Brief Report: Whole-Exome Sequencing to Identify Rare Variants and Gene Networks That Increase Susceptibility to Scleroderma in African Americans

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 HsuJessica 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

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Objective: Whole-exome sequencing (WES) studies in systemic sclerosis (SSc) patients of European American (EA) ancestry have identified variants in the ATP8B4 gene and enrichment of variants in genes in the extracellular matrix (ECM)–related pathway that increase SSc susceptibility. This study was undertaken to evaluate the association of the ATP8B4 gene and the ECM-related pathway with SSc in a cohort of African American (AA) patients. Methods: SSc 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 SSc 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 ATP8B4 (P = 0.98). However, we confirmed the previously reported association of the ECM-related pathway with enrichment of variants within the COL13A1, COL18A1, COL22A1, COL4A3, COL4A4, COL5A2, PROK1, and SERPINE1 genes (corrected P = 1.95 × 10−4). Conclusion: In the largest genetic study in AA patients with SSc to date, our findings corroborate the role of functional variants that aggregate in a fibrotic pathway and increase SSc susceptibility.

Original languageEnglish (US)
Pages (from-to)1654-1660
Number of pages7
JournalArthritis and Rheumatology
Issue number10
StatePublished - Oct 2018

ASJC Scopus subject areas

  • Immunology and Allergy
  • Rheumatology
  • Immunology


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