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Abstract Number: 1920

Admixture Mapping and Gene-Based Analysis Identifies Rare Variants in Genes in the IL-13 and TGFβ Signaling Pathways in African Americans with Systemic Sclerosis

Jordan Hicks1, Daniel Shriner2, Ami Shah3, Maureen Mayes4, Ayo P. Doumatey2, Amy R. Bentley1, Robyn Domsic5, Thomas Medsger, Jr6, Paula Ramos7, Richard Silver8, Virginia Steen9, John Varga10, Vivien Hsu11, Lesley Ann Saketkoo12, Dinesh Khanna10, Elena Schiopu13, Jessica Gordon14, Lindsey Criswell15, Heather Gladue16, Chris Derk17, Elana Bernstein18, S. Louis Bridges14, Victoria Shanmugam19, Lorinda Chung20, Suzanne Kafaja21, Reem Jan22, Marcin Trojanowski23, Avram Goldberg24, Benjamin Korman25, James W. Thomas26, Elaine Remmers27, Adebowale Adeyemo2, Charles Rotimi2, Fredrick Wigley28, Francesco Boin29, Daniel Kastner30 and Pravitt Gourh31, 1National institute of Health, Bethesda, MD, 2Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 3Division of Rheumatology, Johns Hopkins University, Ellicott City, MD, 4UTHealth Houston Division of Rheumatology, Houston, TX, 5Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 6Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Verona, PA, 7Medical University of South Carolina, Charleston, SC, 8Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC, 9Georgetown University School of Medicine, Washington, DC, 10University of Michigan, Ann Arbor, MI, 11Department of Medicine, Rheumatology Division, Rutgers-RWJ Medical School, South Plainfield, NJ, 12New Orleans Scleroderma and Sarcoidosis Patient Care and Research Center, Louisiana State University and Tulane University Medical Schools, New Orleans, LA, 13Division of Rheumatology, Medical College of Georgia at Augusta University, Martinez, GA, 14Division of Rheumatology, Weill Cornell Medical College, New York, NY, 15Genomics of Autoimmune Rheumatic Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, Bethesda, MD, 16Arthritis & Osteoporosis Consultants of the Carolinas, Charlotte, NC, 17Division of Rheumatology, University of Pennsylvania, Philadelphia, PA, 18Division of Rheumatology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, 19NIH Office of Autoimmune Disease Research in the Office of Research on Women's Health, National Institutes of Health, Bethesda, MD, Bethesda, MD, 20Stanford University, Woodside, CA, 21Division of Rheumatology, University of California, Los Angeles, Los Angeles, CA, 22Section of Rheumatology, Department of Medicine, University of Chicago, Chicago, IL, 23Department of Rheumatology, Boston University School of Medicine, Boston, MA, 24NYU Langone Health - NYU Hospital for Joint Diseases, Lake Success, NY, 25University of Rochester, Rochester, NY, 26NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 27Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 28Johns Hopkins University, Division of Rheumatology, Baltimore, MD, Baltimore, MD, 29Cedars-Sinai Medical Center, Los Angeles, CA, 30National Human Genome Research Institute, Bethesda, MD, 31National Institutes of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, Bethesda, MD

Meeting: ACR Convergence 2024

Keywords: Disparities, Inflammation, race/ethnicity, Scleroderma, Transforming Growth Factor (TGF)

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Session Information

Date: Monday, November 18, 2024

Title: Healthcare Disparities in Rheumatology Poster III

Session Type: Poster Session C

Session Time: 10:30AM-12:30PM

Background/Purpose: There are significant racial disparities in systemic sclerosis (SSc), with an increased disease burden and worse outcomes among African American (AA) individuals. Reasons for this increased prevalence, severity, and mortality of SSc in AA patients are largely unknown. AA individuals primarily derive their ancestry from West Africa. AA SSc patients, like West Africans, have a higher prevalence of SSc with an earlier age of onset, diffuse skin involvement and pulmonary complications. The objective of this study is to identify genetic variants that explain the increased frequency and severity of SSc in AAs.

Methods: SSc patients from the Genome Research in African American Scleroderma Patients (GRASP) cohort met either the 1980 ACR or 2013 EULAR criteria for SSc, or had at least 3 of 5 features of CREST syndrome. Admixture mapping was performed on 946 patients and 934 controls using 998,750 genotyped markers. Local ancestry was inferred using RFMix (v.1.5.4) and a reference panel of five ancestries derived from the 1000 Genomes Project. The genome-wide significance level was set at 2.3×10-4 and suggestive level was P< 0.05. Genes contained within the admixed regions with at least nominal significance were identified. Gene-based (SKAT-O, Burden, and KBAC) testing was performed on missense or loss of function (LoF) variants with a CADD score >10 suggesting deleteriousness and a minor allele frequency < 0.001 in gnomAD and TOPMed, from the exome sequences of 379 patients and 411 controls. Genes with a P< 0.05 in at least two of three gene-based tests were identified for further analysis.

