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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（由申请人提供）：拟议的项目是第一个探索性假设生成研究，旨在研究影响类风湿关节炎（RA）患者妊娠和产后期间疾病活动的候选基因，在纵向设置中使用基因表达谱。RA在怀孕期间的自然生理缓解和产后疾病的复发尚未得到彻底的检查。了解这些现象可以潜在地发现新的生物标志物和药物靶点，这将对RA的预后和治疗产生巨大影响。该项目的具体目标是：(1)招募一组计划怀孕的类风湿关节炎妇女，以及年龄匹配的对照组，并从受孕前、整个孕期到产后24个月对她们进行前瞻性随访；(2)收集详细的临床数据，包括对当前疾病活动的评估，以及每次随访时的血液样本。(3)对随时间收集的序列RNA样本进行全基因组基因表达谱分析，生成影响RA疾病活动性的候选基因列表。为了克服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处来识别孕前阶段患有类风湿关节炎的妇女。年龄匹配的对照将从同一人群中正常妊娠队列中招募。对于目的2，训练有素的研究护士将在整个研究过程中收集每位患者的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。CRP水平将被测量并用于DAS28- CRP评分的计算，作为疾病活动性的有效测量。全基因组基因表达分析将使用全血RNA进行，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，将使用时间序列微阵列数据可用的统计工具进行统计数据分析，并调整相关协变量。还将比较不同组之间的差异基因表达谱，包括缓解患者与产后（复发后）患者的妊娠谱，以及缓解患者与未缓解患者的妊娠谱。