Multi-Ethnic Study of Autoimmunity and Cardiovascular Disease

描述（由申请人提供）：临床表现明显的冠心病（CHD）与自身免疫性结缔组织疾病（CTD）包括类风湿关节炎和狼疮之间有明确的联系，但确切的机制尚未确定。有人提出CTD和冠心病之间的关联与常见的炎症过程有关。CTD相关的自身抗体在个体发展为类风湿关节炎和狼疮前已被发现，但大多数循环自身抗体阳性的个体不会发展为临床CTD。在冠心病中也发现了循环自身抗体，因此假设自身免疫可能参与动脉粥样硬化的发病机制。然而，目前尚不清楚亚临床ctd相关自身抗体是否与动脉粥样硬化和未来的临床冠心病相关。该团队的初步数据表明，ctd相关抗体与亚临床动脉粥样硬化之间存在关联：我们发现，在非洲裔美国人（AA）和高加索年轻人的储存血清中检测到的抗22糖蛋白I抗体（抗22- gpi）与8年和13年后测量的冠状动脉钙化（CAC）有关。我们希望扩展这一创新发现，以便1)确定这种关系是否存在于其他种族/民族、其他年龄组和其他自身抗体中；2)确认亚临床ctd相关自身抗体与CAC之间的时间关系，并扩展我们的工作以评估与随后的临床心血管疾病（CVD）事件的关系。为了验证亚临床ctd相关自身抗体导致亚临床动脉粥样硬化和临床CVD的假设，我们提出了以下目的，使用6814名多种族中老年受试者，他们将通过问卷调查排除活动性ctd: 1)确定基线（2000-2001年）收集的储存血清中测量的亚临床ctd相关自身抗体与CAC存在之间的横断面关联。2)确定基线亚临床ctd相关自身抗体与CAC发病率和进展之间的关系，随访2年和4年。3)确定基线自身抗体与10年随访期临床CVD事件之间的关系。4)评估自身抗体是否与较高水平的炎症标志物相关，以及自身抗体与CVD结局之间的关系是否由炎症标志物的差异介导。这些目标将由西北大学风湿病学和预防医学系的一组研究人员完成。我们将利用正在进行的多中心多种族动脉粥样硬化研究（MESA），一项自2000年以来随访的6814名高加索人、AA族、西班牙裔和亚裔受试者的前瞻性队列研究，在多种族人群中检查心血管疾病的早期阶段。MESA的血清储存、流行病学数据库、年龄较大、多种族，是本研究的理想资源，可能为预防心血管疾病提供新的途径。

DESCRIPTION (provided by applicant): There is a well established association between clinically apparent coronary heart disease (CHD) and autoimmune connective tissue diseases (CTD) including rheumatoid arthritis and lupus, but the exact mechanism is not established. It has been proposed that the association between CTD and CHD is related to common inflammatory processes. CTD-related autoantibodies have been identified in individuals years before they develop rheumatoid arthritis and lupus, but most individuals with positive circulating autoantibodies do not develop clinical CTD. Circulating autoantibodies have also been identified in CHD, thus it has been hypothesized that autoimmunity may contribute to the pathogenesis of atherosclerosis. However, it is not definitively known if subclinical CTD-related autoantibodies are associated with atherosclerosis and future clinical CHD. Preliminary data from this team suggest that there is an association between CTD-related antibodies and subclinical atherosclerosis: We found that the presence of anti-22 glycoprotein I antibodies (anti-22-GPI) measured in stored serum from African American (AA) and Caucasian young adults was associated with coronary artery calcification (CAC) measured 8 and 13 years later. We wish to extend this innovative finding in order to 1) determine if this relationship exists in other race/ethnicity groups, in other age groups and with other autoantibodies and 2) confirm the temporal relationship between subclinical CTD-related autoantibodies and CAC and extend our work to assess the relationship with ensuing clinical cardiovascular disease (CVD) events. To test our hypothesis that subclinical CTD-related autoantibodies lead to subclinical atherosclerosis and clinical CVD, we propose the following Aims using an existing cohort of 6814 multi-ethnic middle-aged to elderly subjects who will have active CTDs ruled out by a questionnaire: 1) Determine the cross-sectional association between subclinical CTD-related autoantibodies measured in stored sera collected at baseline (years 2000-2001) and presence of CAC. 2) Determine the association between baseline subclinical CTD-related autoantibodies and incidence, as well as progression, of CAC over 2 and 4 years follow-up. 3) Determine the association between baseline autoantibodies and clinical CVD events over 10 years follow-up. 4) Assess whether autoantibodies are associated with higher levels of inflammatory markers, and whether the relationship between autoantibodies and CVD outcomes are mediated by differences in inflammatory markers. These Aims will be accomplished by a team of investigators in the Division of Rheumatology and Department of Preventive Medicine at Northwestern University. We will utilize the ongoing multicenter Multi-Ethnic Study of Atherosclerosis (MESA), a prospective cohort of 6814 Caucasian, AA, Hispanic, and Asian subjects followed since 2000 to examine the early stages of CVD in a multi-ethnic population. With its stored sera, epidemiologic database, older age, and multi-ethnicity, MESA is an ideal resource for this proposed study, which may lead to new approaches for the prevention of CVD.