ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1120

Strong HLA and Novel Non-HLA Associations Identified By Auto-Antibody Subset Analysis of African Americans with Scleroderma from the Genome Research in African American Scleroderma Patients Cohort

Pravitt Gourh1, Elaine F. Remmers2, Theresa Alexander3, Steven Boyden4, Nadia D. Morgan5, Ami A. Shah6, Maureen D. Mayes7, Ayo Doumatey2, Amy Bentley2, Daniel Shriner8, Robyn T. Domsic9, Thomas A. Medsger Jr.10, Virginia D. Steen11, Paula S. Ramos12, Rick Silver13, Benjamin D. Korman14, John Varga15, Elena Schiopu16, Dinesh Khanna17, Vivien Hsu18, Jessica K. Gordon19, Lesley Ann Saketkoo20, Heather Gladue21, Brynn Kron22, Lindsey A. Criswell22, Chris T. Derk23, S. Louis Bridges Jr.24, Victoria Shanmugam25, Kathleen D. Kolstad26, Lorinda Chung27, Reem Jan28, Elana J. Bernstein29, Avram Goldberg30, Marcin Trojanowski31, Suzanne Kafaja32, Kathleen Maksimowicz-McKinnon33, Settara C Chandrasekharappa2, Adebowale Adeyemo2, Charles Rotimi2, Fredrick M. Wigley34, Francesco Boin35 and Daniel L. Kastner36, 1NIAMS-Rheumatology, National Institutes of Health (NIH), National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, 2National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 3National Institutes of Health, Bethesda, MD, 4National Institutes of Health (NIH), National Institute on Deafness and Other Communication Disorders, Bethesda, MD, 5Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, 6Division of Rheumatology, Johns Hopkins University, Baltimore, MD, 7Rheumatology, University of Texas McGovern Medical School, Houston, TX, 8National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD, 9Medicine - Rheumatology, University of Pittsburgh, Pittsburgh, PA, 10University of Pittsburgh, Pittsburgh, PA, 11Rheumatology, MedStar Georgetown University Hospital, Washington, DC, 12Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, 13Rheumatology, Medical University of SC, Charleston, SC, 14Division of Allergy/Immunology and Rheumatology and Center for Musculoskeletal Research, School of Medicine and Dentistry, University of Rochester Medical School, Rochester, New York, USA, Rochester, NY, 15Northwestern University, Chicago, IL, 16University of Michigan, Ann Arbor, MI, 17Division of Rheumatology, Department of Internal Medicine, University of Michigan Scleroderma Program, University of Michigan, Ann Arbor, MI, 18Rheumatology, Robert Wood Johnson Medical School, New Brunswick, NJ, 19Rheumatology, Hospital for Special Surgery, New York, NY, 20Tulane, New Orleans, LA, 21Rheumatology, Arthritis and Osteoporosis Consultants of the Carolinas, Charlotte, NC, 22University of California San Francisco, San Francisco, CA, 23Rheumatology, University of Pennsylvania, Philadelphia, PA, 24Clinical Immunology & Rheum, Univ of Alabama, Birmingham, AL, 25Rheumatology, The George Washington University, Washington, DC, 26Rheumatology, Stanford University Medical Center, Stanford, CA, 27Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, CA, 28Medicine, Rheumatology, University of Chicago, Chicago, IL, 29Rheumatology, Columbia University, New York, NY, 30NYU Langone Medical Center, New York, NY, 31Boston University, Boston, MA, 32David Geffen School of Medicine, UCLA, Los Angeles, CA, 33Rheumatology, Henry Ford Hospital, Detroit, MI, 34Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, 35Rheumatology, University California, San Francisco, San Francisco, CA, 36Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: , , ,

Session Information

Date: Monday, October 22, 2018

Title: Systemic Sclerosis and Related Disorders – Basic Science Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: Anti-fibrillarin (nucleolar, AFA) and anti-topoisomerase I (ATA) autoantibodies are specific to systemic sclerosis (SSc) and are common in African Americans (AA). These autoantibodies define clinically distinct phenotypes but the genetic risk factors contributing towards them are largely unknown.

Methods: Data from the genome-wide association study (GWAS) of AA SSc collected under the Genome Research in African American Scleroderma Patients (GRASP) cohort were utilized. 207 AFA and 245 ATA positive patients were compared to 946 controls. After quality control filtering, SNP imputation was performed using Beagle and classical HLA types were imputed using HLA*IMP:03 web server. Odds ratios for HLA alleles and amino acid residues were calculated using a dominant model.

