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Pregnancy-induced gene expression changes in vivo among women with rheumatoid arthritis: a pilot study

Goin, Dana E. and Smed, Mette Kiel and Pachter, Lior and Purdom, Elizabeth and Nelson, J. Lee and Kjærgaard, Hanne and Olsen, Jørn and Hetland, Merete Lund and Zoffmann, Vibeke and Ottesen, Bent and Jawaheer, Damini (2017) Pregnancy-induced gene expression changes in vivo among women with rheumatoid arthritis: a pilot study. Arthritis Research and Therapy, 19 (1). Art. No. 104. ISSN 1478-6362. PMCID PMC5445464. http://resolver.caltech.edu/CaltechAUTHORS:20170531-131446160

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Abstract

Background: Little is known about gene expression changes induced by pregnancy in women with rheumatoid arthritis (RA) and healthy women because the few studies previously conducted did not have pre-pregnancy samples available as baseline. We have established a cohort of women with RA and healthy women followed prospectively from a pre-pregnancy baseline. In this study, we tested the hypothesis that pregnancy-induced changes in gene expression among women with RA who improve during pregnancy (pregDAS_(improved)) overlap substantially with changes observed among healthy women and differ from changes observed among women with RA who worsen during pregnancy (pregDAS_(worse)). Methods: Global gene expression profiles were generated by RNA sequencing (RNA-seq) from 11 women with RA and 5 healthy women before pregnancy (T0) and at the third trimester (T3). Among the women with RA, eight showed an improvement in disease activity by T3, whereas three worsened. Differential expression analysis was used to identify genes demonstrating significant changes in expression within each of the RA and healthy groups (T3 vs T0), as well as between the groups at each time point. Gene set enrichment was assessed in terms of Gene Ontology processes and protein networks. Results: A total of 1296 genes were differentially expressed between T3 and T0 among the 8 pregDAS_(improved) women, with 161 genes showing at least two-fold change (FC) in expression by T3. The majority (108 of 161 genes) were also differentially expressed among healthy women (q<0.05, FC≥2). Additionally, a small cluster of genes demonstrated contrasting changes in expression between the pregDAS_(improved) and pregDAS_(worse) groups, all of which were inducible by type I interferon (IFN). These IFN-inducible genes were over-expressed at T3 compared to the T0 baseline among the pregDAS_(improved) women. Conclusions: In our pilot RNA-seq dataset, increased pregnancy-induced expression of type I IFN-inducible genes was observed among women with RA who improved during pregnancy, but not among women who worsened. These findings warrant further investigation into expression of these genes in RA pregnancy and their potential role in modulation of disease activity. These results are nevertheless preliminary and should be interpreted with caution until replicated in a larger sample.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1186/s13075-017-1312-2DOIArticle
http://arthritis-research.biomedcentral.com/articles/10.1186/s13075-017-1312-2PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5445464/PubMed CentralArticle
Additional Information:© 2017 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Received: 16 January 2017; Accepted: 2 May 2017; Published: 25 May 2017. We are immensely grateful to the study subjects for their participation in the study. We thank Mr. Kurt Stig Jensen at the Juliane Marie Center for his support. The Rheumatology departments at the following hospitals in Denmark facilitated collection of data and samples: Rigshospitalet (Glostrup), Odense Universitetshospital, Kong Christian X’s Gigthospital (Gråsten), Aarhus University Hospital NBG, and Regionshospitalet Viborg. We thank all members of our project team for making this work possible: Anne-Grethe Rasmussen, Charlotte Schön Frengler, Dorte Heide, Randi Petersen, Tove Thorup Rasmussen, Lone Thomasen, Britta Hvidberg Nielsen, Teresa Rozenfeldt, Kirsten Junker, Lis Kastberg Schubert, Lis Lund, Jette Barlach, Helle Bendtsen, Helle Andersen, and Marjo Westerdahl for their contribution to data and sample collection; and Rikke Godtkjær Andersen, Mie Rams Rasmussen, Pia Pedersen, Stine Birkelund, Louise Mielke, and Andreas Smed for management of data and samples. We also greatly appreciate the valuable assistance provided by Majbritt Norman Nielsen and DANBIO personnel. This work was supported in part by funds from the National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS), USA (grant R21 AR057931); Gigtforeningen, Denmark (grant R87-A1477-B512); and the Juliane Marie Center, Rigshospitalet (Denmark). These funders did not have any role in conducting this study or in the interpretation and reporting of results. Availability of data and materials: The data are governed by Danish privacy laws. The authors are legally forbidden from publicly sharing data under the terms of their agreement with the Danish Data Protection Agency. Data are available upon request from the corresponding author, after approval is granted by the Danish Data Protection Agency. Authors’ contributions: DEG analyzed the data, interpreted the results, and contributed to manuscript writing. MKS was responsible for acquisition of the data. LP and EP contributed to the analysis and interpretation of the data. JLN, HK, and JO contributed to the conception and design of the study. HK was also responsible for data acquisition. MLH, VZ, and BO contributed to the data acquisition. DJ was involved in the conception and design of the experiments, in the analysis and interpretation of the data, and in writing the manuscript. All authors contributed to critically revising the manuscript for important intellectual content. All authors read and approved the final manuscript. HK passed away before the submission of the final version of the manuscript; DJ accepts responsibility for the integrity and validity of the data collected and analyzed. The authors declare that they have no competing interests. Consent for publication: Not applicable. Ethics approval and consent to participate: This study was approved by the ethics committee for Region Hovedstaden (Denmark), the Danish Data Protection Agency, and the Children’s Hospital Oakland Research Institute Institutional Review Board. All subjects provided written informed consent prior to enrollment.
Funders:
Funding AgencyGrant Number
NIHR21 AR057931
GigtforeningenR87-A1477-B512
Juliane Marie Center, RigshospitaletUNSPECIFIED
PubMed Central ID:PMC5445464
Record Number:CaltechAUTHORS:20170531-131446160
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20170531-131446160
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:77860
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:31 May 2017 22:10
Last Modified:31 May 2017 22:10

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