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，残疾和加速死亡率。影响RA中自身抗体生产和疾病严重程度的因素尚未完全定义。但是，数据越来越多，表明吸烟与疾病敏感性相关的吸烟也与RA的结果有关，其影响可能通过编码共享表位（SE）的HLA-DRB1等位基因来改变。研究RA严重程度的研究集中在主要与SE的相互作用上，这些吸烟与仅包括高加索妇女在内的组中的相互作用。这很重要，因为就RA风险而言，吸烟对男性具有最大的影响，而其他与吸烟有关的疾病则不成比例地影响非高加索人。越来越多的数据表明，CD14和Toll样受体（TLR）（在炎症细胞上发现的模式识别受体）的遗传变异可能解释了其他炎症/自身免疫性条件的表达变异性，并且在吸烟的背景下可能尤其重要。我们将研究来自Vara队列的1300名受试者（包括约1040名高加索人）和680名非裔美国人的自身抗体生产和疾病严重程度的决定因素（来自Clear的〜500，来自Vara的〜180）。这项研究的总体假设是，编码CD14/TLR的基因的变化将介导吸烟对RA特异性自身抗体的产生，疾病严重程度以及关节外疾病的患病率（最值得注意的是，类风湿结节和肺参与）的有害作用。这项研究的目的是检查：1）CD14/TLR的遗传变异与疾病特异性自身抗体的产生和RA疾病严重程度的测量以及2）CD14/TLR的遗传变异之间的相互作用作为疾病特异性自身抗体生产和RA疾病严重程度的确定性之间的相互作用。除了CD14/TLR基因的遗传多态性外，要研究的因素还包括SE和蛋白质酪氨酸磷酸酶（PTPN22），RA的危险因素良好。将要检查的特异性结果包括放射线照相措施（修饰的尖锐得分），类风湿因子（RF），抗环状柑橘类肽（CCP）抗体和关节外疾病（结节和肺部参与）。除了传统的统计方法外，还将使用一种新型的递归分区技术，该技术将允许在多个候选基因和吸烟中同时进行检测。这项工作扩展了该团队的高效合作，并代表了首次研究CD14/TLR遗传多态性和在RA中吸烟的双重作用的研究。我们预计这项研究的结果将扩展到其他RA人群。 公共卫生相关性： 叙事（与退伍军人健康相关）：在退伍军人中，关节炎及其相关状况比非退伍军人更为普遍，影响了所有VA医疗保健使用者中的三分之一以上（Dominick KL等人Jrheumatol。2006）。尽管RA影响了一般人口的0.5％至1％，并且在女性中比男性更为普遍，但据估计，它会影响多达2％的VA医疗保健使用者。此外，与女性的RA相比，男性（VA中最常见的人群）的RA会导致更大的发病率和与疾病相关的结果更大。随着老化和主要是男性退伍军人的人口，预计与疾病相关的发病率，死亡率和医疗保健成本将继续上升。在VA医疗保健使用者中常见的吸烟与RA风险和疾病表达较差有关，这种关联似乎是由某些遗传危险因素介导的。这项研究将为CD14/TLR途径基因的吸烟与变异的关联与RA疾病的表达相关联，在两个研究大量研究的RA人群，男性和非裔美国人中。