ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1962

HLA Contributions to Risk and Protection for Anti-Centromere Autoantibody-Positive Scleroderma

Elaine F. Remmers1, Theresa Alexander2, Nadia D. Morgan3, Ami A. Shah4, Maureen D. Mayes5, Adebowale Adeyemo1, Ayo Doumatey1, Amy Bentley1, Daniel Shriner6, Settara C Chandrasekharappa1, Mary A. Carns7, Lorinda Chung8, Lindsey A. Criswell9, Chris T. Derk10, Robyn T. Domsic11, Heather Gladue12, Avram Goldberg13, Jessica K. Gordon14, Vivien Hsu15, Reem Jan16, Dinesh Khanna17, Thomas A. Medsger Jr.18, Paula S. Ramos19, Marcin A. Trojanowski20, Lesley Ann Saketkoo21, Elena Schiopu22, Victoria Shanmugam23, Benjamin D. Korman24, Brynn Kron9, S. Louis Bridges Jr.25, Kathleen D. Kolstad26, Elana J. Bernstein27, Suzanne Kafaja28, Kathleen Maksimowicz-McKinnon29, Rick Silver30, Virginia D. Steen31, John Varga32, Charles Rotimi1, Francesco Boin33, Fredrick M. Wigley34, Daniel L. Kastner35 and Pravitt Gourh36, 1National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 2National Institutes of Health, Bethesda, MD, 3Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, 4Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, 5Rheumatology, University of Texas McGovern Medical School, Houston, TX, 6National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD, 7Northwestern University, Feinberg School of Medicine Scleroderma Program, Chicago, IL, 8Immunology and Rheumatology, Stanford University School of Medicine, Palo Alto, CA, 9University of California San Francisco, San Francisco, CA, 10Rheumatology, University of Pennsylvania, Philadelphia, PA, 11Medicine - Rheumatology, University of Pittsburgh, Pittsburgh, PA, 12Rheumatology, Arthritis and Osteoporosis Consultants of the Carolinas, Charlotte, NC, 13NYU Langone Medical Center, New York, NY, 14Rheumatology, Hospital for Special Surgery, New York, NY, 15Rheumatology, Robert Wood Johnson University Scleroderma Program, New Brunswick, NJ, 16Medicine, Rheumatology, University of Chicago, Chicago, IL, 17Division of Rheumatology, Department of Internal Medicine, University of Michigan Scleroderma Program, University of Michigan, Ann Arbor, MI, 18University of Pittsburgh, Pittsburgh, PA, 19Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, 20Boston University School of Medicine, Boston, MA, 21Rheumatology, Tulane University School of Medicine, New Orleans, LA, 22University of Michigan, Ann Arbor, MI, 23Rheumatology, The George Washington University, Washington, DC, 24Division 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, 25Clinical Immunology & Rheum, Univ of Alabama, Birmingham, AL, 26Rheumatology, Stanford University Medical Center, Stanford, CA, 27Rheumatology, Columbia University, New York, NY, 28David Geffen School of Medicine, UCLA, Los Angeles, CA, 29Rheumatology, Henry Ford Hospital, Detroit, MI, 30Rheumatology, Medical University of SC, Charleston, SC, 31Rheumatology, MedStar Georgetown University Hospital, Washington, DC, 32Northwestern University, Chicago, IL, 33Rheumatology, University California, San Francisco, San Francisco, CA, 34Rheum Div/Mason F Lord, Johns Hopkins University, Baltimore, MD, 35Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 36Rheumatology, NIAMS, National Institutes of Health, Bethesda, MD

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: , , ,

Session Information

Date: Tuesday, October 23, 2018

Session Title: Genetics, Genomics and Proteomics Poster

Session Type: ACR Poster Session C

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

Background/Purpose:  Anti-nuclear autoantibodies are a hallmark of scleroderma with anti-centromere antibody (ACA) recognizing centromeric antigens.  ACA-positive patients have longstanding Raynaud’s, limited cutaneous disease and increased risk for pulmonary arterial hypertension.  We investigated the role of HLA classical genes and alleles on risk for ACA-positive scleroderma in a large collection of patients with scleroderma and genetically matched controls.

Methods:  SNP genotypes of 723 scleroderma cases and 5,561 controls, all of European ancestry, were obtained from dbGaP.  Classical HLA types were imputed with SNP2HLA using the Type I Diabetes Genetic Consortium reference of 5,225 individuals.  Association of HLA classical alleles was tested by a dominant model regression analysis coding the HLA types as numeric values (1 for present, 0 for absent).  Regression tests were corrected for genetic dissimilarity by including the top 5 principal components as covariates.

