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.

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

 

 

HLA and autoantibodies define scleroderma subtypes and risk in African and European Americans and suggest a role for molecular mimicry.

Gourh P, Safran SA, Alexander T, Boyden SE, Morgan ND, Shah AA, Mayes MD, Doumatey A, Bentley AR, Shriner D, Domsic RT, Medsger TA Jr, Ramos PS, Silver RM, Steen VD, Varga J, Hsu V, Saketkoo LA, Schiopu E, Khanna D, Gordon JK, Kron B, Criswell LA, Gladue H, Derk CT, Bernstein EJ, Bridges SL Jr, Shanmugam VK, Kolstad KD, Chung L, Kafaja S, Jan R, Trojanowski M, Goldberg A, Korman BD, Steinbach PJ, Chandrasekharappa SC, Mullikin JC, Adeyemo A, Rotimi C, Wigley FM, Kastner DL, Boin F, Remmers EF
Proceedings of the National Academy of Sciences of the United States of America.
2020 Jan 7;
117(1).
doi: 10.1073/pnas.1906593116
PMID: 31871193

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

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
Arthritis & rheumatology (Hoboken, N.J.).
2018 Oct;
70(10).
doi: 10.1002/art.40541
PMID: 29732714

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.

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
Medicine.
2017 Dec;
96(51).
doi: 10.1097/MD.0000000000008980
PMID: 29390428

Phenotypic and Genotypic Characterization and Treatment of a Cohort With Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome.

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
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.
2016 Oct;
31(10).
doi: 10.1002/jbmr.2870
PMID: 27164190

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.

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
The Journal of rheumatology.
2012 May;
39(5).
doi: 10.3899/jrheum.111270
PMID: 22422496

Novel identification of the IRF7 region as an anticentromere autoantibody propensity locus in systemic sclerosis.

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.
Annals of the rheumatic diseases.
2012 Jan;
71(1).
doi: 10.1136/annrheumdis-2011-200275
PMID: 21926187

Identification of novel genetic markers associated with clinical phenotypes of systemic sclerosis through a genome-wide association strategy.

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
PLoS genetics.
2011 Jul;
7(7).
doi: 10.1371/journal.pgen.1002178
PMID: 21779181

Association study of ITGAM, ITGAX, and CD58 autoimmune risk loci in systemic sclerosis: results from 2 large European Caucasian cohorts.

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
The Journal of rheumatology.
2011 Jun;
38(6).
doi: 10.3899/jrheum.101053
PMID: 21362770

Analysis of the influence of PTPN22 gene polymorphisms in systemic sclerosis.

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
Annals of the rheumatic diseases.
2011 Mar;
70(3).
doi: 10.1136/ard.2010.130138
PMID: 21131644

Whole-blood gene expression profiling in ankylosing spondylitis shows upregulation of toll-like receptor 4 and 5.

Assassi S, Reveille JD, Arnett FC, Weisman MH, Ward MM, Agarwal SK, Gourh P, Bhula J, Sharif R, Sampat K, Mayes MD, Tan FK
The Journal of rheumatology.
2011 Jan;
38(1).
doi: 10.3899/jrheum.100469
PMID: 20952467

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Last Updated: May 2020