Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


A High-Density Genome-Wide Association Study by the Sjgren's Genetics Network (SGENE) Identifies Both Novel Susceptibility Loci for Primary Sjgren's Syndrome and Overlapping Effects with Other Autoimmune Disorders.

Lessard3,  Christopher J., Adrianto1,  Indra, Kaufman1,  Kenneth, Jonsson14,  Roland, Illei10,  Gabor, Rischmueller12,  Maureen, Nordmark16,  Gunnel

Arthritis and Immunology Research Program, Oklahoma Medical Research Foundation
National Institute of Dental and Craniofacial Research, NIH
Newcastle University, England
The Queen Elizabeth Hospital and Health Service, Australia
Universite Paris-Sud
University of Bergen, Norway
University of Minnesota
Uppsala University Hospital, Sweden
US Department of Veterans Affairs Medical Center, Department of Medicine, University of Oklahoma Health Sciences Center, and Cincinnati Children's Hospital Medical Center
Arthritis and Immunology Research Program, Oklahoma Medical Research Foundation and Department of Pathology, University of Oklahoma Health Sciences Center
Arthritis and Immunology Research Program, Oklahoma Medical Research Foundation and Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
Carolinas Medical Center
Center for Autoimmune Diseases Research (CREA), Universidad del Rosario, Bogota, Columbia
Hannover Medical School, Germany
Hennepin County Medical Center, Minneapolis
Karolinska Institute, Sweden

Background:

Sjögren's syndrome (SS) is a clinically heterogeneous autoimmune disease characterized by exocrine gland dysfunction and involves both innate and adaptive immune responses. A complex genetic architecture has been hypothesized, however, genetic studies to date have been primarily limited to candidate genes approaches. We used high-density genotyping arrays to perform a genome-wide association (GWA) scan in an unbiased manner to identify SS susceptibility loci.

Methods:

We have established the Sjogrens Genetics Network (SGENE) to assemble samples (currently >4000 subjects) for large-scale genetic studies. We used the Illumina OMNI1-Quad arrays containing >1.1×10E6 variants in a discovery cohort of 272 European-derived primary SS cases and 387 healthy controls. Stringent quality control criteria, adjustments for population stratification, and standard GWA statistical methodologies were used to compare allele frequencies between cases and controls. A total of ~774,000 single nucleotide polymorphisms (SNPs) were tested for association to SS in our final GWA dataset. For replication, we used a DNA pooling approach in an independent collection of cases and controls of European-decent, also genotyped using the OMNI1-Quad arrays. Weighted Z scores were used to determine meta p-values for combined discovery and replication data.

Results:

The most significant region associated with risk of disease was the major histocompatibility complex (MHC) with 45 SNPs exceeding a genome-wide significance threshold of 5×10E-8, all of which replicated in our independent pooled samples. Within the MHC, peak significance was observed at HLA-DRA for rs9268832 (p=1.65×10E-10, odds ratio 2.3, CI: 1.8–3.0). Analysis in the replication cohort for rs9268832 resulted in p=1.61×10E-4, and an overall combined p=2.56×10E-13. Additional results across the extended MHC support association with multiple loci throughout this region. Evidence for novel genetic associations outside of the MHC were also observed. For example, association of SS with rs13282959 in both the discovery and replication cohorts was identified (meta p=1.93×10E-6). This SNP is located in a region of high regulatory potential near the musculin (MSC) gene. MSC is a multi-functional transcription factor involved in signaling pathways following B cell receptor activation. We specifically evaluated our data for evidence of association with ~30 loci previously established in systemic lupus erythematosus (SLE), a closely related autoimmune disease. Association of IRF5 and TNIP1 was observed in both our discovery and replication cohorts. Support for other associated genes in both SLE and SS was observed for BANK1, PRDM1, JAZF1, STAT4, and IL12B.

Conclusions:

This study represents the most comprehensive assessment of the genetic contribution to SS performed to date. We have identified and replicated numerous loci associated with disease, some of which have been previously associated with SLE and other related autoimmune diseases. Further characterization of these effects are warranted to precisely define causal variants and determine functional consequences that contribute to disease pathogenesis.

To cite this abstract, please use the following information:
Lessard, Christopher J., Adrianto, Indra, Kaufman, Kenneth, Jonsson, Roland, Illei, Gabor, Rischmueller, Maureen, et al; A High-Density Genome-Wide Association Study by the Sjgren's Genetics Network (SGENE) Identifies Both Novel Susceptibility Loci for Primary Sjgren's Syndrome and Overlapping Effects with Other Autoimmune Disorders. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1579
DOI: 10.1002/art.29345

Abstract Supplement

Meeting Menu

2010 ACR/ARHP