Overview

Principal Investigator

Pravitt Gourh, M.D.

Dr. Gourh is a board-certified rheumatologist with a long-standing interest in scleroderma and currently directs a translational research program focused on understanding the genetics of scleroderma, biomarker discovery, and disease classification.

Scleroderma Genomics and Health Disparities Unit is focused on enhancing our understanding of the genetic risk factors involved in scleroderma pathogenesis. Scleroderma (systemic sclerosis) is a chronic multisystem disease that is clinically characterized by progressive fibrosis of the skin and internal organs, vasculopathy, and autoimmunity. Scleroderma causes significant morbidity and mortality, and the only treatment options are organ based and primarily symptom management. Scleroderma is a health disparity in African Americans who have a higher prevalence of scleroderma than European Americans. African Americans with scleroderma have an earlier age of onset and are more likely to manifest diffuse skin involvement, interstitial lung disease (ILD), and pulmonary arterial hypertension (Table 1).

Table 1
Table 1. Click to enlarge. Clinical Manifestations of scleroderma patients in the GRASP cohort (Morgan, Gourh, et al, Medicine 2017).

Family studies have suggested a role for genetic etiological factors in this disease with an increased sibling recurrence risk (λs) for scleroderma in African Americans than European Americans. Candidate gene and genome-wide association studies (GWAS) conducted mostly in European American scleroderma patients have revealed autoimmune disease susceptibility loci but these loci are not unique to scleroderma. Our understanding of genetic susceptibility in African American scleroderma is very limited and restricted to Human leukocyte antigen (HLA), due to a lack of systematic and comprehensive studies in the African American scleroderma population. We hypothesize that African-ancestry derived variants may explain the increased frequency and severity of scleroderma in African Americans, and admixture mapping is an effective tool for identifying such ancestry-specific effects (Figure 1).

Admixture plots
Figure 1. Admixture plot of the 1000 Genomes populations along with the SSc patients and controls (Gourh et al, Arthritis and Rheumatology 2018)

Thus, we have established the “Genome Research in African American Scleroderma Patients” (GRASP) consortium comprising of 24 centers across the United States to enroll African American patients with scleroderma (Figure 2).

Location of GRASP centers map
Figure 2. Location of GRASP centers

We are taking a comprehensive approach to test both rare and common genetic variants in scleroderma and are utilizing cutting edge technologies to understand scleroderma with the following three approaches:

1. Discover common variants leading to scleroderma susceptibility

The aim is to identify previously unrecognized multi-ethnic scleroderma susceptibility loci, and perhaps to identify African ancestry-specific variants increasing scleroderma genetic risk that could have a major impact in this underserved population with a more severe disease burden. Scleroderma samples from the GRASP cohort and controls are being genotyped on the Illumina Multi-Ethnic Global Array (MEGA) which contains 1.7 million markers, and a custom Illumina OmniExpressExome array that contains 1 million markers. Data from these arrays will be extracted and undergo quality control including population stratification and relatedness analysis.

African American Scleroderma GWAS of MEGA array graphic
Figure 3. African American Scleroderma GWAS of MEGA array

Genome-wide association analysis will be conducted after performing SNP imputation and cross-platform validation of the top hits (Figure 3). Fine-mapping disease loci, admixture analysis, and utilizing publicly available expression quantitative trait loci (eQTL) datasets such as HaploReg and GTEx for in silico eQTL analysis will be performed. We will use pathway analysis approaches and machine learning methods to identify a combination of common variants that increase scleroderma susceptibility. Functional characterization of these non-coding variants that are likely regulatory in function will be performed utilizing the Encyclopedia Of DNA Elements (ENCODE) dataset. Since Class II HLA genes are the strongest genetic risk factor in scleroderma, elucidating the role of MHC molecules in antigen recognition, peptide presentation and autoimmunity induction will be another major focus of the lab.

2. Discover rare and low frequency variants leading to scleroderma susceptibility

Scleroderma has a unique phenotype and is a relatively rare disease. Rare and low frequency variants increasing scleroderma susceptibility will likely not be seen in other individuals or diseases. We are generating whole exome sequencing (WES) and targeted resequencing data. These data will be combined with detailed phenotypic and autoantibody information from the GRASP cohort to stratify scleroderma patients into subsets for gene-level testing and pathway analysis (Table 2). Each of the genes enriched in rare and low frequency variants has its own unique story and may involve fibrosis, cytokine signaling, inflammatory pathways or epithelial to mesenchymal transition. Functional characterization of the role of rare and low frequency variants will be performed using the CRISPR/Cas9-mediated precise genome editing system to introduce single variant changes in the cell line of interest.

