Interstitial lung disease (ILD) is a major complication and the leading cause of mortality in scleroderma (SSc, systemic sclerosis). The morbidity and mortality rates in African American scleroderma patients are higher when compared with SSc patients of other races. The goal of this project is to fill gaps in knowledge of pathophysiologic links between African American race and SSc-ILD that may account for the racial differences in SSc-ILD outcomes, and potentially other rheumatic lung disease outcomes as well. In studies to date we identified a genetic variant in African American SSc patients that is likely to be responsible for the higher severity of SSc-ILD in African-Americans. In particular, we found that hepatocyte growth factor (HGF) receptor c-MET in lung fibroblasts from African American SSc-ILD patients contains the mutation D1398G that is not observed in white patients. Moreover, in cultured SSc lung fibroblasts from whites HGF downregulates the expression of extracellular matrix (ECM) proteins, whereas in fibroblasts from the African American SSc patients who have mutation D1398G, HGF does not exhibit this activity due to its inability to induce c-MET phosphorylation. Thus, our results suggest that the defective phosphorylation of HGF receptor in African American SSc lung fibroblasts is a direct consequence of the D1398G mutation. Our organizing hypotheses that drive this component project of the MCRC are that severity of SSc-ILD in African American patients is caused by a defect in the phosphorylation mechanisms of c-MET regulation of ECM proteins in lung, and that the D1398G variant of the c-MET gene is the source of this defect.
Specific Aim 1 will test the hypothesis that D1398G variant of c-MET gene is a somatic mutation that modulates the disease severity in SSc-ILD patients.
Specific Aim 2 will test the hypothesis that specific SNPs within the coding region of c-MET gene will be associated with D1398G variant of c-MET in SSc-ILD patients, thereby leading to a potential biomarker of SSc-ILD severity.
Specific Aim 3 will test the hypothesis that D1398G variant of c-MET gene is causally responsible for the defective HGF signaling in African American SSc patients. The combined results of these studies will enhance our understanding of the molecular mechanisms of SSc-ILD and ultimately may lead to the development of effective diagnostics, prognostics and therapies that will depend on and can be tailored to the patient s genotype.

Public Health Relevance

Interstitial lung disease (ILD) is a major complication and the leading cause of mortality in scleroderma (SSc, systemic sclerosis) with significantly higher morbidity and mortality rates in African American scleroderma patients. The studies described in the current proposal will be first in the field of scleroderma research to provide genetic and mechanistic evidence underpinning the known health disparities in African American SSc patients.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Comprehensive Center (P60)
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Special Emphasis Panel (ZAR1-KM)
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Medical University of South Carolina
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Pandey, Janardan P; Namboodiri, Aryan M; Wolf, Bethany et al. (2018) Endogenous antibody responses to mucin 1 in a large multiethnic cohort of patients with breast cancer and healthy controls: Role of immunoglobulin and Fc? receptor genes. Immunobiology 223:178-182
Zollars, Eric S; Hyer, Madison; Wolf, Bethany et al. (2018) Measuring lupus arthritis activity using contrasted high-field MRI. Associations with clinical measures of disease activity and novel patterns of disease. Lupus Sci Med 5:e000264
Faith, Trevor D; Egede, Leonard; Williams, Edith M (2018) Research Ethics in Behavioral Interventions Among Special Populations: Lessons From the Peer Approaches to Lupus Self-Management Study. Am J Med Sci 355:104-112
Faith, Trevor D; Flournoy-Floyd, Minnjuan; Ortiz, Kasim et al. (2018) My life with lupus: contextual responses of African-American women with systemic lupus participating in a peer mentoring intervention to improve disease self-management. BMJ Open 8:e022701
Patel, Zubin; Lu, Xiaoming; Miller, Daniel et al. (2018) A plausibly causal functional lupus-associated risk variant in the STAT1-STAT4 locus. Hum Mol Genet :
Putterman, Chaim; Pisetsky, David S; Petri, Michelle et al. (2018) The SLE-key test serological signature: new insights into the course of lupus. Rheumatology (Oxford) 57:1632-1640
Ruiz, Daniel; Oates, Jim C; Kamen, Diane L (2018) Antiphospholipid Antibodies and Heart Valve Disease in Systemic Lupus Erythematosus. Am J Med Sci 355:293-298
Wolf, Bethany J; Ramos, Paula S; Hyer, J Madison et al. (2018) An Analytic Approach Using Candidate Gene Selection and Logic Forest to Identify Gene by Environment Interactions (G × E) for Systemic Lupus Erythematosus in African Americans. Genes (Basel) 9:
Williams, Edith M; Hyer, J Madison; Viswanathan, Ramakrishnan et al. (2018) Peer-to-Peer Mentoring for African American Women With Lupus: A Feasibility Pilot. Arthritis Care Res (Hoboken) 70:908-917
Gourh, Pravitt; Remmers, Elaine F; Boyden, Steven E et al. (2018) Brief Report: Whole-Exome Sequencing to Identify Rare Variants and Gene Networks That Increase Susceptibility to Scleroderma in African Americans. Arthritis Rheumatol 70:1654-1660

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