Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.


Gene Expression Profiling in a Cohort of 275 European American Sjgren's Syndrome Patients and Controls.

Kelly1,  Jennifer A., Lessard1,  Christopher J., Adrianto1,  Indra, Ice1,  John A., Li1,  He, Glenn1,  Stuart B., Hefner2,  Kimberly

Oklahoma Medical Research Foundation, Oklahoma City, OK
Univ of Minnesota, Minneapolis, MN
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, US Department of Veterans Affairs Medical Center and Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK
Hefner Eye Care and Optical Center, Oklahoma City, OK
University of Santo Tomas, Taguig City, Philippines
University of Oklahoma Health Sciences Center, Oklahoma City, OK
University of Minnesota, Minneapolis, MN
Cincinnati Children's Hospital Medical Center and the US Department of Veterans Affairs Medical Center, Cincinnati, OH
Harvard Clinical and Translational Science Center, Boston, MA
Valley Bone & Joint Clinic, Grand Forks, ND
Universidad del Rosario-Corporacion para Investigaciones Biologicas, Bogota, Colombia

Background/Purpose:

Sjögren's syndrome (SS) is a progressive, heterogeneous autoimmune exocrinopathy. We chose to perform global gene expression profiling (GEP) in order to better understand the molecular pathways involved in the pathophysiology of SS. We present the largest GEP analysis to date in SS.

Methods:

A total of 48803 mRNA transcript levels were measured using the Illumina HumanWG-6 v3.0 Expression BeadChip in 215 European American SS cases and 65 healthy controls. Raw intensity values were background subtracted and probe level analysis was performed using the LUMI package for R. After quantile normalization, Welsh t-tests, q-values (to correct for multiple testing) and fold changes (FC) were calculated. Differentially expressed (DE) genes between cases and controls were selected using 1) maximum expression values > 32, 2) q<0.05 and 3) |FC| >1.25 or <0.8. Ingenuity Pathway Analysis was utilized to identify canonical pathways among the DE genes.

Results:

A total of 1117 genes were DE between SS cases and controls (7.20×10E-24<q<0.05). Phospholipase A2, group X (PLA2G10) was the most up-regulated gene in SS cases (FC=84.45), while transembrane protein 45A (TMEM45A) was the most down-regulated (FC=-29.17). Twenty interferon inducible (IFI) genes were among the top 114 DE genes (q<1×10E-10), of which interferon alpha-inducible protein 27 (IFI27) demonstrated the greatest fold change (FC=22.4; q=1.0×10E-17). Indeed, the top canonical pathway was the interferon signaling pathway, with 13 of this 34 pathway's genes (38%) DE in our dataset (Fishers p=4.85×10E-12) (Table 1). Another disregulated pathway included genes involved in recognition of bacteria and viruses with 16.9% of this pathway's genes DE in our dataset (Fishers p=3.73×10E-7). Top ranked genes previously implicated in SS included TAP2, an antigen presentation gene reportedly associated with SS in Japanese and Columbian cases (rank 69; q=3.2×10–13; FC=1.44); CXCL10, a Th1-chemokine that regulates immune responses and is up-regulated in SS salivary glands (rank 79; q=1×10E-12;FC=2.69); and MUC1, a human mucin previously found to be associated with dry eyes and dry mouth (rank 104; q=3.66×10E-11; FC=1.54). Common functions observed included cellular movement, growth and proliferation, development, function and maintenance and cellular death. Genes implicated in liver hepatitis as well as cardiac and renal necrosis were also up-regulated in SS cases.

Table 1. Genes in top SS canonical pathways

PathwayGene SymbolGene NameFold ChangeFDR q-value
Interferon SignalingIFIT3interferon-induced protein with tetratricopeptide repeats 33.085.82E-19
OAS12',5'-oligoadenylate synthetase 1, 40/46kDa2.912.77E-11 
 IFIT1interferon-induced protein with tetratricopeptide repeats 12.899.37E-07
 MX1myxovirus resistance 1, interferon-inducible protein p782.494.06E-16
 IFI35interferon-induced protein 351.721.64E-12
 STAT2signal transducer and activator of transcription 2, 113kDa1.601.36E-16
 SOCS1suppressor of cytokine signaling 11.584.32E-09
 STAT1signal transducer and activator of transcription 1, 91kDa1.549.13E-18
 BAXBCL2-associated X protein1.398.49E-04
 JAK2Janus kinase 21.363.16E-07
 TAP1transporter 1, ATP-binding cassette, sub-family B (MDR/TAP)1.361.61E-09
 IRF9interferon regulatory factor 91.333.34E-11
 IFITM1interferon induced transmembrane protein 1 (9–27)1.304.06E-05
Recognition of Viruses and BacteriaOAS32'-5'-oligoadenylate synthetase 3, 100kDa4.181.26E-09
 C1QCcomplement component 1, q subcomponent, C chain2.891.97E-05
 OAS22'-5'-oligoadenylate synthetase 2, 69/71kDa2.157.57E-15
EIF2AK2eukaryotic translation initiation factor 2-alpha kinase 22.052.05E-20 
 C1QBcomplement component 1, q subcomponent, B chain2.051.29E-04
IFIH1interferon induced with helicase C domain 11.901.63E-20 
 DDX58DEAD (Asp-Glu-Ala-Asp) box polypeptide 581.851.28E-17
 IRF7interferon regulatory factor 71.857.66E-14
 C3AR1complement component 3a receptor 11.777.38E-15
 C1QAcomplement component 1, q subcomponent, A chain1.635.78E-05
CASP1caspase 1, apoptosis-related cysteine peptidase (interleukin 1, beta, convertase)1.392.79E-10 
 TICAM1toll-like receptor adaptor molecule 11.311.72E-03

Conclusion:

The results demonstrate a role for not only innate but also adaptive immunity in SS and overexpression of interferon-related genes continues to play a strong role in this disorder. Additional cellular processes appear to be involved in SS that provide hypotheses to better understand this disorder. Clearly, many of the up-regulated genes are strong candidates for disease biomarkers or susceptibility.

To cite this abstract, please use the following information:
Kelly, Jennifer A., Lessard, Christopher J., Adrianto, Indra, Ice, John A., Li, He, Glenn, Stuart B., et al; Gene Expression Profiling in a Cohort of 275 European American Sjgren's Syndrome Patients and Controls. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :489
DOI:

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