Brief Report: Whole‐Exome Sequencing to Identify Rare Variants and Gene Networks That Increase Susceptibility to Scleroderma in African Americans
Year: 2018
Type: article
Study design: Observational Study
Abstract: Objective Whole‐exome sequencing ( WES ) studies in systemic sclerosis ( SS c) patients of European American ( EA ) ancestry have identified variants in the ATP 8B4 gene and enrichment of variants in genes in the extracellular matrix ( ECM )–related pathway that increase SS c susceptibility. This study was undertaken to evaluate the association of the ATP 8B4 gene and the ECM ‐related pathway with SS c in a cohort of African American ( AA ) patients. Methods SS c patients of AA ancestry were enrolled from 23 academic centers across the US under the Genome Research in African American Scleroderma Patients consortium. Unrelated AA individuals without serologic evidence of autoimmunity who were enrolled in the Howard University Family Study were used as unaffected controls. Functional variants in genes reported in the 2 WES studies in EA patients with SS c were selected for gene association testing using the optimized sequence kernel association test ( SKAT ‐O) and pathway analysis by Ingenuity Pathway Analysis in 379 patients and 411 controls. Results Principal components analysis demonstrated that the patients and controls had similar ancestral backgrounds, with roughly equal proportions of mean European admixture. Using SKAT ‐O, we examined the association of individual genes that were previously reported in EA patients and none remained significant, including ATP 8B4 ( P = 0.98). However, we confirmed the previously reported association of the ECM ‐related pathway with enrichment of variants within the COL 13A1 , COL 18A1 , COL 22A1 , COL 4A3 , COL 4A4 , COL 5A2 , PROK 1 , and SERPINE 1 genes (corrected P = 1.95 × 10 −4 ). Conclusion In the largest genetic study in AA patients with SS c to date, our findings corroborate the role of functional variants that aggregate in a fibrotic pathway and increase SS c susceptibility.
Source: Arthritis & Rheumatology
DOI: 10.1002/art.40541
Authors: Pravitt Gourh, Elaine F. Remmers, Steven E. Boyden, Theresa Alexander, Nadia D. Morgan, Ami A. Shah, Maureen D. Mayes, Ayo Doumatey, Amy R. Bentley, Daniel Shriner, Robyn T. Domsic, Thomas A. Medsger, Virginia D. Steen, Paula S. Ramos, Richard M. Silver, Benjamin Korman, John Varga, Elena Schiopu, Dinesh Khanna, Vivien Hsu, Jessica K. Gordon, Lesley Ann Saketkoo, Heather Gladue, Brynn Kron, Lindsey A. Criswell, Chris T. Derk, S. Louis Bridges, Victoria K. Shanmugam, Kathleen D. Kolstad, Lorinda Chung, Reem Jan, Elana J. Bernstein, Avram Goldberg, Marcin Trojanowski, Suzanne Kafaja, Kathleen M. Maksimowicz‐McKinnon, James C. Mullikin, Adebowale Adeyemo, Charles Rotimi, Francesco Boin, Daniel L. Kastner, Fredrick M. Wigley
Institutions: National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Human Genome Research Institute, Johns Hopkins University, University of Pittsburgh, Georgetown University, Medical University of South Carolina, Northwestern University, University of Michigan, Hospital for Special Surgery, Tulane University, University of California, San Francisco, University of Pennsylvania, University of Alabama at Birmingham, George Washington University, Stanford Medicine, Stanford University, VA Palo Alto Health Care System, University of Chicago, NewYork–Presbyterian Hospital, Columbia University, NYU Langone Health, Boston University, University of California, Los Angeles, Henry Ford Health
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Funders: U.S. Department of Defense, Scleroderma Research Foundation, Bristol-Myers Squibb, Pfizer, GlaxoSmithKline, Sanofi, Gilead Sciences, Rheumatology Research Foundation, Henry Ford Health System, CSL Behring, University of South Carolina, Horizon Pharmaceuticals, Astellas Pharma, National Institutes of Health, Defense Advanced Research Projects Agency, Genentech, University of California, Los Angeles, Advanced Research Projects Agency, National Institute of Nursing Research, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences, David Geffen School of Medicine, University of California, Los Angeles, Congressionally Directed Medical Research Programs
Awards: G1067819055, South Carolina Clinical & Translational Research Institute (SCTR), G1333125303, G1409569144, G1609963394, Center for Clinical and Translational Sciences (CCTS), G170348581, DNA methylation biomarkers of scleroderma-associated interstitial lung disease, G2838794211, G3231223337, G3500451638, G3661814986, G3760144424, G3875983964, Two-Stage Genome-Wide Association Study in Systemic Sclerosis, South Carolina Clinical & Translational Research Institute (SCTR), G4119534169, G5010008341, G5479061095, G580208524, Center for Research Translation in Scleroderma, G5850682332, SCLERODERMA FAMILY REGISTRY AND DNA REPOSITORY, G751774546, G767822077, MCRC for Rheumatic Diseases in African Americans, G867380426, G8852914737, G9000031606, G9000091857, G9000334076, RESOURCE-BASED CENTER FOR THE ADVANCEMENT OF PRECISION MEDICINE IN RHEUMATOLOGY, Multidisciplinary Rheumatology Training Program, Training Program in Adult and Pediatric Rheumatology, The role of natural selection in SLE risk among African-Americans
OpenAlex ID: W2802159764