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.


Large-Scale, High-Density Genotyping Performed by the Sjgren's Genetics Network Using the ImmunoChip Identifies PRKRA as a Novel Sjgren's Syndrome Susceptibility Locus and Confirms Associations with IRF5, BLK and MHC.

Lessard1,  Christopher J., Adrianto1,  Indra, Ice1,  John A., Kelly1,  Jennifer A., Jonsson2,  Roland, Illei3,  Gabor G., Rischmueller4,  Maureen

Oklahoma Medical Research Foundation, Oklahoma City, OK
Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK
Valley Bone & Joint Clinic, Grand Forks, ND
Musculoskeletal Research Group Institute of Cellular Medicine, Newcastle University, Newcastle, England
University of Minnesota, Minneapolis, MN
Hennepin County Medical Center, Minneapolis, MN
Oklahoma Medical Research Foundation and Oklahoma University Health Sciences Center, Oklahoma City, OK
Universidad del Rosario-Corporacion para Investigaciones Biologicas, Bogota, Colombia
Cincinnati Children's Hospital Medical Center and the US Department of Veterans Affairs Medical Center, Cincinnati, OH
University of Bergen, Bergen, Norway
NIDCR/ NIH #10 1N110, Bethesda, MD
Queen Elizabeth Hospital, Adelaide, Australia
Department of Medical Sciences, Section of Rheumatology, Uppsala University, Uppsala, Sweden
Bicêtre University Hospital, Le Kremlin Bicêtre, France
Karolinska Institute, Stockholm, Sweden
Hannover Medical School, Hanover, Germany
Carolinas Medical Center, Charlotte, NC

Background/Purpose:

Sjögrens syndrome (SS) is a chronic, inflammatory autoimmune condition characterized by exocrine gland dysfunction and dysregulation of interferon responses. The etiology of SS is largely unknown, but current hypotheses suggest roles for environmental and genetic factors. To date, the identification of SS risk loci has been confined to candidate gene studies. In this study, we sought to evaluate a collection of European-derived SS cases for association with regions previously reported in other related inflammatory conditions (e.g. rheumatoid arthritis, etc).

Methods:

We have established the Sjögrens Genetics Network (SGENE) to assemble a sizable cohort for large-scale genetic studies. We used the ImmunoChip, an Illumina iSelect custom array designed with ~196,000 single nucleotide polymorphisms (SNPs) from 12 inflammatory phenotypes. Stringent quality control measures were applied and principal component (PC) analysis was used to determine genetic outliers. After quality control, ~130,000 variants were available to test for association with 1051 SS cases and 1727 controls. Replication was performed in an independent collection of 268 SS cases and 380 controls. SNP-SS association was tested using logistic regression under an additive genetic model in PLINK while adjusting for the first three PCs and gender. Meta-analysis was conducted using weighted Z-scores in METAP.

Results:

We identified a novel association unique to SS within the 3`-UTR of the gene protein kinase, interferon-inducible double-stranded RNA-dependent activator (PRKRA; P=6.44×10E-24, OR=0.47, 95%CI=0.40–0.54). This result replicated in the independent case-control cohort (P=1.04×10E-6 OR=0.43, 95%CI=0.31–0.61) yielding a Pmeta=1.3×10E-27. PRKRA encodes a double-stranded RNA-activated protein kinase that modulates the interferon cascade upon infection by viruses. Approximately 220 SNPs in the region of interferon regulator factor 5 (IRF5) were typed on this array including variants in genes centromeric (KCP) and telomeric (TNPO3) of this locus. A total of 12 SNPs had P<5×10E-8, with the most significant SNP resulting in a P=4.12×10E-12 (OR=1.52, 95%CI=1.35–1.71). IRF5 encodes a transcription factor involved in the activation of interferon, cell growth and differentiation, apoptosis, and other immunologic-related functions. A SNP in the gene B lymphoid kinase (BLK) was found to be significantly associated with SS (P=4.07×10E-8, OR=1.40, 95%CI=1.24–1.58). BLK encodes for a non-receptor protein kinase involved in B cell receptor signaling and B cell development. The strongest overall association identified was within the major histocompatibility complex (MHC) with 1467 SNPs resulting in P<5×10E-8. Peak association was observed in HLA-DRB1 with P=1.55×10E-52 (OR=3.675, 95%CI=3.10–4.34).

Conclusion:

We have discovered and independently confirmed a novel association unique to SS in PRKRA, and report, for the first time, IRF5 and BLK exceeding the genome-wide significance threshold. In addition, we replicate association with the MHC. Collectively these genes illustrate the importance of both the innate and adaptive immune responses in the etiology of SS.

To cite this abstract, please use the following information:
Lessard, Christopher J., Adrianto, Indra, Ice, John A., Kelly, Jennifer A., Jonsson, Roland, Illei, Gabor G., et al; Large-Scale, High-Density Genotyping Performed by the Sjgren's Genetics Network Using the ImmunoChip Identifies PRKRA as a Novel Sjgren's Syndrome Susceptibility Locus and Confirms Associations with IRF5, BLK and MHC. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :773
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