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Abstract Number: 1120

Transcriptome-Wide Association Study of Sjögren’s Disease Risk Alleles Identifies Novel Genes with Altered Expression in Minor Salivary Gland and Other Tissues

Marcin Radziszewski1, Mandi Wiley1, Bhuwan Khatri1, Kandice Tessneer1, Astrid Rasmussen1, Professor Simon Bowman2, Lida Radfar3, Roald Omdal4, Marie Wahren-Herlenius5, Blake Warner6, Torsten Witte7, Roland Jonsson8, Maureen Rischmueller9, Patrick Gaffney1, Judith James1, Lars Ronnblom10, R. Hal Scofield3, Xavier Mariette11, Marta Alarcon-Riquelme12, Fai Ng13, Gunnel Nordmark10, Umesh Deshmukh1, A. Darise Farris1 and Christopher Lessard1, 1Oklahoma Medical Research Foundation, Oklahoma City, OK, 2University Hospitals Birmingham, Birmingham, United Kingdom, 3University of Oklahoma Health Sciences Center, Oklahoma City, OK, 4Stavanger University, Stavanger, Norway, 5Karolinska Institutet, Stockholm, Sweden, 6National Institutes of Health, Bethesda, MD, 7MH-Hannover, Hannover, Germany, 8University of Bergen, Bergen, Norway, 9RheumatologySA, Adelaide, Australia, 10Uppsala University, Uppsala, Sweden, 11Paris-Saclay University, Rueil Malmaison, Ile-de-France, France, 12Center for Genomics and Oncological Research (GENYO), Granada, Spain, 13Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom

Meeting: ACR Convergence 2022

Keywords: Bioinformatics, Epigenetics, Gene Expression, genetics, Sjögren's syndrome

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Session Information

Date: Sunday, November 13, 2022

Title: Genetics, Genomics and Proteomics Poster

Session Type: Poster Session C

Session Time: 1:00PM-3:00PM

Background/Purpose: Sjögren’s disease (SjD) is an autoimmune disease characterized by reduced function of exocrine glands, but also has systemic manifestations affecting multiple organs, including abnormal pulmonary or liver functions in 75% or 50% of patients, respectively [1,2]. Genetic and transcriptional changes influence epithelial-immune cell interactions in SjD pathogenesis, but mechanisms remain understudied.

Methods: SNPs from 16 regions with SNP-SjD associations (P< 5×10-8) in our genome-wide association studies (GWAS) [3,4] were interrogated for expression quantitative trait loci (eQTLs) in Genotype-Tissue Expression (GTEx) minor salivary gland (MSG) data. Genes that were identified as eQTLs in the MSG and showed differential expression or accessibility in RNA-seq and ATAC-seq, respectively, from the submaxillary salivary gland epithelial cell line, A253, were analyzed by pathway enrichment analysis using gProfiler. Transcriptome-wide association study (TWAS) was performed using GWAS summary statistics and MSG, liver, and lung eQTL GTEx data.

Results: In total, 5884 genome-wide significant (GWS) SNPs spanning 10 risk loci were identified as MSG eQTLs using two discovery thresholds: p(FDR)< 0.05 provided by eQTL study (3566 SNPs) and p(FDR) >0.05 and p< 0.05 in eQTL study (2318 SNPs). MSG eQTLs for 155 unique genes exhibited coalescence of RNA- and ATAC-seq data in A253 cells. Many SNPs altered expression of the nearest gene, such as IRF5 and TNPO3 on chromosome 7 at 128Mb. This locus had 12 additional genes that were eQTLs in MSG. In contrast, other loci had no reported eQTLs for the nearest gene, but several reported eQTLs for distant loci, such as TYK2 on chromosome 19 at 10Mb that showed no change in TYK2 expression but eQTLs for 8 distant genes, including ICAM1. Pathway enrichment analysis revealed Butyrophilin (BTN) family interactions (PAdj=1.564×10-5), including the BTN2A1, BTN2A2, BTN3A1, BTN3A2 and BTN3A3 gene cluster in the MHC region. TWAS of MSG and SjD GWAS summary statistics (after Bonferroni correction) showed association between SjD and BTN3A2 (PAdj=1.19×10-50), among many loci in the MHC region. Several long non-coding RNAs (lncRNAs) were also significant. LINC02210 (PAdj=1.21×10-6) on chromosome 17 exhibited opposing z-scores in the TWAS of liver (6.02) relative to lung (-5.99) and MSG (-6.27).

Conclusion: SjD risk alleles influence disease by altering tissue-specific gene expression. Interestingly, we observed MSG eQTLs for several BTN family genes, which act as cell-surface binding partners to regulate cell-cell interactions, such as those between epithelial cells and activated T cells [5]. Further, tissue-specific changes in lncRNA expression suggest that these uncharacterized transcripts may play important pathogenic roles. Additional studies in MSG and other affected tissues are needed for further insights into SjD pathology.

References:
1. Verstappen. Nat Rev Rheumatol 2021;17(6):333-348.
2. Negrini et al. Clin Exp Med. 2022; 22(1): 9–25.
3. Lessard, et al. Nat Genet 2013 Nov;45(11):1284-92.
4. Khatri, et al. Annals of Rheumatic Diseases 2020;79:30-31.
5. Arnett HA, Viney JL. Nature Reviews Immunology 2014;14:559-569.


Disclosures: M. Radziszewski, None; M. Wiley, None; B. Khatri, None; K. Tessneer, None; A. Rasmussen, None; P. Bowman, Novartis, AstraZeneca, AbbVie/Abbott, Galapagos; L. Radfar, None; R. Omdal, None; M. Wahren-Herlenius, None; B. Warner, Pfizer, Astellas Bio; T. Witte, AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Chugai, Janssen, Lilly, MSD, Mylan, Novartis, Pfizer, Roche, UCB, Galapagos; R. Jonsson, None; M. Rischmueller, None; P. Gaffney, None; J. James, Bristol-Myers Squibb(BMS), AstraZeneca, Novartis, Progentec Biosciences; L. Ronnblom, None; R. Scofield, None; X. Mariette, AstraZeneca, Bristol Myers Squibb, Galapagos, GSK, Novartis, Pfizer; M. Alarcon-Riquelme, None; F. Ng, None; G. Nordmark, None; U. Deshmukh, None; A. Farris, Janssen; C. Lessard, Janssen.

To cite this abstract in AMA style:

Radziszewski M, Wiley M, Khatri B, Tessneer K, Rasmussen A, Bowman P, Radfar L, Omdal R, Wahren-Herlenius M, Warner B, Witte T, Jonsson R, Rischmueller M, Gaffney P, James J, Ronnblom L, Scofield R, Mariette X, Alarcon-Riquelme M, Ng F, Nordmark G, Deshmukh U, Farris A, Lessard C. Transcriptome-Wide Association Study of Sjögren’s Disease Risk Alleles Identifies Novel Genes with Altered Expression in Minor Salivary Gland and Other Tissues [abstract]. Arthritis Rheumatol. 2022; 74 (suppl 9). https://acrabstracts.org/abstract/transcriptome-wide-association-study-of-sjogrens-disease-risk-alleles-identifies-novel-genes-with-altered-expression-in-minor-salivary-gland-and-other-tissues/. Accessed .
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