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 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

doi:10.1002/art.40541

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1654-1660
Number of pages	7
Journal	Arthritis and Rheumatology
Volume	70
Issue number	10
DOIs	https://doi.org/10.1002/art.40541
State	Published - Oct 2018

ASJC Scopus subject areas

Immunology and Allergy
Rheumatology
Immunology

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Gourh, P., Remmers, E. F., Boyden, S. E., Alexander, T., Morgan, N. D., Shah, A. A., Mayes, M. D., Doumatey, A., Bentley, A. R., Shriner, D., Domsic, R. T., Medsger, T. A., Steen, V. D., Ramos, P. S., Silver, R. M., Korman, B., Varga, J., Schiopu, E., Khanna, D., ... Wigley, F. M. (2018). Brief Report: Whole-Exome Sequencing to Identify Rare Variants and Gene Networks That Increase Susceptibility to Scleroderma in African Americans. Arthritis and Rheumatology, 70(10), 1654-1660. https://doi.org/10.1002/art.40541

Gourh, P, Remmers, EF, Boyden, SE, Alexander, T, Morgan, ND, Shah, AA, Mayes, MD, Doumatey, A, Bentley, AR, Shriner, D, Domsic, RT, Medsger, TA, Steen, VD, Ramos, PS, Silver, RM, Korman, B, Varga, J, Schiopu, E, Khanna, D, Hsu, V, Gordon, JK, Saketkoo, LA, Gladue, H, Kron, B, Criswell, LA, Derk, CT, Bridges, SL, Shanmugam, VK, Kolstad, KD, Chung, L, Jan, R, Bernstein, EJ, Goldberg, A, Trojanowski, M, Kafaja, S, Maksimowicz-McKinnon, KM, Mullikin, JC, Adeyemo, A, Rotimi, C, Boin, F, Kastner, DL & Wigley, FM 2018, 'Brief Report: Whole-Exome Sequencing to Identify Rare Variants and Gene Networks That Increase Susceptibility to Scleroderma in African Americans', Arthritis and Rheumatology, vol. 70, no. 10, pp. 1654-1660. https://doi.org/10.1002/art.40541

@article{3204585926fd43cab8174fe3781acd0e,

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

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.",

author = "Pravitt Gourh and Remmers, {Elaine F.} and Boyden, {Steven E.} and Theresa Alexander and Morgan, {Nadia D.} and Shah, {Ami A.} and Mayes, {Maureen D.} and Ayo Doumatey and Bentley, {Amy R.} and Daniel Shriner and Domsic, {Robyn T.} and Medsger, {Thomas A.} and Steen, {Virginia D.} and Ramos, {Paula S.} and Silver, {Richard M.} and Benjamin Korman and John Varga and Elena Schiopu and Dinesh Khanna and Vivien Hsu and Gordon, {Jessica K.} and Saketkoo, {Lesley Ann} and Heather Gladue and Brynn Kron and Criswell, {Lindsey A.} and Derk, {Chris T.} and Bridges, {S. Louis} and Shanmugam, {Victoria K.} and Kolstad, {Kathleen D.} and Lorinda Chung and Reem Jan and Bernstein, {Elana J.} and Avram Goldberg and Marcin Trojanowski and Suzanne Kafaja and Maksimowicz-McKinnon, {Kathleen M.} and Mullikin, {James C.} and Adebowale Adeyemo and Charles Rotimi and Francesco Boin and Kastner, {Daniel L.} and Wigley, {Fredrick M.}",

note = "Funding Information: Dr. Gourh is recipient of a Scientist Development award from the Rheumatology Research Foundation. Ms Morgan{\textquoteright}s work was supported by the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases [NIAMS] grant T32-AR-048522) and the Rheumatology Research Foundation (Scientist Development award). Dr. Shah{\textquoteright}s work was supported by the NIH (NIAMS grant K23-AR-061439). Dr. Mayes{\textquoteright} work was supported by NIAMS grant P50-AR-054144 from the Centers of Research Translation, NIH grants N01-AR-02251 and R01-AR-055258, and the Department of Defense Congressionally Directed Medical Research Program (grants W81XWH-07–1–011 and WX81XWH-13–1-0452). Dr. Ramos{\textquoteright} work was supported by the NIH (grants K01-AR-067280, R03-AR-065801, and P60-AR-062755) and the South Carolina Clinical and Translational Research Institute (Medical University of South Carolina) through the NIH (grants UL1-RR-029882 and UL1-TR-000062). Dr. Silver{\textquoteright}s work was supported by the NIH (grant P60-AR-062755) and the South Carolina Clinical and Translational Research Institute (Medical University of South Carolina) through the NIH (grants UL1-RR-029882 and UL1-TR-000062). Dr. Khanna{\textquoteright}s work was supported by NIAMS grant K24-AR-063120. Dr. Shanmugam{\textquoteright}s work was supported by the NIH (grant R01-NR-013888 from the National Institute of Nursing Research), the Defense Advanced Research Projects Agency, and the Scleroderma Research Foundation. Dr. Boin{\textquoteright}s work was supported by the Nina Ireland Program for Lung Health. Publisher Copyright: {\textcopyright} 2018, American College of Rheumatology",

