Gene Expression Profiling in a Large Cohort of Europeans with Sjögren’s Syndrome Reveals Candidate Genes in Viral, Immune, and Interferon-Related Pathways

He Li¹, John A. Ice², Jennifer A. Kelly³, Indra Adrianto², Stuart B. Glenn⁴, Kimberly S. Hefner⁵, Evan G. Vista⁶, Donald U. Stone⁷, Raj Gopalakrishnan⁸, Glen D. Houston⁹, David M. Lewis¹⁰, Michael Rohrer⁸, Pamela Hughes⁸, John B. Harley¹¹, Courtney G. Montgomery², James Chodosh⁷, James A. Lessard¹², Juan-Manuel Anaya¹³, Barbara M. Segal¹⁴, Nelson L. Rhodus¹⁵, Lida Radfar¹⁶, Mark B. Frank¹⁷, R. Hal Scofield¹⁸, Christopher J. Lessard¹⁹ and Kathy Moser Sivils³, ¹Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation; University of Oklahoma Health Sciences Center, Oklahoma City, OK, ²Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, ³Oklahoma Medical Research Foundation, Oklahoma City, OK, ⁴Arthritis and Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, ⁵Hefner Eye Care and Optical Center, Oklahoma City, OK, ⁶Rheumatology and Clinical Immunology, University of Santo Tomas, Taguig City, Philippines, ⁷Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, ⁸Diagnostic and Biological Sciences, University of Minnesota, Minneapolis, MN, ⁹Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, ¹⁰College of Dentistry, University of Oklahoma Health Sciences Center, Oklahoma City, OK, ¹¹Division 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, ¹²Valley Bone and Joint Clinic, Grand Forks, ND, ¹³School of Medicine and Health Sciences, Universidad del Rosario. Center for Autoimmune Diseases Research (CREA), Bogotá, Colombia, ¹⁴Rheumatology, Hennepin County Medical Center, Minneapolis, MN, ¹⁵University of Minnesota, Minneapolis, MN, ¹⁶University of Oklahoma Health Sciences Center, Oklahoma City, OK, ¹⁷Arthritis & Immunology, Oklahoma Medical Research Foundation, 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), characterized by lymphocytic infiltration of exocrine glands, is a progressive autoimmune exocrinopathy present in 0.7-1% of Europeans. To better understand the molecular pathways involved in SS pathophysiology, we performed global gene expression profiling (GEP) on SS cases and healthy controls.

Methods: GEP was determined on 48803 probes from the Illumina HumanWG-6 v3.0 BeadChip microarray using whole blood from 162 primary SS cases and 58 healthy controls of European ancestry. Analyses were performed in the R Bioconductor suite. After quality control assessments, 20035 probes were quantile normalized, and differentially expressed (DE) genes were determined using q-values and mean expression fold change (FC) (significance thresholds: q<0.05; and FC >1.25 or <0.87). Pathway analysis for DE genes was carried out in Genomatix. Subsequent cis-expression quantitative trait loci (c-eQTL) analysis was performed in SS cases on selected genes using Matrix eQTL package.

Results: In total, 2410 genes were DE between SS cases and controls. OTOF was the most upregulated gene in SS patients (FC=94.87, q<1E-7, expressed in 86/162 cases compared to 2/58 controls), while LRRN3 was the most downregulated (FC=0.39, q<1E-3). Interestingly, mutations in OTOF are responsible for hearing loss, a symptom observed in approximately one third of SS patients. Several DE genes overlap with genetic associations identified through genome-wide association studies in SS, including the MHC genes TRIM38 (q<10E-12), TAP1 (q<1E-14), and TAP2 (q<1E-13), in addition to those identified previously by candidate gene approaches, including IL1RN (q<1E-5), FAS (q<1E-2), and EBF1 (q<1E-2). Additionally, c-eQTL analysis identified 51 single-nucleotide polymorphisms (SNPs) within and flanking TAP2 associated with gene expression levels (1E-10Conclusion: These results highlight alterations in immunologically-relevant pathways in SS, reveal several new candidate expression quantitative trait loci, and provide focus for the development of novel hypotheses for further studies of this complex autoimmune disorder.

Disclosure:

H. Li,
None;

J. A. Ice,
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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