Scleroderma Twin Studies

Howard Chang, MD, PHD

Stanford University School of Medicine
Howard Hughes Medical Institute

About Dr. Chang
Project Overview

Dr. Chang: Systemic sclerosis is challenging to study because it is rare and multifactorial. The conventional approach to medical study is to find a large number of subjects afflicted with a disease and to compare them to a large number of healthy controls. The hope is that, somehow, the average profile of patients and controls would balance each other out and reveal a disease-relevant signal. This approach has been applied to scleroderma with limited success because the small number of scleroderma patients and controls is often not sufficient to tease apart relevant disease-causing factors from inadvertent associations.

In this study, we are employing a new precision approach to understanding scleroderma pathogenesis. We are recruiting genetically identical twins where one twin has scleroderma and the other twin does not. Such “divergent twins” are uniquely informative because we have a perfect control for each patient—the same genes, same age, same household—the small differences we find between the twins will hopefully pinpoint disease-relevant differences. Our experience with a more common disease, asthma, in divergent twins shows that this is a uniquely powerful approach to identify disease-relevant mechanisms.  We estimate that the number of subjects needed for this twin approach is far less (perhaps by 100-fold) than conventionally designed studies. Our study involves three key components: (i) careful evaluation of the clinical findings of each twin pair; (ii) a new ultra-sensitive technology called ATAC-seq to map the functional difference in gene control from the blood cells of the twin pairs; (iii) advanced bioinformatics methods to identify disease-relevant biomarkers and pathways.

Research Update

The SRF has played crucial roles in my research. They approached me a number of years ago about working on scleroderma and it is the reason my lab is working in this field. I have been continually impressed and moved by the dedication and vision of the people at the SRF. SRF supported me to take risks and apply the newest powerful technologies to scleroderma and connected me with clinical investigators to bring these concepts to scleroderma patients.

The SRF is absolutely special because they seek out the best scientists and bring them in to work on scleroderma. The SRF creates a community that works together to tackle scleroderma. The Foundation brings not only money but also organization and leadership to the search for a cure. I believe that SRF is one of the most important engines of progress against this disease.

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