Dan Kastner, MD, PhD
National Human Genome Research Institute
Fredrick Wigley, MD
Johns Hopkins University
Francesco Boin, MD
University of California San Francisco
Research conducted in several centers around the United States has confirmed that scleroderma has a higher incidence and prevalence among African-Americans, manifesting with earlier onset, more aggressive disease course, and ultimately higher mortality. Previous studies, including genome-wide association studies (GWAS), have identified several genetic factors conferring general susceptibility for scleroderma. However, these investigations have been mostly focused on Caucasian patients of European descent and have not been replicated in other populations.
The GRASP (Genome Research in African-American Scleroderma Patients) consortium was established with the main goal of defining how changes in the DNA across the genome of African-American patients affected by scleroderma may explain why in this ethnic population the disease manifests with greater severity. The enrollment of a very large cohort of more than 1,000 African-American scleroderma patients from 16 participating centers across the U.S. and the study of their DNA with cutting-edge techniques will allow the investigators to determine whether specific variations in the sequence of the bases of the DNA may explain their increased risk to developed scleroderma as well as its severe clinical manifestations.
The GRASP study has made significant progress over the past year. The main goal was to collect samples from at least 1,000 African-American patients and 1,000 healthy controls. The team has surpassed this initial goal and now are continuing further subject enrollment and sample collection. The 1,000 healthy controls have been screened for ANA positivity and the investigators included in the study only those who were ANA negative. The team’s second goal was to perform whole exome sequencing (WES) on 400 scleroderma patients and 400 controls to identify rare coding variants associated with scleroderma. The sequencing has been completed and the genetic data have been assembled after multiple quality control measures. Preliminary analyses are underway. GRASP researchers are currently in the process of replicating the findings from the whole exome sequencing in the remaining 600 patients and 600 controls. The third goal for study was to perform single nucleotide polymorphism (SNP) genotyping using two Illumina arrays to identify low frequency and common variants associated with scleroderma. The custom Illumina HumanOmniExpressExome array has been synthesized including 20,000 variants from the WES. One-third of this array genotyping is completed, and the remaining is ongoing. The Illumina Multi-Ethnic Genotyping (MEGA) array genotyping is also ongoing and approximately 500 samples (including cases and controls) have been already processed.
The team expects to fully analyze the exome sequencing data and replicate the findings within the next year. GRASP leaders also plan to start functional studies based on the confirmed genetic associations. The genotyping of 1,000 scleroderma cases and 1,000 healthy controls will continue using the two different Illumina arrays until completion and will include approximately 2.5 million single nucleotide polymorphisms.
The GRASP study and its results will ultimately benefit patients by helping researchers and clinicians to understand with more precision the genes responsible for increased risk of developing scleroderma. Additionally these findings will likely shed light on the disease process in patients of all racial backgrounds.
Dr. Wigley on GRASP:
"The GRASP study is a foundation for further studies to understand why the disease process is worse in a particular group of patients, but it will help us understand what is triggering scleroderma in all patients. This will be a big step toward a therapeutic intervention.
If we can find the gene that triggers a more aggressive type of the disease, then we can turn that gene off. It may be done with drugs that are available to us now. It is a matter of getting insight into the process so that we can trigger it."
Dr. Boin on Why SRF Research Matters:
“The Scleroderma Research Foundation has streamlined and accelerated the pipeline from public awareness to scientific discovery. Their ability to attract substantial funding dedicated to scleroderma research matched by the partnership with the most brilliant scientists in the field of immunology, genetics, fibrosis and vascular biology have been rewarded by some of the most outstanding discoveries in the field of scleroderma of the past 10 years. The SRF continues to be at the forefront of the ultimate fight to find a cure for this dreadful disease. ”