Identification of Novel Sjogren's Syndrome Risk Loci in the Regions of TNFAIP3 and PRDM1

Christopher J. Lessard^1,2, He Li^1,2, John Ice², Indra Adrianto³, Astrid Rasmussen², Kiely Grundahl⁴, Jennifer A. Kelly⁵, Corinne Miceli⁶, Simon Bowman⁷, Susan Lester⁸, Johan G. Brun^9,10, Lasse G. Goransson¹¹, Erna Harboe¹¹, Joel M. Guthridge², Kenneth M. Kaufman^12,13, Per Eriksson¹⁴, Maija-Leena Eloranta¹⁵, Marika Kvarnström¹⁶, Deborah S. Cunninghame-Graham¹⁷, A. Darise Farris², Michael T. Brennan¹⁸, James Chodosh¹⁹, Raj Gopalakrishnan²⁰, Andrew J.W. Huang²¹, Pamela Hughes²², David M. Lewis²³, Lida Radfar²⁴, Michael D. Rohrer²⁵, Donald U. Stone²⁶, Timothy J. Vyse¹⁷, Patrick M. Gaffney², Judith A. James^1,5,27, John B. Harley^12,28, Roald Omdal¹¹, Marie Wahren-Herlenius¹⁶, Gabor G. Illei²⁹, Torsten Witte³⁰, Roland Jonsson^10,31, Maureen Rischmueller^32,33, Lars Rönnblom³⁴, Xavier Mariette³⁵, Juan-Manuel Anaya³⁶, Wan-Fai Ng³⁷, Gunnel Nordmark³⁴, Courtney G. Montgomery², Nelson L. Rhodus³⁸, Barbara M. Segal³⁹, R. Hal Scofield^2,27,40 and Kathy L. Sivils^1,2, ¹Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, ²Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, ³Oklahoma Medical Research Foundation, Oklahoma City, OK, ⁴Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma CIty, OK, ⁵Arthritis & Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, ⁶Rheumatology, PARIS, France, ⁷Rheumatology Dept, University Hospital Birmingham, Birmingham, United Kingdom, ⁸Queen Elizabeth Hospital, Adelaide, Australia, ⁹Institute of Internal Medicine, University of Bergen, Bergen, Norway, ¹⁰Department of Rheumatology, Haukeland University Hospital, Bergen, Norway, ¹¹Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway, ¹²US Department of Veterans Affairs Medical Center, Cincinnati, OH, ¹³Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, ¹⁴Department of Clinical and Experimental Medicine, Rheumatology/AIR, Linköping University, Linköping, Sweden, Linköping, Sweden, ¹⁵Department of Medical Sciences, SciLife Lab, Rheumatology, Uppsala University, Uppsala, Sweden, Uppsala, Sweden, ¹⁶Department of Medicine, Karolinska Institutet, Stockholm, Sweden, ¹⁷Department of Medical and Molecular Genetics, King's College London, London, United Kingdom, ¹⁸Department of Oral Medicine, Carolinas Medical Center, Charlotte, NC, ¹⁹Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, ²⁰Diagnostic and Biological Sciences, Division of Oral Pathology, University of Minnesota, Minneapolis, MN, ²¹Department of Ophthalmology and Visual Sciences, Washington University, St Louis, MO, ²²Division of Oral and Maxillofacial Surgery, Department of Developmental and Surgical Science, University of Minnesota School of Dentistry, Minneapolis, MN, ²³College of Dentistry, Department of Oral and Maxillofacial Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, ²⁴Oral Diagnosis and Radiology Department, University of Oklahoma Health Sciences Center College of Dentistry, Oklahoma City, OK, ²⁵Hard Tissue Research Laboratory, University of Minnesota School of Dentistry, Minneapolis, MN, ²⁶Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, ²⁷Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, ²⁸Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Children's Hospital Medical Center, Cincinnati, OH, ²⁹National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, ³⁰Hannover Medical School, Hanover, Germany, ³¹Broegelmann Research Laboratory, The Gade Institute, University of Bergen, Bergen, Norway, ³²University of Adelaide, Adelaide, Australia, ³³Department of Rheumatology, The Queen Elizabeth Hospital, Adelaide, Australia, ³⁴Rheumatology, Department of Medical Sciences and Science for Life Laboratory, Uppsala University, Uppsala, Sweden, ³⁵AP-HP, Hopitaux Universitaires Paris-Sud, Université Paris-Sud, Paris, France, ³⁶Center for Autoimmune Diseases Research (CREA), Universidad del Rosario, Bogotá, Colombia, ³⁷Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom, ³⁸Department of Oral Surgery, University of Minnesota School of Dentistry, Minneapolis, MN, ³⁹Division of Rheumatology, University of Minnesota Medical School, Minneapolis, MN, ⁴⁰US Department of Veterans Affairs Medical Center, Oklahoma City, OK

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: B cells, Sjogren's syndrome, T cells and genetics

Session Information

Date: Sunday, November 8, 2015

Title: Sjögren's Syndrome I: Basic Insights

Session Type: ACR Concurrent Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: Sjögren’s syndrome (SS) is a complex autoimmune disease with both environmental and genetic factors playing important roles in its pathophysiology. The goal of this study was replicate suggestive loci that failed to exceed the genome-wide significance (GWS) threshold of 5x10E-8 in our previously published work. This list included: TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2, and PHIP.

