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Abstract Number: 1525

Intergenic HLA Variants in African American Patients with Systemic Sclerosis Regulate Expression of HLA-DRB1

Urvashi Kaundal1, Julia Hartman2, Chloe Borden2, Janet Wang3, Ami Shah4, Maureen Mayes5, Ayo Doumatey6, Amy Bentley7, Daniel Shriner6, Robyn Domsic8, Thomas Medsger9, Paula Ramos10, Richard Silver11, Virginia Steen12, John Varga13, Vivien Hsu14, Lesley Ann Saketkoo15, Elena Schiopu16, Dinesh Khanna17, Jessica Gordon18, Lindsey Criswell19, Heather Gladue20, Chris Derk21, Elana Bernstein22, S. Louis Bridges23, Victoria Shanmugam24, Kathleen Kolstad25, Lorinda Chung26, Suzanne Kafaja27, Reem Jan28, Marcin Trojanowski29, Avram Goldberg30, Benjamin Korman31, Monique Hinchcliff32, Settara Chandrasekharappa6, Massimo Gadina2, Davide Randazzo2, Stefania Dell'Orso2, Adebowale Adeyemo6, Charles Rotimi6, Elaine Remmers6, Fredrick Wigley33, Rafael Casellas2, Daniel Kastner6, Francesco Boin34 and Pravitt Gourh1, 1National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, 2National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD, 3National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NIH, Beachwood, OH, 4Johns Hopkins University School of Medicine, Ellicott City, MD, 5University of Texas Houston McGovern Medical School, Division of Rheumatology and Clinical Immunogenetics, Houston, TX, 6National Human Genome Research Institute (NHGRI), NIH, Bethesda, MD, 7National Human Genome Research Institute (NHGRI), NIH, Bethedsa, MD, 8University of Pittsburgh School of Medicine, Pittsburgh, PA, 9University of Pittsburgh School of Medicine, Verona, PA, 10Medical University of South Carolina, Charleston, SC, 11Medical University of South Carolina, Charleston, 12Division of Rheumatology, Department of Medicine, MedStar Georgetown University Hospital, Washington, DC, 13Northwestern University, Chicago, IL, 14Rutgers-RWJ Medical School, South Plainfield, NJ, 15Scleroderma Patient Care and Research Center, Tulane University, New Orleans, LA, 16Michigan Medicine, Ann Arbor, MI, 17University of Michigan, Ann Arbor, MI, 18Hospital for Special Surgery, New York, NY, 19Rosalind Russell/Ephraim P. Engleman Rheumatology Research Center, University of California San Francisco, San Francisco, CA, 20Arthritis and Osteoporosis Consultants of the Carolinas, Charlotte, NC, 21University of Pennsylvania, Philadelphia, PA, 22Columbia University, New York, NY, 23University of Alabama at Birmingham, Mountain Brk, AL, 24The George Washington University, Washington, DC, 25Division of Immunology & Rheumatology, Stanford University School of Medicine, Palo Alto, CA, 26Stanford University School of Medicine and Palo Alto VA Health Care System, Palo Alto, CA, 27David Geffen School of Medicine, UCLA, Los Angeles, CA, 28Pritzker School of Medicine, University of Chicago, Chicago, IL, 29Boston University Medical Center, BOSTON, MA, 30NYU Langone Medical Center - NYU Hospital for Joint Diseases, Lake Success, NY, 31Department of Medicine, University of Rochester Medical Center, Rochester, NY, 32Yale School of Medicine, Westport, CT, 33Johns Hopkins University School of Medicine, Baltimore, MD, 34University of California San Francisco, Cedars-Sinai, West Hollywood, CA

Meeting: ACR Convergence 2020

Keywords: B-Lymphocyte, Epigenetics, Gene Expression, Genome Wide Association Studies, Scleroderma

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Session Information

Date: Sunday, November 8, 2020

Title: Systemic Sclerosis & Related Disorders – Basic Science (1522–1526)

Session Type: Abstract Session

Session Time: 3:00PM-3:50PM

Background/Purpose: Genome-wide association study (GWAS) from the Genome Research in African American Scleroderma Patients (GRASP) cohort has identified the human leukocyte antigen (HLA) region as the strongest genetic risk factor in SSc. The functional roles of HLA variants in SSc susceptibility are largely unknown. We hypothesize that SSc-associated HLA variants overlap with one of the classes of cis-regulatory modules (CRMs) such as enhancer to regulate gene expression. CRMs can be mapped using DNase I hypersensitive site sequencing (DNase-Seq) or assay for transposase-accessible chromatin with high throughput sequencing (ATAC-Seq) giving information regarding chromatin accessibility. Thus, chromatin accessibility in the SSc-relevant cell types would be crucial in interpreting the function of these variants.

Methods: Genotyping data using the Illumina Multi-Ethnic Global array (MEGA) from the GRASP cohort were analyzed to identify the top HLA variant. Expression quantitative trait loci (eQTL) analysis was performed for the risk variants using RNA sequencing data from the Genotype-Tissue Expression (GTEx) project. Epstein-Barr virus-transformed B (EBV-B) cells with wild type, heterozygous and homozygous alleles for the most highly associated HLA variant were used to confirm the expression of HLA-II genes using RNA-sequencing. Protein expression was confirmed by flow cytometry and confocal microscopy. Chromatin accessibility at the variant position in EBV-B cells is being identified using ATAC-seq.

