ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2671

A Genome-Wide Association Study Establishes Muliple Susceptibility Loci for Sjögren’s Syndrome

Christopher J. Lessard1, He Li2, Indra Adrianto3, John A. Ice3, Roland Jonsson4, Gabor G. Illei5, Maureen Rischmueller6, Gunnel Nordmark7, Xavier Mariette8, Corinne Miceli-Richard9, Marie Wahren-Herlenius10, Torsten Witte11, Michael T. Brennan12, Roald Omdal13, Patrick M. Gaffney3, James A. Lessard14, Wan-Fai Ng15, Nelson L. Rhodus16, Barbara M. Segal17, R. Hal Scofield18, Judith A. James19, Juan-Manuel Anaya20, John B. Harley21, Courtney G. Montgomery3 and Kathy Moser Sivils19, 1Arthritis and Clinical Immunology Research Program, 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, 3Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 4Broegelmann Research Laboratory, the Gade Institute, University of Bergen, Bergen, Norway, 5Sjogren's Clinic, NIDCR/ NIH, Bethesda, MD, 6Rheumatology Department, Queen Elizabeth Hospital, Adelaide, Australia, 7Rheumatology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden, 8Rheumatology, Université Paris-Sud, Le Kremlin Bicetre, France, 9Hopital Bicêtre, Le Kremlin Bicêtre, France, 10Dept of Medicine, Karolinska Institutet, Stockholm, Sweden, 11Clinical Immunology and Rheumatology, Medical University Hannover, Hanover, Germany, 12Nidcr NIH, Carolinas Medical Center, Charlotte, NC, 13Department of Internal Medicine, Stavanger university Hospital, Stavanger, Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway, 14Valley Bone and Joint Clinic, Grand Forks, ND, 15Musculoskeletal Research Group Institute of Cellular Medicine, Newcastle University, Newcastle University, Newcastle, England, 16University of Minnesota, Minneapolis, MN, 17Rheumatology, Hennepin County Medical Center, Minneapolis, MN, 18Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 19Oklahoma Medical Research Foundation, Oklahoma City, OK, 20School of Medicine and Health Sciences, Universidad del Rosario. Center for Autoimmune Diseases Research (CREA), Bogotá, Colombia, 21Division 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

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: , ,

Session Information

Title: Sjögren's Syndrome I - Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Sjögren’s syndrome (SS) is a common, 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 limited to candidate gene approaches. We sought to perform the first genome-wide association scan (GWAS) in an unbiased manner to identify SS susceptibility loci. 

Methods:

We used high-density Illumina OMNI1-Quad genotyping arrays in a discovery cohort of 424 European-derived SS cases and 2120 healthy controls for the GWAS discovery phase. Stringent quality control (QC) criteria, adjustments for population stratification, and standard GWA statistical methodologies were used to compare allele frequencies between cases and controls. A total of ~650,000 single nucleotide polymorphisms (SNPs) were tested for association to SS (Pomni). For replication, an independent set of 1194 SS cases and 2930 healthy controls were genotyped using the ImmunoChip (IC; PIC) with ~26,000 overlapping SNPs with the GWAS after QC. Meta-analysis between the GWAS and IC was done using METAL (Pmeta).  Of the 1618 SS case, 133 also had gene expression data from the Illumina WG-6 microarray from whole blood. Expressed quantitative trait loci (eQTL) analysis was done using the MATRIXeQTL package in R.  Probes and SNPs in a 50 kb region flanking 4 selected genes were analyzed.

Results:

The most significantly associated region with SS was the major histocompatibility complex (MHC), with 1071 overlapping SNPs between the GWAS and IC exceeding a genome-wide significance (GWS) threshold of 5x10E-8.  The peak association was observed in MSH5 (rs3117574 Pmeta=5.33x10E-79). Results across the extended MHC support association with multiple loci throughout this region. In the GWAS, 2 SNPs, rs485497 and rs4680536, were identified near IL12A with Pomni<6x10E-4. Both rs485497 (PIC=1.88x10E-7) and rs4680536 (PIC=2.06x10E-5) replicated yielding Pmeta=4.81x10E-10 and Pmeta=1.69x10E-8, respectively. In addition, we observed associations surpassing GWS for the first time with loci previously implicated in SS, including IRF5 (rs10488631 Pmeta=5.25x10E-13), BLK (rs922483 Pmeta=1.50x10E-8), and STAT4 (rs10168266 Pmeta=3.59x10E-8). We also identified statistically significant eQTL in the IRF5 region with 13 SNPs at P<5x10E-8.  BLK also showed significant eQTLs with 8 SNPs at P<7x10E-4. IL12A, IRF5 and STAT4 are involved in type I interferon responses. IL12A encodes the p35 subunit of IL12 and is secreted by monocytes and dendritic cells ultimately stimulating the production of IFN-γ. Interestingly, responses to IL12 are mediated through STAT4.

Conclusion:

We present the first GWAS of SS identifying and confirming IL12A as a novel susceptibility locus. We also observed IRF5, BLK and STAT4 for the first time at GWS establishing them as risk loci for SS. We report eQTLs in the region of IRF5 and BLK in SS cases suggesting expression of these loci is important in the pathogenesis as has been reported in SLE. Collectively these genes illustrate the importance of both the innate and adaptive immune responses in the etiology of SS.

Disclosure:

C. J. Lessard,
None;

H. Li,
None;

I. Adrianto,
None;

J. A. Ice,
None;

R. Jonsson,
None;

G. G. Illei,
None;

M. Rischmueller,
None;

G. Nordmark,
None;

X. Mariette,
None;

C. Miceli-Richard,
None;

M. Wahren-Herlenius,
None;

T. Witte,
None;

M. T. Brennan,
None;

R. Omdal,
None;

P. M. Gaffney,
None;

J. A. Lessard,
None;

W. F. Ng,
None;

N. L. Rhodus,
None;

B. M. Segal,
None;

R. H. Scofield,
None;

J. A. James,
None;

J. M. Anaya,
None;

J. B. Harley,

ERBA Diagnostics,

7,

ERBA Diagnostics ,

5,

ERBA DIagnostics,

1;

C. G. Montgomery,
None;

K. Moser Sivils,
None.

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