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 (Pmeta=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; Pmeta=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 (Pmeta=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 (Pmeta<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.
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 August 11, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/genome-wide-association-study-identifies-novel-sjogrens-syndrome-risk-loci-in-the-regions-of-nab1-tyk2-and-pttg1-mir146a/