year = "2018",

month = oct,

doi = "10.1002/art.40541",

language = "English (US)",

volume = "70",

pages = "1654--1660",

journal = "Arthritis and Rheumatology",

issn = "2326-5191",

publisher = "John Wiley and Sons Ltd",

number = "10",

}

TY - JOUR

T1 - Brief Report

T2 - Whole-Exome Sequencing to Identify Rare Variants and Gene Networks That Increase Susceptibility to Scleroderma in African Americans

AU - Gourh, Pravitt

AU - Remmers, Elaine F.

AU - Boyden, Steven E.

AU - Alexander, Theresa

AU - Morgan, Nadia D.

AU - Shah, Ami A.

AU - Mayes, Maureen D.

AU - Doumatey, Ayo

AU - Bentley, Amy R.

AU - Shriner, Daniel

AU - Domsic, Robyn T.

AU - Medsger, Thomas A.

AU - Steen, Virginia D.

AU - Ramos, Paula S.

AU - Silver, Richard M.

AU - Korman, Benjamin

AU - Varga, John

AU - Schiopu, Elena

AU - Khanna, Dinesh

AU - Hsu, Vivien

AU - Gordon, Jessica K.

AU - Saketkoo, Lesley Ann

AU - Gladue, Heather

AU - Kron, Brynn

AU - Criswell, Lindsey A.

AU - Derk, Chris T.

AU - Bridges, S. Louis

AU - Shanmugam, Victoria K.

AU - Kolstad, Kathleen D.

AU - Chung, Lorinda

AU - Jan, Reem

AU - Bernstein, Elana J.

AU - Goldberg, Avram

AU - Trojanowski, Marcin

AU - Kafaja, Suzanne

AU - Maksimowicz-McKinnon, Kathleen M.

AU - Mullikin, James C.

AU - Adeyemo, Adebowale

AU - Rotimi, Charles

AU - Boin, Francesco

AU - Kastner, Daniel L.

AU - Wigley, Fredrick M.

N1 - Funding Information: Dr. Gourh is recipient of a Scientist Development award from the Rheumatology Research Foundation. Ms Morgan’s work was supported by the NIH (National Institute of Arthritis and Musculoskeletal and Skin Diseases [NIAMS] grant T32-AR-048522) and the Rheumatology Research Foundation (Scientist Development award). Dr. Shah’s work was supported by the NIH (NIAMS grant K23-AR-061439). Dr. Mayes’ work was supported by NIAMS grant P50-AR-054144 from the Centers of Research Translation, NIH grants N01-AR-02251 and R01-AR-055258, and the Department of Defense Congressionally Directed Medical Research Program (grants W81XWH-07–1–011 and WX81XWH-13–1-0452). Dr. Ramos’ work was supported by the NIH (grants K01-AR-067280, R03-AR-065801, and P60-AR-062755) and the South Carolina Clinical and Translational Research Institute (Medical University of South Carolina) through the NIH (grants UL1-RR-029882 and UL1-TR-000062). Dr. Silver’s work was supported by the NIH (grant P60-AR-062755) and the South Carolina Clinical and Translational Research Institute (Medical University of South Carolina) through the NIH (grants UL1-RR-029882 and UL1-TR-000062). Dr. Khanna’s work was supported by NIAMS grant K24-AR-063120. Dr. Shanmugam’s work was supported by the NIH (grant R01-NR-013888 from the National Institute of Nursing Research), the Defense Advanced Research Projects Agency, and the Scleroderma Research Foundation. Dr. Boin’s work was supported by the Nina Ireland Program for Lung Health. Publisher Copyright: © 2018, American College of Rheumatology

PY - 2018/10

Y1 - 2018/10

N2 - 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.

AB - 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.

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

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