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.

A High-Density Genome-Wide Association Study by the Sjgren's Genetics Network Identifies Five Novel Susceptibility Loci for Primary Sjgren's Syndrome and Confirms Association with MHC, IRF5, and BLK.

Montgomery1,  Courtney G., Moser19,  Kathy L., Harley18,  John B., Anaya17,  Juan-Manuel, for ACCESS,  , Rybicki,  Benjamin A., Scofield1,  R. Hal

Oklahoma Medical Research Foundation, Oklahoma City, OK
Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway
Divisions of Genetics and Molecular Medicine and Immunology, King's College London, London, United Kingdom
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
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
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK
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


Sjögren's syndrome (SS) is a clinically heterogeneous autoimmune disease characterized by exocrine gland dysfunction that 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 gene studies. We used high-density genotyping arrays to perform a genome-wide association scan (GWAS) in an unbiased manner to identify SS susceptibility loci.


We have established the Sjögrens Genetics Network (SGENE) to assemble a large cohort of samples for large-scale genetic studies. We used the Illumina OMNI1-Quad arrays containing >1.1 million variants in a discovery cohort of 424 European-derived SS cases and 728 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 (Pomni). A secondary analysis was performed using data from 1398 additional controls from the Illumina iControl database typed on the HumanHap 550 with ~289,000 SNPs in common with the OMNI1-Quad. For replication, we used a DNA pooling approach in an independent collection of 450 cases and controls of European descent, and also genotyped using the OMNI1-Quad arrays (Ppool). Weighted Z-scores were used to determine meta-P-values for combined discovery and replication data (Pmeta).


The most significantly associated region with risk of SS was the major histocompatibility complex (MHC), with 1304 SNPs exceeding a genome-wide significance threshold of 5×10E-8. The peak association was observed in HLA-DRA within Pomni=1.68×10E-23 and replicated with Ppool=8.47×10E-5, leading to a Pmeta=6.92×10E-29. 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. A SNP between PIK3R1 and SLC30A5 was found to be associated with SS in both the discovery and replication cohorts resulting in Pmeta=7.55×10E-8. Association (Pmeta<10E-5) with SS was also identified with SNPs in or near CTNNA2, VASP, FGFR1OP2, and LCK. In addition, we observed association with SNPs previously implicated as risk factors for SS, including IRF5 (Pmeta=2.66×10E-8) and BLK (Pmeta=6.66×10E-5).


We have performed the first GWAS in SS, and have identified PIK3R1/SLC30A5, CTNNA2, VASP, FGFR1OP2, and LCK as putative risk loci. We have also confirmed associations previously reported with MHC, IRF5, and BLK. Currently, we are genotyping ~1500 SNPs in >3200 subjects to replicate additional effects observed in the discovery phase.

To cite this abstract, please use the following information:
Montgomery, Courtney G., Moser, Kathy L., Harley, John B., Anaya, Juan-Manuel, for ACCESS, , Rybicki, Benjamin A., et al; A High-Density Genome-Wide Association Study by the Sjgren's Genetics Network Identifies Five Novel Susceptibility Loci for Primary Sjgren's Syndrome and Confirms Association with MHC, IRF5, and BLK. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :481

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