Pravitt Gourh1, Elaine F Remmers2, Steven E Boyden2, Theresa Alexander3, Nadia D Morgan4, Ami A Shah4, Maureen D Mayes5, Ayo Doumatey2, Amy R Bentley2, Daniel Shriner2, Robyn T Domsic6, Thomas A Medsger6, Virginia D Steen7, Paula S Ramos8, Richard M Silver8, Benjamin Korman9, John Varga9, Elena Schiopu10, Dinesh Khanna10, Vivien Hsu11, Jessica K Gordon12, Lesley Ann Saketkoo13, Heather Gladue14, Brynn Kron15, Lindsey A Criswell15, Chris T Derk16, S Louis Bridges17, Victoria K Shanmugam18, Kathleen D Kolstad19, Lorinda Chung20, Reem Jan21, Elana J Bernstein22, Avram Goldberg23, Marcin Trojanowski24, Suzanne Kafaja25, Kathleen M Maksimowicz-McKinnon26, James C Mullikin27, Adebowale Adeyemo2, Charles Rotimi2, Francesco Boin15, Daniel L Kastner2, Fredrick M Wigley4. 1. NIAMS and National Human Genome Research Institute, NIH, Bethesda, Maryland. 2. National Human Genome Research Institute, NIH, Bethesda, Maryland. 3. NIAMS, NIH, Bethesda, Maryland. 4. Johns Hopkins University School of Medicine, Baltimore, Maryland. 5. University of Texas McGovern Medical School, Houston. 6. University of Pittsburgh, Pittsburgh, Pennsylvania. 7. Georgetown University School of Medicine, Washington, DC. 8. Medical University of South Carolina, Charleston. 9. Northwestern University, Feinberg School of Medicine, Chicago, Illinois. 10. University of Michigan, Ann Arbor. 11. Robert Wood Johnson University, New Brunswick, New Jersey. 12. Hospital for Special Surgery, New York, New York. 13. Tulane University School of Medicine, New Orleans, Louisiana. 14. Arthritis and Osteoporosis Consultants of the Carolinas, Charlotte, North Carolina. 15. University of California, San Francisco. 16. University of Pennsylvania, Philadelphia. 17. University of Alabama at Birmingham. 18. The George Washington University, Washington, DC. 19. Stanford University School of Medicine, Stanford, California. 20. Stanford University School of Medicine, Stanford, California, and Palo Alto VA Health Care System, Palo Alto, California. 21. University of Chicago, Pritzker School of Medicine, Chicago, Illinois. 22. New York Presbyterian Hospital, Columbia University, New York, New York. 23. New York University Langone Medical Center, New York, New York. 24. Boston University School of Medicine, Boston, Massachusetts. 25. David Geffen School of Medicine, University of California, Los Angeles. 26. Henry Ford Health System, Detroit, Michigan. 27. National Human Genome Research Institute, NIH Intramural Sequencing Center, Rockville, Maryland.
Abstract
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.
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.