Results: The top variant in the African American GWAS was rs9469201, near the HLA-DQA1 gene with an odds ratio of 2.13 (P=4.5×10-20). eQTL analysis suggested decreased expression of HLA-DQA1/-DQB1 (in whole blood) and increased expression of HLA-DRB1 (in EBV-B cells) for the risk allele (Figure 1). This is particularly intriguing because we have previously reported two HLA-DRB1 alleles (HLA-DRB1*08:04 and -DRB1*11:02) as independent risk factors in African American SSc. The rs9469201 variant was found not to be in linkage disequilibrium with the HLA-DRB1*08:04 allele. Flow cytometry (Figure 2) and confocal microscopy (Figure 3) confirmed the expression of HLA-DRB1 and HLA-DQB1. ATAC-Seq analysis of the EBV-B cells is currently ongoing.

Conclusion: Our preliminary findings suggest that peptide presentation by HLA molecules as well as the relative expression of the specific HLA molecule presenting the peptide are both important in SSc pathogenesis. Future directions will involve CRISPR/Cas9 based deletion of CRMs-with overlapping HLA variants, and subsequent evaluation of the changes in HLA-II gene expression. Transcription factor binding at the HLA variant site will be accessed using chromatin immunoprecipitation with sequencing (ChIP-seq) in EBV-B cells. This study will elucidate the functional role of the HLA variants in allele-specific HLA-II gene expression in SSc.

Figure 1. GTEx HLA-DRB1, HLA-DQA1 and HLA-DQB1 expression by rs9469201 variant

Figure 2. Flow cytometry plots for EBV-B cells with wild type allele stained for HLA-DRB1 and HLA-DQB1 protein using fluorochrome conjugated antibodies.

Figure 3. Confocal microscopy image for HLA-DRB1 and HLA-DQB1 stained cells for the wild type allele.


Disclosure: U. Kaundal, None; J. Hartman, None; C. Borden, None; J. Wang, None; A. Shah, None; M. Mayes, Actelion Pharmaceuticals, 1, Boehringer Ingelheim, 1, 2, Corbus, 1, Eicos Sciences, 1, Galapagos, 1; A. Doumatey, None; A. Bentley, None; D. Shriner, None; R. Domsic, Formation Biologics, 5, Eicos Sciences, Inc, 5, Corbus Pharmaceutical Holdings, 5; T. Medsger, None; P. Ramos, None; R. Silver, Boehringer Ingelheim, 1, 2, Actelion, 1, Corbus, 1, Forbius, 1; V. Steen, Boehringer Ingelheim, 2, 5, corbus, 2, 5, eicos, 2, 5, genetech, 2, forbius, 5, galapagos, 5; J. Varga, None; V. Hsu, None; L. Saketkoo, None; E. Schiopu, Octapharma, 2; D. Khanna, Bayer, 2, BMS, 2, Horizon, 2, Pfizer, 2, NIH, 2, Immune Tolerance Network, 2, Eicos Sciences Inc, 4, Acceleron,, 5, Actelion,, 5, Abbvie,, 5, Amgen,, 5, Bayer,, 5, Boehringer Ingelheim, 5, CSL Behring, 5, Corbus,, 5, Galapagos,, 5, Genentech/Roche, 5, GSK, 5, Horizon, 5, Merck,, 5, Mitsubishi Tanabe Pharma, 5, Sanofi-Aventis, 5, United Therapeutics, 5, Impact PH, 9, Scleroderma Development, 6, CiviBioPharma/Eicos Sciences Inc, 6; J. Gordon, None; L. Criswell, None; H. Gladue, None; C. Derk, None; E. Bernstein, None; S. Bridges, None; V. Shanmugam, None; K. Kolstad, None; L. Chung, Eicos, 1, Reata, 1, Boehringer Ingelheim, 1, 2, Mitsubishi Tanabe, 1; S. Kafaja, None; R. Jan, None; M. Trojanowski, None; A. Goldberg, None; B. Korman, None; M. Hinchcliff, None; S. Chandrasekharappa, None; M. Gadina, None; D. Randazzo, None; S. Dell'Orso, None; A. Adeyemo, None; C. Rotimi, None; E. Remmers, None; F. Wigley, None; R. Casellas, None; D. Kastner, None; F. Boin, None; P. Gourh, None.

To cite this abstract in AMA style:

Kaundal U, Hartman J, Borden C, Wang J, Shah A, Mayes M, Doumatey A, Bentley A, Shriner D, Domsic R, Medsger T, Ramos P, Silver R, Steen V, Varga J, Hsu V, Saketkoo L, Schiopu E, Khanna D, Gordon J, Criswell L, Gladue H, Derk C, Bernstein E, Bridges S, Shanmugam V, Kolstad K, Chung L, Kafaja S, Jan R, Trojanowski M, Goldberg A, Korman B, Hinchcliff M, Chandrasekharappa S, Gadina M, Randazzo D, Dell'Orso S, Adeyemo A, Rotimi C, Remmers E, Wigley F, Casellas R, Kastner D, Boin F, Gourh P. Intergenic HLA Variants in African American Patients with Systemic Sclerosis Regulate Expression of HLA-DRB1 [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/intergenic-hla-variants-in-african-american-patients-with-systemic-sclerosis-regulate-expression-of-hla-drb1/. Accessed .
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