Results: In the GRASP cohort, 22.2% of patients had nucleolar ANA pattern (AFA) after removing other nucleolar staining, SSc specific autoantibodies. In the AFA+ subset, HLA-DRB1*08:04 demonstrated the strongest association with P=4.2 x 10-27, OR=5.98 (95% CI 4.2-8.5) (Figure 1A). HLA-DRB1*08:04 is a predominantly African ancestry allele and its leucine 74 residue in the peptide binding groove was strongly associated with AFA+ SSc with OR=5.12 (95% CI 3.7-7.1). The top SNP in the HLA region was rs573310147 with P=1.3 x 10-19. ATA positivity was seen in 26.2% of patients in the GRASP cohort. In the ATA+ subset, rs28667353 was the top SNP with P=1.4 x 10-19 (Figure 1B). HLA-DPB1*13:01 was seen in 15.8% of ATA+ SSc as compared to 6.2% in ATA- SSc and 5.1% in controls. HLA-DPB1*13:01 demonstrated the strongest association with P=1.1 x 10-16, OR=4.1 (95% CI 2.9-5.8) in the ATA+ subset. HLA-DPB1*13:01 has been reported as a risk loci in ATA+ subset in SSc patients from several different ancestries. Meta-analysis with the European ancestry SSc yielded a highly significant P=2.18 x 10-61. On examining the amino acid residues, isoleucine 76 in the peptide binding groove of HLA-DPB1 increased risk for SSc with OR=2.8 (95% CI 2.1-3.8). Six other previously unreported, non-HLA loci were identified in the AFA + subset and two in the ATA + subset at genome-wide significance with the top one being FSD2 (Fibronectin type III and SPRY domain containing 2).

Conclusion: HLA-DRB1*08:04 is a predominantly African ancestry allele that increases SSc risk 6-fold in AFA subset which is primarily observed in AAs with SSc. This may help explain the increased prevalence and severity of SSc in AAs. HLA-DPB1*13:01 increases risk of SSc in not only AAs but all ancestral populations. Also, HLA-DPB1*13:01 control frequency in a population correlates with the prevalence of SSc in that ancestral population. Functional roles of these novel non-HLA loci need to be experimentally evaluated. Understanding the mechanism of peptide presentation by these two HLA alleles will lead to a better recognition of the trigger that leads to autoimmunity in SSc.

Disclosure: P. Gourh, None; E. F. Remmers, None; T. Alexander, None; S. Boyden, None; N. D. Morgan, None; A. A. Shah, None; M. D. Mayes, Boehringer-Ingelheim, 2, 5,Corbus, 2,Reata, 2,Sanofi, 2,Mitsubishi-Tanabe, 5,Roche-Genentech, 2; A. Doumatey, None; A. Bentley, None; D. Shriner, None; R. T. Domsic, None; T. A. Medsger Jr., None; V. D. Steen, Bayer, 2, 5,Reata, 2; P. S. Ramos, None; R. Silver, None; B. D. Korman, None; J. Varga, BSM, 2,Pfizer, Inc., 2,Boehringer, 5,Mitsubishi, 5,Corbus, 5,Scleroderma Foundation, 6; E. Schiopu, BMS, 2; D. Khanna, Eicos Sciences, 1,Pfizer, Inc., 2,Horizon, 2,BMS, 2,Actelion, 5,Bayer, 5,Bayer, 2,Corbus, 5,Cytori, 5,EMD Serono, 5,Genentech, Inc., 5,Sanofi-Aventis, 5,GSK, 5,Boehringer Ingelheim, 5; V. Hsu, None; J. K. Gordon, None; L. A. Saketkoo, None; H. Gladue, None; B. Kron, None; L. A. Criswell, None; C. T. Derk, None; S. L. Bridges Jr., None; V. Shanmugam, None; K. D. Kolstad, None; L. Chung, Third Rock Ventures; Incyte, 5; R. Jan, None; E. J. Bernstein, Genentech, Inc., 5; A. Goldberg, None; M. Trojanowski, None; S. Kafaja, None; K. Maksimowicz-McKinnon, None; S. C. Chandrasekharappa, None; A. Adeyemo, None; C. Rotimi, None; F. M. Wigley, None; F. Boin, None; D. L. Kastner, None.

To cite this abstract in AMA style:

Gourh P, Remmers EF, Alexander T, Boyden S, Morgan ND, Shah AA, Mayes MD, Doumatey A, Bentley A, Shriner D, Domsic RT, Medsger TA Jr., Steen VD, Ramos PS, Silver R, Korman BD, Varga J, Schiopu E, Khanna D, Hsu V, Gordon JK, Saketkoo LA, Gladue H, Kron B, Criswell LA, Derk CT, Bridges SL Jr., Shanmugam V, Kolstad KD, Chung L, Jan R, Bernstein EJ, Goldberg A, Trojanowski M, Kafaja S, Maksimowicz-McKinnon K, Chandrasekharappa SC, Adeyemo A, Rotimi C, Wigley FM, Boin F, Kastner DL. Strong HLA and Novel Non-HLA Associations Identified By Auto-Antibody Subset Analysis of African Americans with Scleroderma from the Genome Research in African American Scleroderma Patients Cohort [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 9). https://acrabstracts.org/abstract/strong-hla-and-novel-non-hla-associations-identified-by-auto-antibody-subset-analysis-of-african-americans-with-scleroderma-from-the-genome-research-in-african-american-scleroderma-patients-cohort/. Accessed .

« Back to 2018 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/strong-hla-and-novel-non-hla-associations-identified-by-auto-antibody-subset-analysis-of-african-americans-with-scleroderma-from-the-genome-research-in-african-american-scleroderma-patients-cohort/