Genome-Wide Association Study Identifies Novel Sjögren's Syndrome Risk Loci in the Regions of NAB1, TYK2, and PTTG1-mir146a

Christopher J. Lessard¹, Indra Adrianto¹, John Ice¹, Astrid Rasmussen², Kiely Grundahl³, Jennifer A. Kelly⁴, R. Hal Scofield¹, Simon Bowman⁵, Susan Lester⁶, Per Eriksson⁷, Maija-Leena Eloranta⁸, Johan G. Brun⁹, Lasse G. Goransson¹⁰, Erna Harboe¹⁰, Marika Kvarnström¹¹, Michael T. Brennan¹², James Chodosh¹³, Raj Gopalakrishnan¹⁴, Andrew J.W. Huang¹⁵, Pamela Hughes¹⁶, David M. Lewis¹⁷, Michael D. Rohrer¹⁸, Donald U. Stone¹⁹, Nelson L. Rhodus²⁰, Barbara M. Segal²¹, Lida Radfar²², A. Darise Farris²³, Joel M. Guthridge²⁴, Patrick M. Gaffney¹, Judith A. James¹, John B. Harley²⁵, Lars Rönnblom⁸, Juan-Manuel Anaya²⁶, Deborah S. Cunninghame-Graham²⁷, Timothy J. Vyse²⁸, Ilias Alevizos²⁹, Xavier Mariette³⁰, Roald Omdal¹⁰, Marie Wahren-Herlenius³¹, Torsten Witte³², Roland Jonsson³³, Maureen Rischmueller³⁴, Lindsey A. Criswell³⁵, Courtney G. Montgomery¹, Wan-Fai Ng³⁶, Gunnel Nordmark³⁷ and Kathy L. Sivils¹, ¹Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, ²Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, USA, Oklahoma City, OK, ³Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma CIty, OK, ⁴Arthritis & Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, ⁵Department of Rheumatology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom, ⁶Queen Elizabeth Hospital, University of Adelaide, Adelaide, Australia, ⁷University Hospital, Rheumatology clinic, Linköping, Sweden, ⁸Uppsala University, Department of Medical Sciences, Rheumatology and Science for Life Laboratory, Uppsala, Sweden, ⁹Department of Rheumatology, Haukeland University Hospital, Bergen, Norway, ¹⁰Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway, ¹¹Karolinska Institutet, Stockholm, Sweden, ¹²Department of Oral Medicine, Carolinas Medical Center, Charlotte, NC, ¹³Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, ¹⁴Diagnostic and Biological Sciences, Division of Oral Pathology, University of Minnesota School of Dentistry, Minneapolis, MN, ¹⁵Washington University,, St Louis, MO, ¹⁶Division of Oral and Maxillofacial Surgery, Department of Developmental and Surgical Science, University of Minnesota School of Dentistry, Minneapolis, MN, ¹⁷Department of Oral and Maxillofacial Pathology, University of Oklahoma College of Dentistry, Oklahoma City, OK, ¹⁸Hard Tissue Research Laboratory, University of Minnesota School of Dentistry, Minneapolis, MN, ¹⁹Dean McGee Eye Institute, Oklahoma City, OK, ²⁰Department of Diagnostic and Biological Sciences, University of Minnesota School of Dentistry, Minneapolis, MN, ²¹Division of Rheumatology, University of Minnesota Medical School, Minneapolis, MN, ²²Oral Diagnosis and Radiology Department, University of Oklahoma College of Dentistry, Oklahoma City, OK, ²³Arthritis & Immunology Program, Oklahoma Medical Research Foun, Oklahoma City, OK, ²⁴Arthritis & Clinical Immunology, Oklahoma Medical Research Foundation, Oklahoma City, OK, ²⁵Center for Autoimmune Genomics and Etiology (CAGE), Cincinnati Childrens Hospital, Cincinnati, OH, ²⁶Center for Autoimmune Diseases Research (CREA). School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia., Bogotá, Colombia, ²⁷Department of Medical and Molecular Genetics, King's College London, London, United Kingdom, ²⁸Division of Immunology, Infection and Inflammatory Disease, King’s College London, London, United Kingdom, ²⁹Sjögren's Syndrome Clinic, National Institute of Dental and Craniofacial Research, Bethesda, MD, ³⁰Institut National de la Santé et de la Recherche Médicale, Université Paris-Sud, AP-HP, Hôpitaux Universitaires Paris-Sud, Paris, France, ³¹Department of Medicine, Solna, Unit of Experimental Rheumatology, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden, Stockholm, Sweden, ³²Department of Clinical Immunology and Rheumatology, Hannover Medical School, Hannover, Germany, ³³Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Bergen, Norway, ³⁴Rheumatology, University of Adelaide, Adelaide, Australia, ³⁵Division of Rheumatology, UCSF, San Francisco, CA, ³⁶Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom, ³⁷Rheumatology, Department of Medical Sciences, Uppsala University, Sweden, Uppsala, Sweden

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Gene Expression, genetics and genomics

Session Information

Date: Wednesday, November 16, 2016

Title: Sjögren's Syndrome II: Basic Insights

Session Type: ACR Concurrent Abstract Session

Session Time: 11:00AM-12:30PM

Background/Purpose: Sjögren’s syndrome (SS) is a complex autoimmune disease with both environmental and genetic factors contributing to pathophysiology. The goal of this genome-wide association study (GWAS) was to identify SS risk loci that exceed the genome-wide significance (GWS) threshold of 5x10E-8 in European-derived cohort.

