ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 2646

Rare Variants in the IL1RAP Gene Implicate the IL-1 Signaling Pathway in the Pathogenesis of Systemic Sclerosis in African and European Ancestries

Yosuke Kunishita1, Urvashi Kaundal2, Martin Kerick3, Ryan Routsong4, Justin Lack4, Ami Shah5, Maureen Mayes6, Daniel Shriner7, Ayo P. Doumatey7, Amy Bentley7, Robyn Domsic8, Thomas Medsger, Jr9, Paula Ramos10, Richard Silver11, Virginia Steen12, John Varga13, Vivien Hsu14, Lesley Ann Saketkoo15, Dinesh Khanna13, Elena Schiopu16, Jessica Gordon17, Lindsey Criswell18, Heather Gladue19, Chris Derk20, Elana Bernstein21, S. Louis Bridges17, Victoria Shanmugam22, Lorinda Chung23, Suzanne Kafaja24, Reem Jan25, Marcin Trojanowski26, Avram Goldberg27, Benjamin Korman28, James W. Thomas29, Elaine Remmers30, Adebowale Adeyemo7, Charles Rotimi7, Fredrick Wigley31, Francesco Boin32, Javier Martin3, Daniel Kastner33 and Pravitt Gourh34, 1Scleroderma Genomics and Health Disparities Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, 2Scleroderma Genomics and Health Disparities Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Chevy Chase, MD, 3Instituto de Parasitología y Biomedicina ‘López-Neyra’, CSIC, PTS Granada, Spain, Granada, Spain, 4Integrated Data Sciences Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 5Division of Rheumatology, Johns Hopkins University, Ellicott City, MD, 6UTHealth Houston Division of Rheumatology, Houston, TX, 7Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 8Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 9Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, Verona, PA, 10Medical University of South Carolina, Charleston, SC, 11Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC, 12Georgetown University School of Medicine, Washington, DC, 13University of Michigan, Ann Arbor, MI, 14Department of Medicine, Rheumatology Division, Rutgers-RWJ Medical School, South Plainfield, NJ, 15New Orleans Scleroderma and Sarcoidosis Patient Care and Research Center, Louisiana State University and Tulane University Medical Schools, New Orleans, LA, 16Division of Rheumatology, Medical College of Georgia at Augusta University, Martinez, GA, 17Division of Rheumatology, Weill Cornell Medical College, New York, NY, 18Genomics of Autoimmune Rheumatic Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, Bethesda, MD, 19Arthritis & Osteoporosis Consultants of the Carolinas, Charlotte, NC, 20Division of Rheumatology, University of Pennsylvania, Philadelphia, PA, 21Division of Rheumatology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, 22Office of Autoimmune Disease Research, Office of Research on Women's Health, National Institutes of Health, Great Falls, VA, 23Stanford University, Woodside, CA, 24Division of Rheumatology, University of California, Los Angeles, Los Angeles, CA, 25Section of Rheumatology, Department of Medicine, University of Chicago, Chicago, IL, 26Department of Rheumatology, Boston University School of Medicine, Boston, MA, 27NYU Langone Health - NYU Hospital for Joint Diseases, Lake Success, NY, 28University of Rochester, Rochester, NY, 29NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 30Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 31Johns Hopkins University, Division of Rheumatology, Baltimore, MD, Baltimore, MD, 32Cedars-Sinai Medical Center, Los Angeles, CA, 33National Human Genome Research Institute, Bethesda, MD, 34National Institutes of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, Bethesda, MD

Meeting: ACR Convergence 2024

Keywords: , ,

Session Information

Date: Monday, November 18, 2024

Title: Abstracts: Systemic Sclerosis & Related Disorders – Clinical II

Session Type: Abstract Session

Session Time: 3:00PM-4:30PM

Background/Purpose: Systemic sclerosis (SSc) is an autoimmune disease characterized by systemic inflammation and fibrosis. Interleukin-1 receptor accessory protein (IL1RAP) is a co-receptor for the Interleukin-1 (IL-1) family of cytokines. It plays an essential role in the signaling of IL-1, IL-33, and IL-36, which are known to mediate inflammation and fibrosis. Recently, preclinical data indicated that the anti-IL1RAP antibody CAN10, inhibited IL-1, IL-33, and IL-36 signaling and dermal and pulmonary fibrosis. In this study, we examined the potential association of rare variants in the IL-1 family of ligands and receptors with SSc.

