Ancestry-Specific Classical HLA Alleles Define Phenotypic Subsets in the African American Scleroderma Population

Pravitt Gourh ¹, Sarah Safran², Steven Boyden ³, Ami Shah ⁴, Maureen Mayes ⁵, Ayo Doumatey ⁶, Amy Bentley ⁶, Daniel Shriner ⁶, Robyn Domsic ⁷, Thomas Medsger Jr ⁸, Paula Ramos ⁹, Richard Silver ¹⁰, Virginia Steen ¹¹, John Varga ¹², Vivien Hsu ¹³, Lesley Saketkoo ¹⁴, Elena Schiopu ¹⁵, Dinesh Khanna ¹⁶, Jessica Gordon ¹⁷, Brynn Kron ¹⁸, Lindsey Criswell ¹⁹, Heather Gladue ²⁰, Chris Derk ²¹, Elana Bernstein ²², S Louis Bridges ²³, Victoria Shanmugam ²⁴, Kathleen Kolstad ²⁵, Lorinda Chung ²⁶, Suzanne Kafaja ²⁷, Reem Jan ²⁸, Marcin Trojanowski ²⁹, Avram Goldberg ³⁰, Benjamin Korman ³¹, Peter Steinbach ³², Settara Chandrasekharappa ⁶, James Mullikin ⁶, Adebowale Adeyemo ⁶, Charles Rotimi ⁶, Frederick Wigley ³³, Daniel Kastner ³⁴, Francesco Boin ³⁵, Elaine Remmers ⁶ and Theresa Alexander ³⁶, ¹National Institutes of Rheumatology, Bethesda, ²National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Bethesda, MD, ³University of Utah, SALT LAKE CITY, UT, ⁴Johns Hopkins Hospital, Baltimore, MD, ⁵Division of Rheumatology and Clinical Immunogenetics, University of Texas McGovern Medical School, Houston, Texas, USA, Houston, TX, ⁶National Human Genome Research Institute (NHGRI), Bethesda, MD, ⁷University of Pittsburgh, Pittsburgh, PA, ⁸University of Pittsburg School of Medicine, Pittsburg, PA, ⁹Medical University of South Carolina, Charleston, ¹⁰Division of Rheumatology, Medical University of South Carolina, Charleston, SC, ¹¹Georgetown University, Washington, D.C., USA, Georgetown, ¹²Northwestern University, Chicago,, IL, ¹³Rutgers- RWJ Medical School, SOUTH PLAINFIELD, NJ, ¹⁴New Orleans Scleroderma and Sarcoidosis Patient Care and Research Center, New Orleans; Tulane University School of Medicine, University Medical Center – Comprehensive Pulmonary Hypertension Center, USA, New Orleans, ¹⁵Department of Rheumatology, University of Michigan, Ann Arbor, ¹⁶Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA, Ann Arbor, ¹⁷Hospital for Special Surgery, New York, NY, ¹⁸University of California San Francisco, San Francisco, CA, ¹⁹University of California, San Francisco, San Francisco, ²⁰Arthritis & Osteoporosis Consultants Of The Carolinas, Charlotte, NC, ²¹University of Pennsylvania, Philadelphia, PA, ²²Division of Rheumatology, Columbia University, New York, NY, ²³University of Alabama at Birmingham, Birmingham, ²⁴George Washington University, Georgetown, DC, ²⁵Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, ²⁶Stanford University, Palo Alto, CA, ²⁷Department of Medicine. Rheumatology Division. UCLA, Los Angeles, CA, ²⁸University of Chicago Pritzker School of Medicine, Chicago, IL, ²⁹Boston University Medical Center, Boston, MA, ³⁰New York University Langone Medical Center, New York, NY, ³¹University of Rochester Medical Center, Rochester, NY, ³²Center for Molecular Modeling, Center for Information Technology, National Institutes of Health, Bethesda, MD, ³³Johns Hopkins University, Division of Rheumatology, Baltimore, ³⁴National Institutes of Health, Bethesda, MD, ³⁵UCSF, San Francisco, CA, ³⁶University of Maryland, College Park, MD

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: African-Americans and human leukocyte antigens (HLA), Scleroderma, Systemic sclerosis

Session Information

Date: Wednesday, November 13, 2019

Title: 6W023: Systemic Sclerosis & Related Disorder – Clinical III: Predictors of Outcome (2912–2917)

Session Type: ACR Abstract Session

Session Time: 11:00AM-12:30PM

Background/Purpose: Systemic sclerosis (SSc), or scleroderma, is a heterogeneous disease that is divided into limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc) forms based on the extent of skin involvement, and internal organ involvement also adds to phenotypic variability. The three main internal organ complications are interstitial lung disease (ILD), pulmonary arterial hypertension (PAH) and scleroderma renal crisis (SRC).

