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Gene Expression Profiling in a Prospective Rheumatoid Arthritis Pregnancy Cohort

预期类风湿性关节炎妊娠队列中的基因表达谱

基本信息

批准号：
8061651
负责人：
Damini Jawaheer
金额：
$ 18.24万
依托单位：
CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-12 至 2014-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8061651
关键词：
Age Antirheumatic Agents Biological Biological Assay Biological Markers Birth Blood specimen Candidate Disease Gene Clinical Clinical Data Cohort Studies Collection Complex Conceptions DNA Data Data Analyses Data Set Denmark Diagnosis Disease Disease Marker Disease remission Drug Delivery Systems Epigenetic Process Female Funding Future Gene Expression Gene Expression Profiling Genome Goals Investigation Joints Letters Longitudinal Studies Measures Molecular Profiling Morphologic artifacts Nurses Patients Pharmaceutical Preparations Physiological Play Population Pregnancy Property Protocols documentation RNA Recording of previous events Recruitment Activity Recurrent disease Registries Relapse Research Research Design Rheumatoid Arthritis Rheumatology Role Sampling Series Serum Source Staging Statistical Data Interpretation Swelling System Time Tissue-Specific Gene Expression Training Variant Whole Blood Woman base case control cohort experience follow-up normal aging novel outcome forecast pregnant prospective public health relevance repository reproductive rheumatologist therapeutic development tool

项目摘要

DESCRIPTION (provided by applicant): The proposed project is the first exploratory hypothesis-generating study to investigate candidate genes that influence disease activity during pregnancy and the post-partum period in rheumatoid arthritis (RA) patients, using gene expression profiling in a longitudinal setting. The natural physiological remission of RA during pregnancy and the post-partum relapse of the disease have not been thoroughly examined. An understanding of these phenomena can potentially uncover novel biomarkers and drug targets, which will have a huge impact on RA prognosis and treatment. The specific aims of the proposed project are (1) to recruit a cohort of women with RA who are planning to get pregnant, and age-matched controls, and follow them prospectively from before conception, throughout pregnancy and until 24 months post-partum, (2) to collect detailed clinical data, including assessment of current disease activity, as well as blood samples at each follow up, and (3) to perform whole-genome gene expression profiling on the serial RNA samples collected over time to generate a list of candidate genes that influence disease activity in RA. To overcome recruitment difficulties in the US and achieve aim 1, the proposed project will take advantage of an existing national rheumatology registry to identify women with RA at the pre-conception stage. Age-matched controls will be recruited from an ongoing collection of a normal pregnancy cohort from the same population. For aim 2, trained study nurses will collect detailed clinical information on each patient's history of RA and medication use, and their disease status (including measures of disease activity) and medication use throughout the study. Blood samples will also be drawn from the cases and controls at each time-point. CRP levels will be measured and used in computation of DAS28- CRP scores, as a validated measure of disease activity. Whole-genome gene expression analyses will be performed using RNA from whole blood to get a comprehensive view of gene expression profiles of the patients and controls at each time point. In order to take advantage of the longitudinal study design, statistical data analyses will be performed using statistical tools available for time-series microarray data, adjusting for relevant covariates. Differential gene expression profiles will also be compared between different groups, including gestation profiles compared to post-partum (after relapse) profiles among patients who undergo remission, and gestation profiles of patients who undergo remission compared to those who do not. PUBLIC HEALTH RELEVANCE: The underlying mechanisms for the amelioration and relapse of rheumatoid arthritis (RA) during and after pregnancy are unknown and have not been thoroughly explored mainly due to difficulties in recruiting pregnant RA patients. By investigating longitudinal changes in gene expression associated with changes in RA disease activity, the proposed study will provide a better understanding regarding the basis of the natural phenomena of remission and relapse of RA during and after pregnancy, respectively. Thus, it has the potential to uncover novel disease markers and new targets for therapeutic development, which may impact prognosis and treatment of RA.

描述(申请人提供)：该项目是第一个探索性的假说生成研究，使用纵向设置中的基因表达谱来调查影响类风湿关节炎(RA)患者孕期和产后疾病活动的候选基因。妊娠期类风湿性关节炎的自然生理缓解和产后复发尚未得到彻底的研究。对这些现象的了解可能会发现新的生物标记物和药物靶点，这将对RA的预后和治疗产生巨大影响。拟议项目的具体目标是(1)招募一组计划怀孕的RA患者和年龄匹配的对照组，并从受孕前、怀孕期间到产后24个月对她们进行前瞻性跟踪，(2)收集详细的临床数据，包括评估当前疾病活动，以及每次跟进时的血液样本，以及(3)对随着时间推移收集的系列RNA样本进行全基因组基因表达谱分析，以生成影响RA疾病活动的候选基因列表。为了克服在美国的招募困难并实现目标1，拟议的项目将利用现有的国家风湿病登记制度，在怀孕前阶段识别患有类风湿性关节炎的妇女。年龄匹配的对照组将从同一人群中持续收集的正常妊娠队列中招募。对于目标2，训练有素的研究护士将在整个研究过程中收集每个患者的RA病史和药物使用的详细临床信息，以及他们的疾病状态(包括疾病活动的测量)和药物使用情况。还将在每个时间点从病例和对照中抽取血液样本。C反应蛋白水平将被测量并用于计算DAS28-C反应蛋白评分，作为疾病活动性的有效衡量标准。将使用来自全血的RNA进行全基因组基因表达分析，以全面了解患者和对照组在每个时间点的基因表达谱。为了利用纵向研究设计，将使用可用于时间序列微阵列数据的统计工具进行统计数据分析，并对相关协变量进行调整。还将比较不同组之间的差异基因表达谱，包括缓解期患者与产后(复发后)患者的妊娠期差异，以及缓解期患者与非缓解期患者的妊娠期差异。公共卫生相关性：类风湿性关节炎(RA)在怀孕期间和怀孕后改善和复发的潜在机制尚不清楚，也没有得到彻底的探索，主要是因为招募怀孕的RA患者存在困难。通过研究与RA疾病活动性变化相关的基因表达的纵向变化，拟议的研究将提供关于RA在怀孕期间和怀孕后缓解和复发的自然现象的基础的更好的理解。因此，它有可能发现新的疾病标志物和治疗发展的新靶点，这可能会影响RA的预后和治疗。