Authors: Li Gao; Mary J Emond; Tin Louie; Chris Cheadle; Alan E Berger; Nicholas Rafaels; Candelaria Vergara; Yoonhee Kim; Margaret A Taub; Ingo Ruczinski; Stephen C Mathai; Stephen S Rich; Deborah A Nickerson; Laura K Hummers; Michael J Bamshad; Paul M Hassoun; Rasika A Mathias; Kathleen C Barnes Journal: Arthritis Rheumatol Date: 2016-01 Impact factor: 10.995
Authors: Timothy R D J Radstake; Olga Gorlova; Blanca Rueda; Jose-Ezequiel Martin; Behrooz Z Alizadeh; Rogelio Palomino-Morales; Marieke J Coenen; Madelon C Vonk; Alexandre E Voskuyl; Annemie J Schuerwegh; Jasper C Broen; Piet L C M van Riel; Ruben van 't Slot; Annet Italiaander; Roel A Ophoff; Gabriela Riemekasten; Nico Hunzelmann; Carmen P Simeon; Norberto Ortego-Centeno; Miguel A González-Gay; María F González-Escribano; Paolo Airo; Jaap van Laar; Ariane Herrick; Jane Worthington; Roger Hesselstrand; Vanessa Smith; Filip de Keyser; Fredric Houssiau; Meng May Chee; Rajan Madhok; Paul Shiels; Rene Westhovens; Alexander Kreuter; Hans Kiener; Elfride de Baere; Torsten Witte; Leonid Padykov; Lars Klareskog; Lorenzo Beretta; Rafaella Scorza; Benedicte A Lie; Anna-Maria Hoffmann-Vold; Patricia Carreira; John Varga; Monique Hinchcliff; Peter K Gregersen; Annette T Lee; Jun Ying; Younghun Han; Shih-Feng Weng; Christopher I Amos; Fredrick M Wigley; Laura Hummers; J Lee Nelson; Sandeep K Agarwal; Shervin Assassi; Pravitt Gourh; Filemon K Tan; Bobby P C Koeleman; Frank C Arnett; Javier Martin; Maureen D Mayes Journal: Nat Genet Date: 2010-04-11 Impact factor: 38.330
Authors: Frank C Arnett; Pravitt Gourh; Sanjay Shete; Chul W Ahn; Robert E Honey; Sandeep K Agarwal; Filemon K Tan; Terry McNearney; Michael Fischbach; Marvin J Fritzler; Maureen D Mayes; John D Reveille Journal: Ann Rheum Dis Date: 2009-07-12 Impact factor: 19.103
Authors: Angel C Y Mak; Paul L F Tang; Clare Cleveland; Melanie H Smith; M Kari Connolly; Tamiko R Katsumoto; Paul J Wolters; Pui-Yan Kwok; Lindsey A Criswell Journal: Arthritis Rheumatol Date: 2016-09 Impact factor: 10.995
Authors: Maureen D Mayes; James V Lacey; Jennifer Beebe-Dimmer; Brenda W Gillespie; Brenda Cooper; Timothy J Laing; David Schottenfeld Journal: Arthritis Rheum Date: 2003-08
Authors: Nadia D Morgan; Ami A Shah; Maureen D Mayes; Robyn T Domsic; Thomas A Medsger; Virginia D Steen; John Varga; Mary Carns; Paula S Ramos; Richard M Silver; Elena Schiopu; Dinesh Khanna; Vivien Hsu; Jessica K Gordon; Heather Gladue; Lesley A Saketkoo; Lindsey A Criswell; Chris T Derk; Marcin A Trojanowski; Victoria K Shanmugam; Lorinda Chung; Antonia Valenzuela; Reem Jan; Avram Goldberg; Elaine F Remmers; Daniel L Kastner; Fredrick M Wigley; Pravitt Gourh; Francesco Boin Journal: Medicine (Baltimore) Date: 2017-12 Impact factor: 1.817
Authors: Pravitt Gourh; Sarah A Safran; Theresa Alexander; Steven E Boyden; Nadia D Morgan; Ami A Shah; Maureen D Mayes; Ayo Doumatey; Amy R Bentley; Daniel Shriner; Robyn T Domsic; Thomas A Medsger; Paula S Ramos; Richard M Silver; Virginia D Steen; John Varga; Vivien Hsu; Lesley Ann Saketkoo; Elena Schiopu; Dinesh Khanna; Jessica K Gordon; Brynn Kron; Lindsey A Criswell; Heather Gladue; Chris T Derk; Elana J Bernstein; S Louis Bridges; Victoria K Shanmugam; Kathleen D Kolstad; Lorinda Chung; Suzanne Kafaja; Reem Jan; Marcin Trojanowski; Avram Goldberg; Benjamin D Korman; Peter J Steinbach; Settara C Chandrasekharappa; James C Mullikin; Adebowale Adeyemo; Charles Rotimi; Fredrick M Wigley; Daniel L Kastner; Francesco Boin; Elaine F Remmers Journal: Proc Natl Acad Sci U S A Date: 2019-12-23 Impact factor: 11.205