Table 2
Table 2. Click to enlarge. Pathway analysis of the candidate genes in the GRASP cohort (Gourh et al, Arthritis and Rheumatology 2018).

3. Identify de novo dominant or rare recessive alleles

We are studying scleroderma families and trios and extreme phenotypes of scleroderma and utilizing whole exome sequencing (WES) and whole genome sequencing (WGS) for the discovery of high-penetrance mutations that may provide insight into the function of the implicated gene, it’s role in fibrosis, and ultimately shed some light on the pathogenesis of scleroderma.

Staff

Postbaccalaureate Fellow
301-402-6776
Head
Adjunct Investigator, National Institute on Minority Health and Health Disparities (NIMHD)
301-496-9773
Postbaccalaureate Fellow
301-402-6776
Postbaccalaureate Fellow
301-402-6776

Image & Media Gallery

Career Opportunities

LAB ALUMNI:

Theresa Alexander, Postbac 2017-2018
Pursuing Ph.D. in Computational Biology at University of Maryland, College Park

Sarah Ayla Safran, Postbac 2018-2019
Pursuing M.D. at Columbia University

Scientific Publications

Gourh P, Remmers EF, Boyden SE, Alexander T, Morgan ND, Shah AA, Mayes MD, Doumatey A, Bentley AR, Shriner D, Domsic RT, Medsger TA Jr, 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 Jr, 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. Brief Report: Whole-Exome Sequencing to Identify Rare Variants and Gene Networks That Increase Susceptibility to Scleroderma in African Americans. Arthritis Rheumatol. 2018 Oct;70(10):1654-1660. doi: 10.1002/art.40541. Epub 2018 Aug 29. PubMed PMID: 29732714; PubMed Central PMCID: PMC6160338.

Morgan ND, Shah AA, Mayes MD, Domsic RT, Medsger TA Jr, Steen VD, Varga J, Carns M, Ramos PS, Silver RM, Schiopu E, Khanna D, Hsu V, Gordon JK, Gladue H, Saketkoo LA, Criswell LA, Derk CT, Trojanowski MA, Shanmugam VK, Chung L, Valenzuela A, Jan R, Goldberg A, Remmers EF, Kastner DL, Wigley FM, Gourh P, Boin F. Clinical and serological features of systemic sclerosis in a multicenter
African American cohort: Analysis of the genome research in African American scleroderma patients clinical database. Medicine (Baltimore). 2017 Dec;96(51):e8980. doi: 10.1097/MD.0000000000008980. PubMed PMID: 29390428; PubMed Central PMCID: PMC5758130.

Ramnitz MS, Gourh P, Goldbach-Mansky R, Wodajo F, Ichikawa S, Econs MJ, White KE, Molinolo A, Chen MY, Heller T, Del Rivero J, Seo-Mayer P, Arabshahi B, Jackson MB, Hatab S, McCarthy E, Guthrie LC, Brillante BA, Gafni RI, Collins MT. Phenotypic and Genotypic Characterization and Treatment of a Cohort With Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome. J Bone Miner Res. 2016 Oct;31(10):1845-1854. doi: 10.1002/jbmr.2870. Epub 2016 Sep 20. PubMed PMID: 27164190; PubMed Central PMCID: PMC5071128.

Coustet B, Bouaziz M, Dieudé P, Guedj M, Bossini-Castillo L, Agarwal S, Radstake T, Martin J, Gourh P, Elhai M, Koumakis E, Avouac J, Ruiz B, Mayes M, Arnett F, Hachulla E, Diot E, Cracowski JL, Tiev K, Sibilia J, Mouthon L, Frances C, Amoura Z, Carpentier P, Cosnes A, Meyer O, Kahan A, Boileau C, Chiocchia G,
Allanore Y. Independent replication and meta analysis of association studies establish TNFSF4 as a susceptibility gene preferentially associated with the subset of anticentromere-positive patients with systemic sclerosis. J Rheumatol. 2012 May;39(5):997-1003. doi: 10.3899/jrheum.111270. Epub 2012 Mar 15. PubMed PMID: 22422496; PubMed Central PMCID: PMC3687343.

