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Abstract Number: 525

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

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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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ACR Meeting Abstracts - https://acrabstracts.org/abstract/gene-expression-profiling-in-a-large-cohort-of-europeans-with-sjogrens-syndrome-reveals-candidate-genes-in-viral-immune-and-interferon-related-pathways/

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