Methods: We investigated classical HLA alleles and polymorphic amino acids for association with clinical subsets of SSc. A conditional association analysis with a Bonferroni-corrected significance threshold of P-value (P) < 0.00005 identified multiple subset-specific SSc risk factors in an African American cohort of 934 SSc patients and 946 unaffected controls.

Results: HLA-DRB1*08:04, an African-ancestry predominant allele, was the strongest risk factor with odds ratios (ORs) ranging from 2.7 to 3.3-fold in the lcSSc, dcSSc, ILD+ and PAH+ subsets of SSc. The allele HLA-DPB1*13:01 also independently increased risk in the dcSSc and ILD+ subsets, with ORs of 2.0 (95% CI 1.4-2.8) and 2.5 (95% CI 1.8-3.6), respectively. There were no significant associations in the SRC+ subset at the chosen P threshold, but the strongest association was with HLA-DQB1*03:19 (P = 0.0002), which is in linkage disequilibrium with HLA-DRB1*08:04. For the first time, a protective effect of HLA-DRB4*01:01 was identified in SSc, with a stronger effect in the lcSSc subset (OR = 0.4, 95% CI 0.4-0.7) than in the dcSSc subset (OR = 0.5, 95% CI 0.4-0.7). The presence of this allele is also linked to HLA-DRB1*07:01, which has been reported as protective for SSc in European ancestry cohorts. Further stratification of clinical subsets by autoantibody status revealed more striking effects of certain alleles, despite the reduced sample size. On comparing the dcSSc with the lcSSc none of the alleles met the statistical significance threshold due to reduction in sample size. Interestingly, the top two associations were both class I HLA alleles, HLA-A*74:01 (OR = 0.5, 95% CI 0.3-0.8) and HLA-C*17:01 (OR = 1.7, 95% CI 1.1-2.6), and these associations became even stronger upon comparing patients with dcSSc to those with CREST syndrome (OR = 0.4 and 2.0 and P = 0.0008 and 0.003, respectively).

Conclusion: This is the largest genetic study of African American SSc patients identifying classical HLA alleles increasing risk in clinical subsets of SSc. Class II HLA alleles are responsible for increasing risk for scleroderma in general and the class I HLA alleles play a more prominent role in defining the extent of skin involvement. Increased risk from the HLA genes along with previously implicated genes in SSc susceptibility (CD247, CSK, PTPN22) together with the newly identified role of HLA-DRB4 point towards the important role of CD4 T cells and the relevance of T cell receptor (TCR) signaling in SSc pathogenesis.

Table 1

Figure 1

Figure 1 | Scleroderma risk factors and the T cell receptor -TCR- signaling pathway. Three genes -CD247, CSK, and PTPN22- that have been previously implicated in scleroderma susceptibility are all involved in the initiation of the TCR signaling pathway. HLA-DRB4, which was identified in this study, is also involved in this pathway, suggesting an important role of TCR signaling in scleroderma pathogenesis.