Carmona FD, Gutala R, Simeón CP, Carreira P, Ortego-Centeno N, Vicente-Rabaneda E, García-Hernández FJ, García de la Peña P, Fernández-Castro M, Martínez-Estupiñán L, Egurbide MV, Tsao BP, Gourh P, Agarwal SK, Assassi S, Mayes MD, Arnett FC, Tan FK, Martín J; Spanish Scleroderma Group. Novel identification of the IRF7 region as an anticentromere autoantibody propensity locus in systemic
sclerosis. Ann Rheum Dis. 2012 Jan;71(1):114-9. doi: 10.1136/annrheumdis-2011-200275. Epub 2011 Sep 16. PubMed PMID: 21926187; PubMed Central PMCID: PMC3369428.

Gorlova O, Martin JE, Rueda B, Koeleman BP, Ying J, Teruel M, Diaz-Gallo LM, Broen JC, Vonk MC, Simeon CP, Alizadeh BZ, Coenen MJ, Voskuyl AE, Schuerwegh AJ, van Riel PL, Vanthuyne M, van 't Slot R, Italiaander A, Ophoff RA, Hunzelmann N, Fonollosa V, Ortego-Centeno N, González-Gay MA, García-Hernández FJ, González-Escribano MF, Airo P, van Laar J, Worthington J, Hesselstrand R, Smith V, de Keyser F, Houssiau F, Chee MM, Madhok R, Shiels PG, Westhovens R, Kreuter A, de Baere E, Witte T, Padyukov L, Nordin A, Scorza R, Lunardi C, Lie BA, Hoffmann-Vold AM, Palm O, García de la Peña P, Carreira P; Spanish Scleroderma Group, Varga J, Hinchcliff M, Lee AT, Gourh P, Amos CI, Wigley FM, Hummers LK, Nelson JL, Riemekasten G, Herrick A, Beretta L, Fonseca C, Denton CP, Gregersen
PK, Agarwal S, Assassi S, Tan FK, Arnett FC, Radstake TR, Mayes MD, Martin J. Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy. PLoS Genet. 2011 Jul;7(7):e1002178. doi: 10.1371/journal.pgen.1002178. Epub 2011 Jul 14.

Coustet B, Agarwal SK, Gourh P, Guedj M, Mayes MD, Dieude P, Wipff J, Avouac J, Hachulla E, Diot E, Cracowski JL, Tiev K, Sibilia J, Mouthon L, Frances C, Amoura Z, Carpentier P, Meyer O, Kahan A, Boileau C, Arnett FC, Allanore Y. Association study of ITGAM, ITGAX, and CD58 autoimmune risk loci in systemic
sclerosis: results from 2 large European Caucasian cohorts. J Rheumatol. 2011 Jun;38(6):1033-8. doi: 10.3899/jrheum.101053. Epub 2011 Mar 1. PubMed PMID: 21362770; PubMed Central PMCID: PMC3404507.

Diaz-Gallo LM, Gourh P, Broen J, Simeon C, Fonollosa V, Ortego-Centeno N, Agarwal S, Vonk MC, Coenen M, Riemekasten G, Hunzelmann N, Hesselstrand R, Tan FK, Reveille JD, Assassi S, García-Hernandez FJ, Carreira P, Camps MT, Fernandez-Nebro A, de la Peña PG, Nearney T, Hilda D, González-Gay MA, Airo P, Beretta L, Scorza R, Herrick A, Worthington J, Pros A, Gómez-Gracia I, Trapiella L, Espinosa G, Castellvi I, Witte T, de Keyser F, Vanthuyne M, Mayes MD, Radstake TR, Arnett FC, Martin J, Rueda B. Analysis of the influence of PTPN22 gene polymorphisms in systemic sclerosis. Ann Rheum Dis. 2011 Mar;70(3):454-62. doi: 10.1136/ard.2010.130138. Epub 2010 Dec 3. Erratum in: Ann Rheum Dis. 2011 Aug;70(8):1520. PubMed PMID: 21131644; PubMed Central PMCID: PMC3170726.

Assassi S, Reveille JD, Arnett FC, Weisman MH, Ward MM, Agarwal SK, Gourh P, Bhula J, Sharif R, Sampat K, Mayes MD, Tan FK. Whole-blood gene expression profiling in ankylosing spondylitis shows upregulation of toll-like receptor 4 and 5. J Rheumatol. 2011 Jan;38(1):87-98. doi: 10.3899/jrheum.100469. Epub 2010 Oct 15. PubMed PMID: 20952467; PubMed Central PMCID: PMC3014385.

