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: genomics and interferons, Sjogren's syndrome

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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