ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1217

Identification of Sjogren’s Syndrome-Associated Long Non-Coding RNAs That Are Co-Expressed with Key Protein-Coding Transcripts Involved in Dysregulated Interferon Responses

John A. Ice1, Indra Adrianto1, Michelle L. Joachims2, Jennifer A. Kelly2, Graham B. Wiley1, Astrid Rasmussen1, Kiely Grundahl3, Glen D. Houston4, David M. Lewis4, Lida Radfar5, Donald U. Stone6,7, Joel M. Guthridge2, Barbara M. Segal8, Nelson L. Rhodus9, James Chodosh10,11, Raj Gopalakrishnan12, Andrew J.W. Huang13, Pamela J Hughes14, Michael D. Rohrer15, Judith A. James16,17,18, Courtney G. Montgomery1, R. Hal Scofield1,18,19, Patrick Gaffney1, Kathy L. Sivils2,16 and Christopher J. Lessard1,16, 1Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 2Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, 3Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 4Department of Oral and Maxillofacial Pathology, University of Oklahoma College of Dentistry, Oklahoma City, OK, 5Oral Diagnosis and Radiology Department, University of Oklahoma College of Dentistry, Oklahoma City, OK, 6King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia, 7Department of Ophthalmology, Johns Hopkins University, Baltimore, MD, 8Rheumatology, Hennepin County Medical Center, Minneapolis, MN, 9Department of Diagnostic and Biological Sciences, University of Minnesota School of Dentistry, Minneapolis, MN, 10Harvard Medical School, Boston, MA, 11Massachusetts Eye and Ear Infirmary, Boston, MA, 12Diagnostic and Biological Sciences, Division of Oral Pathology, University of Minnesota School of Dentistry, Minneapolis, MN, 13Department of Ophthalmology and Visual Sciences, Washington University, St. Louis, MO, 14Department of Oral and Maxillofacial Surgery, Oregon Health & Science University School of Dentistry, Portland, OR, 15Hard Tissue Research Laboratory, University of Minnesota School of Dentistry, Minneapolis, MN, 16Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 17Clinical Arthritis and Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, 18Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 19US Department of Veterans Affairs Medical Center, Oklahoma City, OK

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: , , ,

Session Information

Date: Monday, November 14, 2016

Title: Genetics, Genomics and Proteomics - Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: The “interferon signature”, marked by transcriptional upregulation of interferon (IFN)-inducible (IFI) genes, is a common finding in Sjögren’s syndrome (SS) that is associated with anti-Ro production. Recent studies have implicated long non-coding RNAs (lncRNAs) as novel transcriptional regulators of IFI genes, yet their contribution to dysregulated IFN responses in SS remains unknown. In this study, we used RNA sequencing (RNA-seq) to characterize the relationship between lncRNAs and IFN transcriptional responses in anti-Ro-positive SS (SSRo+) and to prioritize lncRNAs for functional evaluation.

Methods: We used RNA-seq to generate whole-blood transcriptional profiles for 27 SSRo+ patients and 27 healthy controls (HCs). Sequences were aligned to the human genome using TOPHAT and identified differentially expressed (DE) transcripts (FC >2 or <0.5 and q<0.05) using DEseq. For those DE IFI transcripts with a coefficient of variation (CV) >100% from a subset of 64 IFI transcripts, we calculated Pearson’s correlation statistic, r, against the 267 DE antisense and 793 DE long-intergenic non-coding RNAs and identified those showing positive (r >+0.70) and negative (r <-0.60) correlation with FDR-corrected significance <0.05. To confirm DE of specific targets, we utilized qRT-PCR in an independent cohort of 16 SSRo+cases and 36 HCs to determine the relative expression of specific transcripts. Statistical significance was determined using an unpaired t-test in Prism.

Results: For the 19 DE IFI transcripts with CV>100%, we identified 6 DE lncRNAs whose expression is significantly correlated with IFI transcripts, including both overexpressed [MX1-AS1 (FC=4.12), OAS123-AS1 (FC=3.35), NRIR (FC=2.73), GBP5-AS1 (FC=2.51)] and underexpressed [ERC1-AS1 (FC=0.45), linc-DCP1B (FC=0.50)] lncRNAs. For only the overexpressed lncRNAs, we noted correlated expression with DE IFI genes in their immediate proximity, such as MX1-AS1 (MX1, r =0.95), OAS123-AS1 (OAS1, r=0.92; OAS2, r=0.91; OAS3, r=0.86), NRIR (RSAD2, r=0.77; CMPK2, r=0.80), and GBP5-AS1 (GBP5, r=0.96). We have replicated the finding of NRIR upregulation in an independent cohort of SSRo+ cases and HCs (p=4.8×10-3), and replication is in progress for the remaining targets.

Conclusion: In this study, we have identified 6 novel SS lncRNAs showing significant co-expression with transcripts found within the IFN signature. Previous studies have implicated NRIR in the negative regulation of a subset of IFI genes that include the neighboring genes RSAD2 and CMPK2. The proximity of additional overexpressed lncRNAs to well-defined IFI genes known to be dysregulated in SS and other autoimmune disorders bolsters the argument that these lncRNAs have regulatory roles and mediate IFI transcriptional responses. Further elucidation of the relationship between lncRNAs and expression differences in both peripheral blood and exocrine gland tissue has the potential to identify peripheral biomarkers that define specific clinical and transcriptional features resulting from IFI gene dysregulation.

Disclosure: J. A. Ice, None; I. Adrianto, None; M. L. Joachims, None; J. A. Kelly, None; G. B. Wiley, None; A. Rasmussen, None; K. Grundahl, None; G. D. Houston, None; D. M. Lewis, None; L. Radfar, None; D. U. Stone, None; J. M. Guthridge, None; B. M. Segal, None; N. L. Rhodus, None; J. Chodosh, None; R. Gopalakrishnan, None; A. J. W. Huang, None; P. J. Hughes, None; M. D. Rohrer, None; J. A. James, None; C. G. Montgomery, None; R. H. Scofield, Eli Lilly and Company, 5,UCB, 5; P. Gaffney, None; K. L. Sivils, None; C. J. Lessard, None.

To cite this abstract in AMA style:

Ice JA, Adrianto I, Joachims ML, Kelly JA, Wiley GB, Rasmussen A, Grundahl K, Houston GD, Lewis DM, Radfar L, Stone DU, Guthridge JM, Segal BM, Rhodus NL, Chodosh J, Gopalakrishnan R, Huang AJW, Hughes PJ, Rohrer MD, James JA, Montgomery CG, Scofield RH, Gaffney P, Sivils KL, Lessard CJ. Identification of Sjogren’s Syndrome-Associated Long Non-Coding RNAs That Are Co-Expressed with Key Protein-Coding Transcripts Involved in Dysregulated Interferon Responses [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/identification-of-sjogrens-syndrome-associated-long-non-coding-rnas-that-are-co-expressed-with-key-protein-coding-transcripts-involved-in-dysregulated-interferon-responses/. Accessed .

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