Methods: Our previous study included 1638 SS cases and 6754 population controls typed either on Illumina Omni1 or ImmunoChip arrays. In the current study, we typed an additional 212 SS cases and 2150 population controls on OmniExpress arrays yielding a combined total of 1850 SS cases and 8904 population controls for analysis. The Omni1 data and the ImmunoChip data were imputed using IMPUTE2 with the 1000 Genomes reference panels. Analysis was done using logistic regression accounting for ancestry and gender. and the results were combined using a weighted Z-score method.

Results: Two regions that have not been previously reported were found to exceed the GWS threshold. Association has been previously established with SS to a risk haplotype that spans the TNFAIP3 coding region originally describe in lupus; however, in the current study we identified a novel effect ~230kb 5’ of the TNFAIP3 coding region (rs6933404, P_meta= 7.79x10E-9, OR= 1.28, 95% CI=1.14-1.44), which was originally describe as a risk effect for rheumatoid arthritis. Association was observed for the haplotype previously established with SS spanning the TNFAIP3 coding region; however, the signal peaks at rs58721818 (P=4.77x10E-4), which is correlated (r2>0.8) with rs7749323, a variant previously described in lupus. Logistic regression analysis adjusting for rs6933404 found that this variant accounted for all association in the TNFAIP3 region. Bioinformatics data provided only limited evidence that rs6933404 might be the true functional/causal variant in this region; however, another variant on this haplotype also surpassing GWS, rs6927172, has been shown to modify 8 transcription factor binding sites, 13 bound proteins in various cell lines by ENCODE, and is located within an enhancer element in CD4⁺CD25^–IL17⁺PMA-Ionomycin stimulated Th17 primary cells by the Epigenetics Road Map Project. The second region to surpass the GWS threshold was PRDM1, which peaked at rs526531 (P_meta= 1.24x10E-8, OR= 1.25, 95% CI=1.12-1.39). Logistic regression adjusting for rs526531 found it accounted for all association in this region. Two additional variants on this haplotype exceeded GWS, but no clear candidate functional/causal variant has emerged based on bioinformatics data. Of the 6 remaining suggestive regions, PTTG1, DGKQ, and FCGR2A continue trending towards GWS.

Conclusion: These data now establish 2 new SS risk haplotypes, TNFAIP3 and PRDM1. TNFAIP3, which codes for the protein A20, is a negative regulator of NF-kB responses. PRDM1, which codes for the protein BLIMP1, is an important transcription factor in regulation of the interferon-beta locus and plasma cell differentiation. Additional studies are needed to determine how these association signals function in the human genome and contribute to SS pathophysiology.

Disclosure: C. J. Lessard, None; H. Li, None; J. Ice, None; I. Adrianto, None; A. Rasmussen, None; K. Grundahl, None; J. A. Kelly, None; C. Miceli, None; S. Bowman, Cellgene, 5,Glenmark, 5,GlaxoSmithKline, 5,Eli Lilly and Company, 5,Novartis Pharmaceutical Corporation, 5,Roche Pharmaceuticals, 5,Takeda, 5,UCB, 5; S. Lester, None; J. G. Brun, None; L. G. Goransson, None; E. Harboe, None; J. M. Guthridge, None; K. M. Kaufman, None; P. Eriksson, None; M. L. Eloranta, None; M. Kvarnström, None; D. S. Cunninghame-Graham, None; A. D. Farris, None; M. T. Brennan, None; J. Chodosh, None; R. Gopalakrishnan, None; A. J. W. Huang, None; P. Hughes, None; D. M. Lewis, None; L. Radfar, None; M. D. Rohrer, None; D. U. Stone, None; T. J. Vyse, None; P. M. Gaffney, None; J. A. James, None; J. B. Harley, None; R. Omdal, None; M. Wahren-Herlenius, None; G. G. Illei, None; T. Witte, None; R. Jonsson, None; M. Rischmueller, None; L. Rönnblom, None; X. Mariette, None; J. M. Anaya, None; W. F. Ng, None; G. Nordmark, None; C. G. Montgomery, None; N. L. Rhodus, None; B. M. Segal, None; R. H. Scofield, None; K. L. Sivils, None.

To cite this abstract in AMA style:

Lessard CJ, Li H, Ice J, Adrianto I, Rasmussen A, Grundahl K, Kelly JA, Miceli C, Bowman S, Lester S, Brun JG, Goransson LG, Harboe E, Guthridge JM, Kaufman KM, Eriksson P, Eloranta ML, Kvarnström M, Cunninghame-Graham DS, Farris AD, Brennan MT, Chodosh J, Gopalakrishnan R, Huang AJW, Hughes P, Lewis DM, Radfar L, Rohrer MD, Stone DU, Vyse TJ, Gaffney PM, James JA, Harley JB, Omdal R, Wahren-Herlenius M, Illei GG, Witte T, Jonsson R, Rischmueller M, Rönnblom L, Mariette X, Anaya JM, Ng WF, Nordmark G, Montgomery CG, Rhodus NL, Segal BM, Scofield RH, Sivils KL. Identification of Novel Sjogren’s Syndrome Risk Loci in the Regions of TNFAIP3 and PRDM1 [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/identification-of-novel-sjogrens-syndrome-risk-loci-in-the-regions-of-tnfaip3-and-prdm1/. Accessed .

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