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

遗传变异 TLR/CD14 通路和吸烟对 RA 的影响

• 批准号: 7687127
• 负责人: TED RICHARD MIKULS
• 金额: --
• 依托单位: OMAHA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7687127
• 关键词: Affect; African American; Aging; Alabama; Alleles; Ally; American; Animal Model; Antigens; Arthritis; Attenuated; Autoantibodies; Autoimmune Process; Autoimmunity; CD14 gene; Candidate Disease Gene; Caucasians; Caucasoid Race; Cells; Collaborations; Data; Detection; Disease; Disease susceptibility; Endotoxins; Epitopes; Evaluation; Exposure to; Fibrinogen; Gene-Modified; General Population; Genes; Genetic; Genetic Polymorphism; Genetic Variation; HLA-DRB1; Health; Health Care Costs; Healthcare; Heat shock proteins; High Prevalence; Inflammatory; Ligands; Link; Lung; Lung nodule; Measures; Mediating; Mediator of activation protein; Minority; Morbidity - disease rate; Natural Immunity; Outcome; PTPN22 gene; Pathology; Pathway interactions; Pattern recognition receptor; Peptide antibodies; Play; Population; Prevalence; Production; Protein Tyrosine Phosphatase; Receptor Gene; Receptor Signaling; Research; Research Personnel; Rheumatoid Arthritis; Rheumatoid Factor; Rheumatoid Nodule; Risk; Risk Factors; Role; Serum; Severities; Severity of illness; Single Nucleotide Polymorphism; Smoker; Smoking; Synovial Membrane; TLR9 gene; Techniques; Testing; Toll-Like Receptor 1; Toll-Like Receptor 2; Toll-Like Receptor Pathway; Toll-like receptor 6; Toll-like receptors; Universities; Variant; Veterans; Woman; adaptive immunity; arthritis registry; cigarette smoking; cigarette smoking; cohort; cyclic citrullinated peptide; cytokine; disability; disease phenotype; genetic risk factor; human TLR7 protein; insight; joint destruction; male; men; mortality; novel; public health relevance; receptor expression; smoking prevalence; toll-like receptor 4

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.

描述（由申请人提供）： 类风湿性关节炎 (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 RA 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 RA 结局相关，其影响可能会被编码共享表位 (SE) 的 HLA-DRB1 等位基因改变。检查 RA 严重程度的研究主要集中在吸烟与 SE 的相互作用上，该群体仅包括白人女性。这一点很重要，因为就 RA 风险而言，吸烟对男性的影响最大，而其他与吸烟相关的疾病对非白种人的影响则不成比例。越来越多的数据表明，CD14 和 Toll 样受体 (TLR)（炎症细胞上发现的模式识别受体）的遗传变异可以解释其他炎症/自身免疫性疾病表达的变异性，并且在吸烟的情况下可能特别重要。我们将检查来自 VARA 队列的 1300 名受试者（包括约 1040 名白种人）和 680 名非裔美国人（约 500 名来自 CLEAR 和约 180 名来自 VARA）的自身抗体产生和疾病严重程度的决定因素。本研究的总体假设是，编码 CD14/TLR 的基因变异将介导吸烟对 RA 特异性自身抗体产生、疾病严重程度和关节外疾病（最明显的是类风湿结节和肺部受累）患病率的不利影响。本研究的目的是检查：1) CD14/TLR 遗传变异与疾病特异性自身抗体产生和 RA 疾病严重程度测量的关联；2) 吸烟与 CD14/TLR 遗传变异之间的相互作用作为 RA 疾病的决定因素。疾病特异性自身抗体的产生和 RA 疾病的严重程度。除了 CD14/TLR 基因的遗传多态性之外，要研究的因素还包括 SE 和蛋白酪氨酸磷酸酶 (PTPN22)，它们是 RA 的明确危险因素。将检查的 RA 特异性结果包括放射学测量（改良的 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之外，还将使用一种新颖的递归分区技术，该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。这项工作扩展了该团队高效的合作，并代表了第一个系统地研究 CD14/TLR 遗传多态性和吸烟在 RA 中的双重作用的研究。我们预计这项研究的结果将推广到其他 RA 人群。 公共卫生相关性： 叙述（与退伍军人健康的相关性）：关节炎及其相关疾病在退伍军人中比非退伍军人更为普遍，影响了所有 VA 医疗保健用户的三分之一以上（Dominick KL 等人 J Rheumatol. 2006）。尽管 RA 影响一般人群的 0.5% 至 1%，并且女性比男性更常见，但据估计，最多 2% 的 VA 医疗保健使用者会受到 RA 的影响。此外，与女性 RA 相比，男性 RA（退伍军人管理局最常治疗的人群）会导致更高的发病率和更差的疾病相关结果。随着退伍军人人口老龄化且以男性为主，预计退伍军人事务部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 VA 医疗保健使用者中很常见，与 RA 风险和病情恶化有关，而且这种关联似乎是由特定的遗传风险因素介导的。这项研究将提供重要的见解，以了解吸烟和 CD14/TLR 通路基因变异与两个被广泛研究的 RA 人群（男性和非裔美国人）中 RA 疾病表达的关系。