Methods: We studied >20,000 subjects that were genotyped on OMNIexpress, OMNI1-Quad, or OMNI2.5 Illumina arrays. Following application of strict standard quality control measures, a total of 2,809 independent SS cases and 17,102 population controls remained. Analysis was performed using logistic regression and accounted for ancestry (first 4 principal components) and gender.

Results were combined using a weighted Z-score method to determine meta P-values. Results: In total, 3101 variants exceeded the GWS threshold and were supported by more than one dataset. The majority of these variants were located within previously established SS risk loci such as HLA, IRF5, STAT4, and TNIP1. In addition, 3 novel loci were identified that exceeded GWS. The first effect was located within the 5’ untranslated region of the gene NAB1 (NGFI-A binding protein 1) peaking at rs2293765 (P_meta=3x10E-11; odds ratio (OR)=1.23). Bioinformatics data in this region denote epigenetic marks that are indicative of enhancer activity in T cells, B cells, monocytes, and neutrophils. Moreover, variation at rs2293765 has also been shown to alter expression in monocytes of neighboring genes including GLS (interferon (IFN) stimulation), TMEM194B (LPS stimulation), and MFSD6 (naïve). NAB1 has been shown by others to form a complex with EGR3 leading to transcriptional downregulation of the IFNGR1 locus upon IFN stimulation. The second novel effect is a missense allele, rs2304256 (V>F; P_meta=1.22x10E-9; OR=0.81), located within TYK2 (tyrosine kinase 2) and predicted to be damaging in 5 transcripts resulting from this locus by SIFT. Additionally, this variant is predicted to influence the expression in monocytes of multiple genes in the region under various conditions: IFN stimulation (ICAM1, TMED1), LPS stimulation (DNMT1), and naïve (ICAM3, TYK2). TYK2 is a Janus kinase family member that is responsive to both type I and III IFN signaling. The third novel effect maps to the intergenic space between PTTG1 (pituitary tumor-transforming 1) and mir-146a, peaking at rs2431697 (P_meta=3.38x10E-9; OR=0.82). Epigenetic marks in this region indicate enhancer element function in T cells, neutrophils, and monocytes as well as expression changes of PTTG1 in whole blood. To date, the role of PTTG1 in the immune system remains elusive, but this locus is a risk factor for various forms of cancer. In addition, several loci showed suggestive association with SS (P_meta<1x10E-5) including XKR6, PDHX-CD44, and ELMO1.

Conclusion: We have established three novel genetic associations with SS involved in pathways important in the disease pathology. Further replication, imputation, fine mapping, and functional studies are needed to elicit the precise causal variants and the impact on SS etiology.

Disclosure: C. J. Lessard, None; I. Adrianto, None; J. Ice, None; A. Rasmussen, None; K. Grundahl, None; J. A. Kelly, None; R. H. Scofield, None; S. Bowman, None; S. Lester, None; P. Eriksson, None; M. L. Eloranta, None; J. G. Brun, None; L. G. Goransson, None; E. Harboe, None; M. Kvarnström, None; M. T. Brennan, None; J. Chodosh, None; R. Gopalakrishnan, None; A. J. W. Huang, None; P. Hughes, None; D. M. Lewis, None; M. D. Rohrer, None; D. U. Stone, None; N. L. Rhodus, None; B. M. Segal, None; L. Radfar, None; A. D. Farris, None; J. M. Guthridge, None; P. M. Gaffney, None; J. A. James, None; J. B. Harley, None; L. Rönnblom, None; J. M. Anaya, None; D. S. Cunninghame-Graham, None; T. J. Vyse, None; I. Alevizos, None; X. Mariette, None; R. Omdal, None; M. Wahren-Herlenius, None; T. Witte, None; R. Jonsson, None; M. Rischmueller, None; L. A. Criswell, None; C. G. Montgomery, None; W. F. Ng, None; G. Nordmark, None; K. L. Sivils, None.

To cite this abstract in AMA style:

Lessard CJ, Adrianto I, Ice J, Rasmussen A, Grundahl K, Kelly JA, Scofield RH, Bowman S, Lester S, Eriksson P, Eloranta ML, Brun JG, Goransson LG, Harboe E, Kvarnström M, Brennan MT, Chodosh J, Gopalakrishnan R, Huang AJW, Hughes P, Lewis DM, Rohrer MD, Stone DU, Rhodus NL, Segal BM, Radfar L, Farris AD, Guthridge JM, Gaffney PM, James JA, Harley JB, Rönnblom L, Anaya JM, Cunninghame-Graham DS, Vyse TJ, Alevizos I, Mariette X, Omdal R, Wahren-Herlenius M, Witte T, Jonsson R, Rischmueller M, Criswell LA, Montgomery CG, Ng WF, Nordmark G, Sivils KL. Genome-Wide Association Study Identifies Novel Sjögren’s Syndrome Risk Loci in the Regions of NAB1, TYK2, and PTTG1-mir146a [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/genome-wide-association-study-identifies-novel-sjogrens-syndrome-risk-loci-in-the-regions-of-nab1-tyk2-and-pttg1-mir146a/. Accessed .

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