Disclosure: P. Gourh, None; S. Safran, None; S. Boyden, None; A. Shah, Bristol Meyer Squibb, 5, Bristol-Myers Squibb, 5; M. Mayes, Boehringer Ingelheim, 5, 8, 9, Corbus, 9, Corbus Pharma, 9, Eicos, 9, Eicos Sciences, 9, Galapagos, 5, 9, GlaxoSmithKline, 9, Mitsubishi Tanabe Pharma, 5, Mitsubishi-Tanabe, 5, Reata Pharma, 9, Reata Pharmaceuticals, 9, Sanofi, 9; A. Doumatey, None; A. Bentley, None; D. Shriner, None; R. Domsic, Boehringer Ingelheim, 5, Boehringer-Ingelheim, 5, Eicos, 5, EICOS Sciences Inc, 5; T. Medsger Jr, None; P. Ramos, None; R. Silver, None; V. Steen, Boehringer Ingelheim, 5, Corbus, 5, 9, CSL, 5, 9, CSL Behring, 2, 5, DSMB, 5, 9, Galapagos, 5, 9; J. Varga, None; V. Hsu, None; L. Saketkoo, None; E. Schiopu, None; D. Khanna, Acceleron, 5, 8, Acceleron Pharma, 5, Actelion, 5, 8, Actelion Pharmaceuticals, 5, Astra Zeneca, 5, Bayer, 2, 5, 8, Behring, 5, Blade, 5, Blade Therapeutics, 5, 8, Blade therapeutics, 5, BMS, 2, 5, 8, Boehringer Ingelham, 5, Boehringer Ingelheim, 5, 8, Boehringer-Ingelheim, 5, Bristol Myers Squibb, 2, 5, Bristol-Myers Squibb, 2, 5, Celegene, 5, Celgene, 5, 8, ChemomAB, 5, ChemomAb, 5, CiviBioPharma, Inc., 3, Corbus, 5, Corobus, 5, Corpus, 5, CSL Behring, 5, 8, Curizon, 5, Curzion, 5, Cytori, 5, 8, Eicos, 4, Eicos Sciences, 4, Eicos Sciences, Inc, 4, Eicos Sciences, Inc/ CiviBioPharma, Inc, 1, 4, Eicos Sciences, Inc/ CiviBioPharma, Inc., 1, Eicos, Inc, 4, Eicos, Inc., 5, 8, Eicos, INC., 4, Galapagos, 5, Genentech, 5, Genentech/Roche, 5, GlaxoSmithKline, 5, GSK, 5, Horizon, 2, 5, Mitsubishi Tanabe Pharma, 5, Mitsubishi Tanabe Pharma Dev America, 5, Mitsubishi Tanabe Pharma Development America, 5, Mitsubishi Tanabi, 5, NIH K24 and R01, 2, NIH / NIAMS K24 AR-063120, 2, NIH/NIAMS R01& K24, 2, Pfizer, 2, 5, Sanofi, 5, Sanofi Aventis, 5, Sanofi-Aventis, 5, 8, Sanofi-Aventis/Genzyme, 5, UCB, 5, UCB Pharma, 5; J. Gordon, Corbus, 2, Corbus Pharmaceuticals, 2, Cumberland, 2, Cumberland Pharmaceuticals, 2, Elcos, 2; B. Kron, None; L. Criswell, None; H. Gladue, None; C. Derk, None; E. Bernstein, None; S. Bridges, None; V. Shanmugam, AbbVie, 2; K. Kolstad, None; L. Chung, BMS, 6, 9, Boehrenger-Ingelheim, 5, Boehringer Ingelheim, 5, Boehringer-Ingelheim, 5, Bristol-Myers Squib, 5, Eicos, 5, 6, 9, Eicos Steering Committee, 5, Mitsubishi Tanabe, 5, Reata, 5, 6, Reata DSMB, 5, Reatta, 5; S. Kafaja, None; R. Jan, None; M. Trojanowski, None; A. Goldberg, None; B. Korman, None; P. Steinbach, None; S. Chandrasekharappa, None; J. Mullikin, None; A. Adeyemo, None; C. Rotimi, None; F. Wigley, None; D. Kastner, None; F. Boin, None; E. Remmers, None; T. Alexander, None.

To cite this abstract in AMA style:

Gourh P, Safran S, Boyden S, Shah A, Mayes M, Doumatey A, Bentley A, Shriner D, Domsic R, Medsger Jr T, Ramos P, Silver R, Steen V, Varga J, Hsu V, Saketkoo L, Schiopu E, Khanna D, Gordon J, Kron B, 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, Steinbach P, Chandrasekharappa S, Mullikin J, Adeyemo A, Rotimi C, Wigley F, Kastner D, Boin F, Remmers E, Alexander T. Ancestry-Specific Classical HLA Alleles Define Phenotypic Subsets in the African American Scleroderma Population [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/ancestry-specific-classical-hla-alleles-define-phenotypic-subsets-in-the-african-american-scleroderma-population/. Accessed .

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