Genome Research in African American Scleroderma Patients (GRASP) Project
Fredrick Wigley, MD
Johns Hopkins University School of Medicine
Francesco Boin, MD
In collaboration with
Dan Kastner, MD, PhD
National Human Genome Research Institute
Pravitt Gourh, MD
National Institute of Arthritis & Musculoskeletal Disease
GRASP Project Overview
Dr. Wigley and Dr. Boin: There is evidence that racial differences exist in the susceptibility to and severity of scleroderma. African Americans have a higher age-specific incidence and prevalence of scleroderma compared to European Americans. In addition, the incidence of severe scleroderma-associated interstitial lung disease (SSc-ILD) and pulmonary hypertension (high blood pressure between the heart and lung; a life-threatening complication in scleroderma) is also reported to be higher in this ethnic group compared to others. As a result, African Americans affected by scleroderma experience greater disease severity and, as a consequence, worse disease burden as measured by morbidity and mortality. Socioeconomic factors and impaired access to health care do not fully account for the predilection of African American scleroderma patients to poor health outcomes. To date, attempts to elucidate the factors influencing increased disease severity have been hindered by the relatively small size of studied African American scleroderma cohorts.
The Genome Research in African American Scleroderma Patients (GRASP) Project was established to enhance our understanding of the clinical manifestations of scleroderma in African Americans and to perform genomic analyses with the aim of identifying key factors contributing to the onset and severity of their disease. In order to achieve these goals, a large cohort of African American scleroderma patients has been gathered and clinical data as well as DNA samples have been collected from all enrolled patients.
The GRASP cohort currently consists of more than 1,200 extensively evaluated African American scleroderma patients enrolled from 23 participating US academic centers. This is the largest multicenter cohort of African American scleroderma patients ever studied. GRASP’s comprehensive clinical database and its significant size are enabling important informative analyses. In our initial phase, these have included a careful characterization of the relevant clinical features and the analysis of the specific repertoire of autoantibodies presented by African American patients. Results from our study confirm and clearly emphasize the unique and severe disease burden of scleroderma in African Americans and highlight key factors associated with clinically relevant disease outcomes.
The GRASP consortium is now working to define how variation in the DNA across the genome of African American patients may affect the expression of scleroderma. Subtle and rare differences between the DNA makeup of African Americans who have scleroderma and African Americans not affected by the disease or other ethnic populations may explain their increased risk of developing scleroderma as well as the particular array of severe clinical manifestations. Consistent with the underlying assumptions of the project, GRASP investigators have found that certain African ancestry-derived genetic variants increase the risk of scleroderma in the modern-day African American population.
How this work will impact patients
One of the challenges of caring and managing a complex multisystem disease like scleroderma is to be able to define not only its stage of activity or progression, but also to predict with precision the future course of the disease. We know that scleroderma does not follow one well-defined path in everyone; rather, each patient is unique and affected by a highly variable combination of disease manifestations. This heterogeneous disease expression (mild in some and severe in others) requires a deeper understanding in order to enable physicians to provide the best treatment for individual patients. We hope that the GRASP Project will provide novel insights into the genetic and biological basis for the unique disease expression observed in African Americans. The discovery of specific genes or segments of the genome strongly associated with particular clinical manifestations will allow clinicians to identify early on individuals at risk for certain outcomes, to follow them closely, and to intervene with more targeted therapies at the appropriate moment in the disease course.
The GRASP Project clearly will broaden our understanding of scleroderma and help us to deliver more effective care to African Americans affected by this condition. We are confident that the discoveries prompted by GRASP will have a major impact also for patients of other racial backgrounds. In fact, variations of genes critical for the development of scleroderma and its specific disease manifestations could be shared across different ethnicities and help us to decipher with greater precision the fundamental biological processes that cause scleroderma to occur and progress.
Role of the Scleroderma Research Foundation
The SRF has been instrumental to the development of the GRASP Project since the very beginning. It was during an annual SRF Workshop, that Drs. Wigley and Kastner envisioned an interactive, multicenter project to study from a genetic standpoint why African Americans are affected by scleroderma more frequently and with greater severity. The strong partnership with the GRASP leadership and the continued financial support provided by the SRF has enabled the participation of a large number of academic centers in the GRASP consortium. Moreover, the SRF has provided the perfect framework for GRASP: an environment that encourages brainstorming, formulation of ambitious research goals, and streamlined collaboration among leaders in the field of scleroderma research and clinical care.
The SRF has a unique philosophy and method of supporting scleroderma research and related programs. In fact, the SRF has steered away from the traditional format of providing research funding. While the door for applications is always open for anybody to apply, their approach is first to proactively search for and identify the most talented researchers (even those who are not directly working on scleroderma) as well as the most outstanding clinical programs and invite them to formulate relevant research proposals. This process of seeking the very best talent has driven over the years the creation of a very robust and comprehensive research program. The SRF is also unique among funding organizations in how they decide whom to support and how to use their funds. The SRF has a gifted professional leadership that is knowledgeable about the disease, biology and research; and it has an incredibly talented, dedicated, and independent Scientific Advisory Board that provide guidance regarding the best research programs and proposals to support. Through this process, the SRF has built a highly successful research network and community of investigators that is making a difference and will continue to bring about important new discoveries.