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.
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.
| Goin, Dana E; Smed, Mette Kiel; Pachter, Lior et al. (2017) Pregnancy-induced gene expression changes in vivo among women with rheumatoid arthritis: a pilot study. Arthritis Res Ther 19:104 |
| Mittal, Anuradha; Pachter, Lior; Nelson, J Lee et al. (2015) Pregnancy-Induced Changes in Systemic Gene Expression among Healthy Women and Women with Rheumatoid Arthritis. PLoS One 10:e0145204 |
| Jawaheer, Damini; Zhu, Jin Liang; Nohr, Ellen A et al. (2011) Time to pregnancy among women with rheumatoid arthritis. Arthritis Rheum 63:1517-21 |