Results:  Of the 723 scleroderma cases, 238 (32.9%) were positive for ACA.  The most significantly ACA-positive scleroderma-associated HLA allele was HLA-DRB1*07:01, which was disease protective (P-value=1.8×10-18, odds ratio (OR)=0.11 (95%CI=0.05 to 0.22)).  This allele was found in only 3.4% of the ACA-positive cases versus 23.6% of controls and 20.8% of the ACA-negative cases.  Regression analysis conditioning on the disease-associated alleles identified HLA-DQB1*05:01 as the most significantly associated disease risk allele (P-value= 3.3×10-08, OR=2.18 (1.66-2.86)) with additional independent risk effects of HLA-DQA1*04:01 and HLA-DQA1*03:01).  A two-locus analysis of the DQB1*05:01 disease-risk and the DRB1*07:01 disease-protective alleles suggested the risk effect of DQB1*05:01 is overridden by the protective effect of DRB1*07:01 (Figure 1).  The odds ratio for ACA-positive disease in individuals carrying both alleles was 0.14, similar to that in individuals carrying DRB1*07:01 without DQB1*05:01 (0.15).  No effect of DRB1*07:01 or DQB1*05:01 was found in the anti-topoisomerase I autoantibody subset (P=0.98 and P=0.054, respectively).  For validation, 62 African American ACA-positive cases and 946 matched controls from the Genomic Research in African American Scleroderma Patients (GRASP) Collection, were similarly analyzed.  DQB1*05:01 was associated with disease risk (P=3.6×10-4, OR=2.68 (1.57-4.58)) and DRB1*07:01 was protective (P=8.6×10-3, OR=0.33 (0.13-0.85)) in the African American sample.

Conclusion:  HLA-DQB1*05:01 is associated with risk and HLA-DRB1*07:01 is associated with protection for ACA-positive scleroderma.  The mechanisms responsible for these effects could be exploited to prevent or treat scleroderma.

 

Disclosure: E. F. Remmers, None; T. Alexander, 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. Adeyemo, None; A. Doumatey, None; A. Bentley, None; D. Shriner, None; S. C. Chandrasekharappa, None; M. A. Carns, None; L. Chung, Third Rock Ventures; Incyte, 5; L. A. Criswell, None; C. T. Derk, None; R. T. Domsic, None; H. Gladue, None; A. Goldberg, None; J. K. Gordon, None; V. Hsu, None; R. Jan, None; 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; T. A. Medsger Jr., None; P. S. Ramos, None; M. A. Trojanowski, None; L. A. Saketkoo, None; E. Schiopu, BMS, 2; V. Shanmugam, None; B. D. Korman, None; B. Kron, None; S. L. Bridges Jr., None; K. D. Kolstad, None; E. J. Bernstein, Genentech, Inc., 5; S. Kafaja, None; K. Maksimowicz-McKinnon, None; R. Silver, None; V. D. Steen, Bayer, 2, 5,Reata, 2; J. Varga, BSM, 2,Pfizer, Inc., 2,Boehringer, 5,Mitsubishi, 5,Corbus, 5,Scleroderma Foundation, 6; C. Rotimi, None; F. Boin, None; F. M. Wigley, None; D. L. Kastner, None; P. Gourh, None.

To cite this abstract in AMA style:

Remmers EF, Alexander T, Morgan ND, Shah AA, Mayes MD, Adeyemo A, Doumatey A, Bentley A, Shriner D, Chandrasekharappa SC, Carns MA, Chung L, Criswell LA, Derk CT, Domsic RT, Gladue H, Goldberg A, Gordon JK, Hsu V, Jan R, Khanna D, Medsger TA Jr., Ramos PS, Trojanowski MA, Saketkoo LA, Schiopu E, Shanmugam V, Korman BD, Kron B, Bridges SL Jr., Kolstad KD, Bernstein EJ, Kafaja S, Maksimowicz-McKinnon K, Silver R, Steen VD, Varga J, Rotimi C, Boin F, Wigley FM, Kastner DL, Gourh P. HLA Contributions to Risk and Protection for Anti-Centromere Autoantibody-Positive Scleroderma [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/hla-contributions-to-risk-and-protection-for-anti-centromere-autoantibody-positive-scleroderma/. Accessed March 8, 2021.

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