Results: Admixture mapping of SSc identified one genome-wide significant and thirteen suggestive regions (Figure 1A). Stratified analysis on SSc autoantibody subsets of SSc identified one genome-wide significant and several suggestive regions (Figure 1B-E). Gene-based testing within these admixed regions identified enrichment of rare variants in twenty-seven genes in overall SSc and one, six, and three genes in the AFA, ATA, and ACA subsets, respectively (Table 1). Four genes (IL13, SCL29A2, OR10C1, and GDF9) were significant in both overall SSc and an autoantibody subset.

Conclusion: Our unique approach of utilizing admixture mapping to map trait gene regions and analyze them for enrichment of rare variants has yielded several potential candidate genes. Perhaps most easily understood are IL13, GDF9, and XPO4, which regulate TGFβ signaling via SMAD3. IL13 encodes an immunoregulatory cytokine that serves to activate an immune response through inflammation and activation of the pro-fibrotic TGFβ pathway. GDF9 encodes a secreted ligand for TGFβ receptors, initiating recruitment and activation of SMAD3. XPO4 is associated with anti-fibrotic activity via mediation of the nuclear export of SMAD3 and regulation of TGFβ signaling. Dysregulated IL13 and TGFβ signaling have been previously reported in SSc. Our unique approach and these findings help explain some of the genetic risk factors in AA subjects with SSc that contribute to the disparate outcomes in this population.

Supporting image 1

Figure 1: Admixture Analysis Plots A. Overall SSc; B. ACA+ Antibody Subset; C. ATA+ Antibody Subset; D. AFA+ Antibody Subset; E. ARA+ Antibody Subset

Supporting image 2

Supporting image 3


Disclosures: J. Hicks: None; D. Shriner: None; A. Shah: Arena Pharmaceuticals, 5, Kadmon, 5, Medpace LLC, 5; M. Mayes: AstraZeneca, 5, Atyr, 5, Boehringer-Ingelheim, 1, 5, Horizon Therapeutics, 5, Merck/MSD, 5; A. Doumatey: None; A. Bentley: None; R. Domsic: AstraZeneca, 2; T. Medsger, Jr: None; P. Ramos: None; R. Silver: None; V. Steen: None; J. Varga: None; V. Hsu: None; L. Saketkoo: None; D. Khanna: AbbVie/Abbott, 2, Amgen, 2, AstraZeneca, 2, Boehringer-Ingelheim, 2, Bristol-Myers Squibb(BMS), 2, Cabaletta, 2, Certa Therapeutics, 2, GlaxoSmithKlein(GSK), 2, Janssen, 2, MDI Therapeutics, 8, Merck/MSD, 2, Novartis, 2, Zura Bio, 2; E. Schiopu: None; J. Gordon: None; L. Criswell: None; H. Gladue: None; C. Derk: None; E. Bernstein: AstraZeneca, 5, aTyr, 5, Boehringer-Ingelheim, 1, 2, 5, Bristol-Myers Squibb(BMS), 5, Cabaletta, 1, 5, Kadmon, 5; S. Bridges: None; V. Shanmugam: None; L. Chung: Boehringer-Ingelheim, 5, Eicos, 1, 2, Eli Lilly, 2, Genentech, 2, IgM Biosciences, 2, Janssen, 1, Kyverna, 2, Mitsubishi Tanabe, 1, 2; S. Kafaja: None; R. Jan: None; M. Trojanowski: None; A. Goldberg: None; B. Korman: None; J. Thomas: None; E. Remmers: None; A. Adeyemo: None; C. Rotimi: None; F. Wigley: None; F. Boin: Adicet Bio, 2; D. Kastner: None; P. Gourh: None.

To cite this abstract in AMA style:

Hicks J, Shriner D, Shah A, Mayes M, Doumatey A, Bentley A, Domsic R, Medsger, Jr T, Ramos P, Silver R, Steen V, Varga J, Hsu V, Saketkoo L, Khanna D, Schiopu E, Gordon J, Criswell L, Gladue H, Derk C, Bernstein E, Bridges S, Shanmugam V, Chung L, Kafaja S, Jan R, Trojanowski M, Goldberg A, Korman B, Thomas J, Remmers E, Adeyemo A, Rotimi C, Wigley F, Boin F, Kastner D, Gourh P. Admixture Mapping and Gene-Based Analysis Identifies Rare Variants in Genes in the IL-13 and TGFβ Signaling Pathways in African Americans with Systemic Sclerosis [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/admixture-mapping-and-gene-based-analysis-identifies-rare-variants-in-genes-in-the-il-13-and-tgf%ce%b2-signaling-pathways-in-african-americans-with-systemic-sclerosis/. Accessed .
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