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

• 批准号: 7772215
• 负责人: Damini Jawaheer
• 金额: $ 15.13万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-12 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7772215
• 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

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的假设生成研究，以调查候选基因，影响疾病活动在妊娠期间和产后期间的类风湿性关节炎（RA）患者，在纵向设置中使用基因表达谱。妊娠期RA的自然生理缓解和产后疾病复发尚未得到彻底检查。对这些现象的理解可能会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。拟议项目的具体目标是：（1）招募一组计划怀孕的类风湿性关节炎女性和年龄匹配的对照组，并从受孕前、整个妊娠期和产后24个月对她们进行前瞻性随访，（2）收集详细的临床数据，包括评估当前疾病活动，以及每次随访时的血液样本，以及（3）对随时间收集的系列RNA样品进行全基因组基因表达谱分析，以产生影响RA中疾病活动性的候选基因的列表。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学登记处来识别处于受孕前阶段的RA女性。将从同一人群的正常妊娠队列的持续收集中招募匹配的对照。对于目标2，经过培训的研究护士将收集关于每例患者的RA和药物使用史及其疾病状态（包括疾病活动性指标）和整个研究期间药物使用的详细临床信息。还将在每个时间点从病例和对照组中采集血样。将测量CRP水平并用于计算DAS 28- CRP评分，作为疾病活动性的经验证指标。将使用来自全血的RNA进行全基因组基因表达分析，以全面了解每个时间点患者和对照的基因表达谱。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，调整相关协变量。还将比较不同组之间的差异基因表达谱，包括在经历缓解的患者中与产后（复发后）谱相比的妊娠谱，以及经历缓解的患者与未经历缓解的患者相比的妊娠谱。 公共卫生相关性：妊娠期间和妊娠后类风湿性关节炎（RA）的改善和复发的潜在机制尚不清楚，主要由于招募妊娠RA患者的困难而未进行彻底探索。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，拟议的研究将分别提供关于妊娠期间和妊娠后RA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开发的新靶点，这可能会影响RA的预后和治疗。