Radstake TR, Gorlova O, Rueda B, Martin JE, Alizadeh BZ, Palomino-Morales R, Coenen MJ, Vonk MC, Voskuyl AE, Schuerwegh AJ, Broen JC, van Riel PL, van 't Slot R, Italiaander A, Ophoff RA, Riemekasten G, Hunzelmann N, Simeon CP, Ortego-Centeno N, González-Gay MA, González-Escribano MF; Spanish Scleroderma Group, Airo P, van Laar J, Herrick A, Worthington J, Hesselstrand R, Smith V, de
Keyser F, Houssiau F, Chee MM, Madhok R, Shiels P, Westhovens R, Kreuter A, Kiener H, de Baere E, Witte T, Padykov L, Klareskog L, Beretta L, Scorza R, Lie BA, Hoffmann-Vold AM, Carreira P, Varga J, Hinchcliff M, Gregersen PK, Lee AT, Ying J, Han Y, Weng SF, Amos CI, Wigley FM, Hummers L, Nelson JL, Agarwal SK, Assassi S, Gourh P, Tan FK, Koeleman BP, Arnett FC, Martin J, Mayes MD. Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nat Genet. 2010 May;42(5):426-9. doi: 10.1038/ng.565. Epub 2010 Apr 11. PubMed PMID: 20383147; PubMed Central PMCID: PMC2861917.

Assassi S, Mayes MD, Arnett FC, Gourh P, Agarwal SK, McNearney TA, Chaussabel D, Oommen N, Fischbach M, Shah KR, Charles J, Pascual V, Reveille JD, Tan FK. Systemic sclerosis and lupus: points in an interferon-mediated continuum. Arthritis Rheum. 2010 Feb;62(2):589-98. doi: 10.1002/art.27224. PubMed PMID: 20112391; PubMed Central PMCID: PMC2879587.

Broen J, Gourh P, Rueda B, Coenen M, Mayes M, Martin J, Arnett FC, Radstake TR; European Consortium on Systemic Sclerosis Genetics. The FAS -670A>G polymorphism influences susceptibility to systemic sclerosis phenotypes. Arthritis Rheum. 2009 Dec;60(12):3815-20. doi: 10.1002/art.24964. PubMed PMID: 19950259; PubMed Central PMCID: PMC2876716.

Gourh P, Agarwal SK, Divecha D, Assassi S, Paz G, Arora-Singh RK, Reveille JD, Shete S, Mayes MD, Arnett FC, Tan FK. Polymorphisms in TBX21 and STAT4 increase the risk of systemic sclerosis: evidence of possible gene-gene interaction and alterations in Th1/Th2 cytokines. Arthritis Rheum. 2009 Dec;60(12):3794-806. doi: 10.1002/art.24958. PubMed PMID: 19950257; PubMed Central PMCID: PMC2998060.

Agarwal SK, Gourh P, Shete S, Paz G, Divecha D, Reveille JD, Assassi S, Tan FK, Mayes MD, Arnett FC. Association of interleukin 23 receptor polymorphisms with anti-topoisomerase-I positivity and pulmonary hypertension in systemic sclerosis. J Rheumatol. 2009 Dec;36(12):2715-23. doi: 10.3899/jrheum.090421. Epub 2009 Nov 16. Erratum in: J Rheumatol. 2010 Sep;37(9):1979. PubMed PMID: 19918037; PubMed Central PMCID: PMC2895677.

Rueda B, Gourh P, Broen J, Agarwal SK, Simeon C, Ortego-Centeno N, Vonk MC, Coenen M, Riemekasten G, Hunzelmann N, Hesselstrand R, Tan FK, Reveille JD, Assassi S, Garcia-Hernandez FJ, Carreira P, Camps M, Fernandez-Nebro A, Garcia de la Peña P, Nearney T, Hilda D, Gónzalez-Gay MA, Airo P, Beretta L, Scorza R, Radstake TR, Mayes MD, Arnett FC, Martin J. BANK1 functional variants are associated with susceptibility to diffuse systemic sclerosis in Caucasians. Ann Rheum Dis. 2010 Apr;69(4):700-5. doi: 10.1136/ard.2009.118174. Epub 2009 Oct 8. Erratum in: Ann Rheum Dis. 2011 May;70(5):880. Ann Rheum Dis. 2011 Aug;70(8):1520. PubMed PMID: 19815934; PubMed Central PMCID: PMC2975737.

Gourh P, Arnett FC, Assassi S, Tan FK, Huang M, Diekman L, Mayes MD, Reveille JD, Agarwal SK. Plasma cytokine profiles in systemic sclerosis: associations with autoantibody subsets and clinical manifestations. Arthritis Res Ther. 2009;11(5):R147. doi: 10.1186/ar2821. Epub 2009 Oct 2. PubMed PMID: 19799786;PubMed Central PMCID: PMC2787259.

