ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 523

Use of Global Gene Expression Profiling to Characterize Sjögren’s Patients Who Underexpress Interferon-Inducible Genes

John A. Ice1, He Li2, Jennifer A. Kelly1, Indra Adrianto1, Stuart B. Glenn3, Kimberly S. Hefner4, Evan G. Vista5, Donald U. Stone6, Raj Gopalakrishnan7, Glen D. Houston8, David M. Lewis9, Michael Rohrer7, Pamela Hughes7, John B. Harley10, Courtney G. Montgomery11, James Chodosh12, James A. Lessard13, Juan-Manuel Anaya14, Barbara M. Segal15, Nelson L. Rhodus16, Lida Radfar17, Mark B. Frank1, R. Hal Scofield18, Christopher J. Lessard19 and Kathy Moser Sivils1, 1Arthritis & Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 2Arthritis and Clinical Immunology Research Program, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 3Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, 4Hefner Eye Care and Optical Center, Oklahoma City, OK, 5Rheumatology and Clinical Immunology, University of Santo Tomas, Taguig City, Philippines, 6Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 7Diagnostic and Biological Sciences, University of Minnesota, Minneapolis, MN, 8Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 9College of Dentistry, University of Oklahoma Health Sciences Center, Oklahoma City, OK, 10Division of Rheumatology and The Center for Autoimmune Genomics & Etiology, University of Cincinnati, Cincinnati Children's Hospital Medical Center; US Department of Veterans Affairs Medical Center, Cincinnati, OH, 11Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 12Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, 13Valley Bone and Joint Clinic, Grand Forks, ND, 14School of Medicine and Health Sciences, Universidad del Rosario. Center for Autoimmune Diseases Research (CREA), Bogotá, Colombia, 15Rheumatology, Hennepin County Medical Center, Minneapolis, MN, 16University of Minnesota, Minneapolis, MN, 17University of Oklahoma Health Sciences Center, Oklahoma City, OK, 18Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 19Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation; University of Oklahoma Health Sciences Center, Oklahoma City, OK

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: ,

Session Information

Title: Sjögren's Syndrome - Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Sjögren’s syndrome (SS) is a progressive autoimmune exocrinopathy characterized by symptoms of dry eyes and mouth.  We previously reported overexpression of interferon-inducible (IFI) genes in a subset of SS patients. Using global gene expression profiling (GEP) and autoantibody serologies, we characterized SS patients who underexpress IFI genes in order to better understand a potentially divergent SS subgroup.

Methods:

A total of 48803 mRNA transcript levels from whole blood were measured using the Illumina HumanWG-6 v3.0 BeadChip in 201 SS cases and 79 healthy controls. After quality control, Welch’s t-tests, q-values, and fold changes (FC) were calculated for 20342 probes (15607 genes). Differentially expressed (DE) transcripts were selected by: q<0.05; and FC >1.25 or <0.87. Hierarchical clustering was performed and cases were divided according to underexpression (UNDER; n=53) or overexpression (OVER; n=128) of 32 IFI genes; both groups were then compared to healthy controls. Pathway analysis for DE genes was carried out in Genomatix.   Antibodies to Ro, La, centromere B, chromatin, dsDNA, Jo-1, ribosomal P (riboP), ribonucleoprotein (RNP), Scl-70, Sm and Sm/RNP were determined using Bioplex assays. Antinuclear antibody (ANA) and rheumatoid factor (RF) were determined by immunofluorescence and ELISA, respectively. Autoantibody composition was compared using Fisher's exact test.

Results:

Comparing the UNDER group (n=53) vs. controls (n=79) and removing IFI genes yields 1767 DE genes involved in cellular metabolism (725/7548 genes; P<10E-13); RNA processing (89/618 genes; P<10E-7); viral transcription (31/140 genes; P<10E-6); and viral reproduction (41/224 genes; P<10E-6). These genes comprise canonical pathways that include: protein import into the nucleus (6/12 genes; P<10E-3); TCR signaling in naïve CD8+ T cells (13/56 genes; P<10E-3) and CD4+ T cells (14/69 genes; P<10E-3); and BCR signaling (14/69 genes; P<10E-2). Additional genes of interest include ANTXR2 (q=2.6x10E-4; FC=1.35) and CTAGE5 (q=3.2x10E-4; FC=1.45).  ANTXR2, an anthrax toxin receptor that binds collagen IV and laminin with potential involvement in extracellular matrix adhesion, has been associated with ankylosing spondylitis, while mutations in this gene cause juvenile hyaline fibromatosis.  CTAGE5 encodes an antigen found in T-cell lymphoma and other cancers. Anti-Ro and anti-La are more common in the OVER group compared to the UNDER group (P<10E-12 and P<10E-7, respectively), as is ANA alone (P<10E-5) and in combination with RF (P<10E-3).  Interestingly, by excluding subjects positive for anti-Ro, anti-La, RF, and ANA, we find that patients in the UNDER group are more likely to produce any combination of antibodies to centromere B, chromatin, dsDNA, Jo-1, riboP, RNP, Scl-70, Sm, or Sm/RNP autoantibodies than are those in the OVER group (P=0.015).

Conclusion:

SS patients who underexpress IFI genes are more likely to produce non-traditional antibodies and are less likely to produce anti-Ro, anti-La, ANA, or ANA/RF than their counterparts. Additionally, GEP within this subphenotype has identified novel candidate genes and molecular pathways for further study that may help elucidate complex SS pathophysiology.

Disclosure:

J. A. Ice,
None;

H. Li,
None;

J. A. Kelly,
None;

I. Adrianto,
None;

S. B. Glenn,
None;

K. S. Hefner,
None;

E. G. Vista,
None;

D. U. Stone,
None;

R. Gopalakrishnan,
None;

G. D. Houston,
None;

D. M. Lewis,
None;

M. Rohrer,
None;

P. Hughes,
None;

J. B. Harley,
None;

C. G. Montgomery,
None;

J. Chodosh,
None;

J. A. Lessard,
None;

J. M. Anaya,
None;

B. M. Segal,
None;

N. L. Rhodus,
None;

L. Radfar,
None;

M. B. Frank,
None;

R. H. Scofield,
None;

C. J. Lessard,
None;

K. Moser Sivils,
None.

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