Methods: Exome sequences of 379 African Americans (AA) subjects with SSc and 411 AA control subjects were examined for rare variants in six ligands and five co-receptors of the IL-1 pathway (Figure 1). Replication analysis was performed in 590 AA subjects with SSc and 360 AA control subjects. The SSc subjects were enrolled at the 24 academic centers participating in the Genome Research in African American Scleroderma Patients (GRASP) consortium. Another cohort of 951 European ancestry SSc subjects and 998 EA control subjects from Spain were examined for replication. Gene-based (SKAT-O, Burden, and KBAC) testing was performed on missense, loss of start, stop gain, frameshift, or splice functional loss variants with a minor allele frequency < 0.001 in Genome Aggregation Database (gnomAD), and a Combined Annotation Dependent Depletion (CADD) score > 10 suggesting deleteriousness. Bonferroni’s multiple testing significance threshold was set at 4.5×10-3 for the discovery and 0.05 for the replication cohort.

Results: All three gene-based tests identified the IL1RAP gene to be enriched for rare variants in AA subjects with SSc in the discovery and combined cohorts (Table 1). Additionally, we confirmed these findings in another large, independent, SSc cohort of European ancestry (SKAT-O p–value 3.7×10-4). Notably, diffuse cutaneous skin involvement (dcSSc) was more common in the AA subjects with SSc carrying the IL1RAP rare variants (15 of 17; 88.2%), compared to the overall AA SSc cohort (58.4%). On examining the IL1RAP association in dcSSc subset, the association was even stronger than overall SSc, whereas no association was observed in SSc patients with limited cutaneous skin involvement (Table 1). All the IL1RAP rare variants identified in SSc patients were bioinformatically predicted to be pathogenic.

Conclusion: This study, for the first time, identifies association of IL1RAP in both African and European ancestral subjects with SSc. In light of the recent preclinical data with the anti-IL1RAP antibody CAN10, prioritizing diffuse cutaneous SSc patients in clinical trials and stratifying patients based on IL1RAP variants, might pave the path for precision medicine in SSc.

Supporting image 1

Figure 1. Schematic representation of IL_1 family signaling pathway.
IRAK; IL_1 receptor-associated kinase, MAPK; mitogen-activated protein kinase, NF-κB; nuclear factor kappa B, TRAF6; tumor necrosis factor receptor-associated factor 6.

Supporting image 2

Table 1. Gene-based testing of IL1RAP-related gene variants in AA with SSc.
Bold indicates statistical significance. AA; African Americans, Chr; chromosome, Ctrl; controls, KBAC; kernel-based adaptive cluster method, SKAT-O; optimal sequencing kernel association test, SSc; systemic sclerosis.

Disclosures: Y. Kunishita: None; U. Kaundal: None; M. Kerick: None; R. Routsong: None; J. Lack: 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; D. Shriner: None; 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; J. Martin: None; D. Kastner: None; P. Gourh: None.

To cite this abstract in AMA style:

Kunishita Y, Kaundal U, Kerick M, Routsong R, Lack J, Shah A, Mayes M, Shriner D, 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, Martin J, Kastner D, Gourh P. Rare Variants in the IL1RAP Gene Implicate the IL-1 Signaling Pathway in the Pathogenesis of Systemic Sclerosis in African and European Ancestries [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/rare-variants-in-the-il1rap-gene-implicate-the-il-1-signaling-pathway-in-the-pathogenesis-of-systemic-sclerosis-in-african-and-european-ancestries/. Accessed .

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