Gourh P, Agarwal SK, Martin E, Divecha D, Rueda B, Bunting H, Assassi S, Paz G, Shete S, McNearney T, Draeger H, Reveille JD, Radstake TR, Simeon CP, Rodriguez L, Vicente E, Gonzalez-Gay MA, Mayes MD, Tan FK, Martin J, Arnett FC. Association of the C8orf13-BLK region with systemic sclerosis in North American and European populations. J Autoimmun. 2010 Mar;34(2):155-62. doi: 10.1016/j.jaut.2009.08.014. Epub 2009 Sep 30. PubMed PMID: 19796918; PubMed Central PMCID: PMC2821978.

Assassi S, Del Junco D, Sutter K, McNearney TA, Reveille JD, Karnavas A, Gourh P, Estrada-Y-Martin RM, Fischbach M, Arnett FC, Mayes MD. Clinical and genetic factors predictive of mortality in early systemic sclerosis. Arthritis Rheum. 2009 Oct 15;61(10):1403-11. doi: 10.1002/art.24734. PubMed PMID: 19790132; PubMed Central PMCID: PMC2883167.

Gourh P, Arnett FC, Tan FK, Assassi S, Divecha D, Paz G, McNearney T, Draeger H, Reveille JD, Mayes MD, Agarwal SK. Association of TNFSF4 (OX40L) polymorphisms with susceptibility to systemic sclerosis. Ann Rheum Dis. 2010 Mar;69(3):550-5. doi: 10.1136/ard.2009.116434. Epub 2009 Sep 23. Erratum in: Ann Rheum Dis. 2011 May;70(5):880. PubMed PMID: 19778912; PubMed Central PMCID: PMC2927683.

Assassi S, Fritzler MJ, Arnett FC, Norman GL, Shah KR, Gourh P, Manek N, Perry M, Ganesh D, Rahbar MH, Mayes MD. Primary biliary cirrhosis (PBC), PBC autoantibodies, and hepatic parameter abnormalities in a large population of systemic sclerosis patients. J Rheumatol. 2009 Oct;36(10):2250-6. doi: 10.3899/jrheum.090340. Epub 2009 Sep 1. PubMed PMID: 19723904; PubMed Central PMCID: PMC2885441.

Arnett FC, Gourh P, Shete S, Ahn CW, Honey RE, Agarwal SK, Tan FK, McNearney T, Fischbach M, Fritzler MJ, Mayes MD, Reveille JD. Major histocompatibility complex (MHC) class II alleles, haplotypes and epitopes which confer susceptibility or protection in systemic sclerosis: analyses in 1300 Caucasian,
African-American and Hispanic cases and 1000 controls. Ann Rheum Dis. 2010 May;69(5):822-7. doi: 10.1136/ard.2009.111906. Epub 2009 Jul 12. Erratum in: Ann Rheum Dis. 2011 May;70(5):880. PubMed PMID: 19596691; PubMed Central PMCID: PMC2916702.

Gourh P, Mayes MD, Arnett FC. CTGF polymorphism associated with systemic sclerosis. N Engl J Med. 2008 Jan 17;358(3):308-9; author reply 309. PubMed PMID: 18203332.

Assassi S, Arnett FC, Reveille JD, Gourh P, Mayes MD. Clinical, immunologic, and genetic features of familial systemic sclerosis. Arthritis Rheum. 2007 Jun;56(6):2031-7. PubMed PMID: 17530643.

Alkassab F, Gourh P, Tan FK, McNearney T, Fischbach M, Ahn C, Arnett FC, Mayes MD. An allograft inflammatory factor 1 (AIF1) single nucleotide polymorphism (SNP) is associated with anticentromere antibody positive systemic sclerosis. Rheumatology (Oxford). 2007 Aug;46(8):1248-51. Epub 2007 May 23. PubMed PMID: 17522098.

Gourh P, Tan FK, Assassi S, Ahn CW, McNearney TA, Fischbach M, Arnett FC, Mayes MD. Association of the PTPN22 R620W polymorphism with anti-topoisomerase I- and anticentromere antibody-positive systemic sclerosis. Arthritis Rheum. 2006 Dec;54(12):3945-53. PubMed PMID: 17133608.

Tan FK, Zhou X, Mayes MD, Gourh P, Guo X, Marcum C, Jin L, Arnett FC Jr. Signatures of differentially regulated interferon gene expression and vasculotrophism in the peripheral blood cells of systemic sclerosis patients. Rheumatology (Oxford). 2006 Jun;45(6):694-702. Epub 2006 Jan 17. PubMed PMID:
16418202.

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Last Reviewed: 03/08/2019