致更高的发病率和更糟糕的疾病相关结果。随着退伍军人人口老龄化和以男性为主，预计退伍军人管理局相应的疾病相关发病率、死亡率和医疗费用将继续上升。吸烟在退伍军人保健使用者中很常见，它与RA风险和更糟糕的疾病表现有关，这种联系似乎是由选定的遗传风险因素介导的。这项研究将对吸烟和CD14/TLR途径基因变异与两个研究极少的类风湿关节炎人群--男性和非裔美国人--的RA疾病表达之间的关系提供重要的见解。

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 severity 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 outcomes and its effect is likely modified by HLA-DRB1 alleles encoding the shared epitope (SE). Studies examining RA severity have focused on the interaction of smoking primarily with SE in groups that have exclusively included Caucasian women. This is important because smoking, in terms of RA risk has its greatest impact in men while other smoking related illnesses disproportionately impact non-Caucasians. There is increasing data that genetic variation in CD14 and Toll-like receptors (TLRs) (pattern recognition receptors found on inflammatory cells) may explain variability in the expression of other inflammatory/autoimmune conditions and may be particularly important in the context of smoking. We will examine determinants of autoantibody production and disease severity in 1300 subjects (including ~1040 Caucasians) from VARA cohort and 680 African Americans (~500 from CLEAR and ~180 from VARA). The overall hypothesis of this study is that variation in genes encoding CD14/TLRs will mediate the detrimental effect of smoking on RA-specific autoantibody production, disease severity, and the prevalence of extra-articular disease (most notably, rheumatoid nodules and lung involvement). The aims of this study are to examine: 1) the associations of genetic variation in CD14/TLR with disease-specific autoantibody production and measures of RA disease severity and 2) the interactions between cigarette smoking and genetic variation in CD14/TLR as determinants of disease-specific autoantibody production and RA disease severity. In addition to genetic polymorphisms of CD14/TLR genes, factors to be studied will include SE and protein tyrosine phosphatase (PTPN22), well characterized risk factors for RA. RA- specific outcomes that will be examined include radiographic measures (modified Sharp score), rheumatoid factor (RF), anti-cyclic citrullinated peptide (CCP) antibody, and extra-articular disease (nodules and lung involvement). 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. This effort extends the highly productive collaborations of this team and represents among the first study to systematically examine the dual role of CD14/TLR genetic polymorphisms and smoking in RA. We anticipate that the results of this study will be extended to other RA populations. PUBLIC HEALTH RELEVANCE: Narrative (Relevance to Veterans Health): Arthritis and its allied conditions are substantially more prevalent among veterans than non-veterans, affecting more than one-third of all VA healthcare users (Dominick KL et al. J Rheumatol. 2006). Although RA affects between 0.5% and 1% of the general population and is more common in women than men, it has been estimated to affect up to 2% of VA healthcare users. Moreover, compared to RA in women, RA in men (the demographic most commonly treated in the VA) leads to greater morbidity and worse disease-related outcomes. With an aging and predominantly male veteran population, it is anticipated that corresponding disease-related morbidity, mortality, and healthcare costs will continue to rise in the VA. Cigarette smoking, common among VA healthcare users, is associated with both RA risk and worse disease expression and this association appears to be mediated by select genetic risk factors. This study will provide important insight into the association of smoking and variation in CD14/TLR pathway genes with RA disease expression in two vastly understudied RA populations, men and African Americans.