ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2672

Genome-Wide Association Analysis Reveals Genetic Heterogeneity of Sjögren’s Syndrome (SS) According to Specific Subphenotypes and Ancestry

Lindsey A. Criswell1, Kimberly E. Taylor2, Caitlin McHugh3, Cathy Laurie3, Kimberly Doheny4, Mi Y. Lam2, Joanne Nititham5, Laura Bierut6, Emily L. Harris7, Alan N. Baer8, Stephen Challacombe9, Yi Dong10, Hector Lanfranchi11, Morten Schiodt12, M. Srinivasan13, Susumu Sugai14, Hisanori Umehara15, Frederick B. Vivino16, Zhao Yan17, Stephen Shiboski2, Troy Daniels18, John S. Greenspan19, Caroline Shiboski19 and SICCA20, 1Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, Division of Rheumatology, University of California, San Francisco, San Francisco, CA, 2University of California, San Francisco, San Francisco, CA, 3University of Washington, Biostatistics, Seattle, WA, 4Center for Inherited Disease Research, Baltimore, MD, 5Medicine, Rosalind Russell Medical Research Center for Arthritis, San Francisco, CA, 6Psychiatry, Washington University, St. Louis, MO, 7National Institute of Dental and Craniofacial Research, Bethesda, MD, 8Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, 9Kings College London, London, United Kingdom, 10Dept of Rheumatology, Peking Univ Med Coll Hospital, East City Beijing, China, 11University of Buenos Aires, Buenos Aires, Argentina, 12Righospitalet, Copenhagen, Denmark, 13Aravind Eye Hospital, Madurai, India, 14Kanazawa Medical University, Ishikawa, Japan, 15Internal Medicine, Division of Hematology and Immunology, Kanazawa Medical University, Kanazawa, Japan, 16Medicine, Penn Presbyt Med Ctr, Philadelphia, PA, 17Department of Rheumatology, Peking Union Medical College Hospital, Beijing, China, 18Orofacial Sciences, Box 0422, UCSF Schools of Medicine & Dentistry, San Francisco, CA, 19Orofacial Sciences, University of California, San Francisco, San Francisco, CA, 20San Francisco, CA

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: ,

Session Information

Title: Sjögren's Syndrome I - Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose: Our goal is to define the contribution of genetic factors to SS and related subphenotypes.

Methods: We studied 2,459 participants in the Sjögren’s International Collaborative Clinical Alliance (SICCA) who were characterized for the Illumina HumanOmni 2.5-Quad marker set. SICCA participants were enrolled according to standardized protocols at 9 international sites, including Argentina (n=342), China (n=290), Denmark (n=446), India (n=65), Japan (n=354), the UK (n=203) and the US (total n=759 from 3 sites).  Additional control data genotyped on the same platform were obtained from the Collaborative Genetic Study of Nicotine Dependence (COGEND, n = 1466). QC measures included filters based on SNP and sample missingness (≥2%), unexpected relatedness, non-Mendelian inheritance, and chromosomal regions of anomaly (> 10Mb).   SICCA participants were classified according to ACR classification criteria for SS (AC&R 2012, 64; 475), including presence of focal lymphocytic sialadenitis (FLS) on minor salivary gland biopsy, presence of KCS based on ocular staining pattern (ocular staining score ≥3), and production of autoantibodies (SSA, SSB, ANA and RF). Principal components (PC) analysis was used to characterize each participant for genetic ancestry, and PCs 1 – 5 were included as covariates in all association analyses. The following phenotypes were examined: SS susceptibility (fulfillment of ACR criteria versus controls, including COGEND), presence of FLS, presence of KCS and autoantibody positive disease.

Results: Out of 2118 subjects with post-QC genotypes and sufficient clinical data, 1000 (47%) met ACR criteria for SS, and an additional 772 fulfilled at least 1 of the 3 criteria, including FLS, KCS or autoantibody positivity (SSA &/or SSB +, or both ANA ≥ 320 and RF +).  A total of 1,445,406 SNPs passed all QC filters and were fully analyzed. For case-control analysis, 1,392,831 SNPs passed QC filters for both cohorts and were analyzed. Multiple variants within the MHC region on chr 6q and the IRF5-TNP03 region on chr 7 were strongly associated with SS susceptibility (lowest p values 1.9e-27 and 3.8e-13, respectively), and with autoantibody production (MHC p=1.7e-30, IRF5 p=3.2e-12) and FLS (MHC p=9.7e-12, IRF5 p=1.5e-10) within SICCA subjects; furthermore the region of MHC association for autoantibody production was much broader (26-33Mb versus 30-33Mb).  In contrast, we did not observe significant genetic associations with KCS, indicating genetic heterogeneity specifically related to the oral, ocular or systemic manifestations of SS. Among SICCA subjects, multiple PCs were strongly associated with some phenotypes examined, suggesting heterogeneity according to genetic ancestry. In particular, a PC separating Asian and European ancestry was strongly associated with autoantibody production (p < 4.5e-38).

Conclusion: These results demonstrate genetic overlap of SS with other autoimmune diseases, and highlight the genetic heterogeneity of the disease according to specific subphenotypes and ancestry. Future work including imputed genetic data and additional study subjects will provide more power for extending these findings and fully characterizing the genetic contribution to SS.

Disclosure:

L. A. Criswell,
None;

K. E. Taylor,
None;

C. McHugh,
None;

C. Laurie,
None;

K. Doheny,
None;

M. Y. Lam,
None;

J. Nititham,
None;

L. Bierut,
None;

E. L. Harris,
None;

A. N. Baer,

Merck Serono,

5,

Cellgene,

5;

S. Challacombe,
None;

Y. Dong,
None;

H. Lanfranchi,
None;

M. Schiodt,
None;

M. Srinivasan,
None;

S. Sugai,
None;

H. Umehara,
None;

F. B. Vivino,
None;

Z. Yan,
None;

S. Shiboski,
None;

T. Daniels,
None;

J. S. Greenspan,
None;

C. Shiboski,
None;

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