A team of researchers at Dartmouth has shown for the first time that different forms of the autoimmune disease scleroderma can be classified solely by variations in gene expression, according to findings published on July 16 in the Public Library of Science journal PLoS One, an online, open-access publication. This research may have wide-ranging implications for the diagnosis and treatment of the disease.
Scleroderma is characterized by excessive deposits of collagen in skin and organ tissues. It is a rare, chronic disorder affecting 300,000 people in the United States, according to the Scleroderma Foundation. More serious forms of the disease can be fatal.
The Dartmouth team, led by genetics professor Michael Whitfield, analyzed skin biopsies from 34 individuals using DNA microarrays. This technique allowed researchers to compare a set of genes across individuals and to determine in what cases certain genes are expressed and in what cases they are not.
Microarrays first proved helpful in cancer research in 2001 and 2002, Whitfield said, as scientists attempted to identify and differentiate cancer subtypes by finding what genes are expressed in certain forms of malignancies. The technique is similarly helpful in identifying different forms of scleroderma.
"The most difficult problem is obtaining patient samples," Whitfield said. "It is a rare disease and the number of patients that come into most clinics is relatively small. Partnering with Dr. Kari Connolly at the University of California, San Francisco, we were able to obtain enough samples to have statistical significance."
Whitfield's analysis points to the existence of three genetic subgroups within the most serious class of the disease, what is called systemic sclerosis with diffuse scleroderma, and two groups within the intermediate form.
The groups are defined by cell proliferation, the presence of inflammatory T-cells or association with the vascular system, all of which can provide clues into the severity and duration of the disease. T-cells may be indicative of an earlier stage of the disease, Whitman said.
"We have used a genomic approach to capture the clinical diversity among different patients in a way that will provide new insight into the complexity of the disease," the PLoS One paper states. "High throughput gene expression data, combined with clinical phenotypic data, provides a powerful new tool to probe the underlying biology of scleroderma."
This conclusion gives researchers an alternative to defining the disease clinically based on "the extent of skin involvement."
"There have been a few studies, but they just looked at just a few patients, kind of lumping them all together," said John Varga, a rheumatology professor at Northwestern University. "This one looks at the heterogeneity of the disease."
Varga, who was not involved in the research but has done previous work with Whitfield, said the findings demonstrate the possibility that scleroderma is not "one disease," but rather "four or six related conditions." Each form of the disease, based on its genetic identity, may need different treatment, Varga said.
"[This study] gives us a far more sophisticated way of looking at this complex disease," he said.
The next step, Whitfield said, is to reproduce the findings with a new group of patients. Ideally, follow-up studies will raise the tally of included patients to 100 or 120, he said, explaining that he has partnered with researchers at UCSF, Boston University and Northwestern to obtain samples.
"We are trying to understand and predict which patients respond to different therapies," Whitfield said. Whitfield said he and his colleagues are working to perform genetic analysis on samples from patients before and after experimental treatments, which may include stem cell transplantation or administration of the drugs Cyclophosphamide and Gleevec, a common cancer therapy.
"Our hope is that using gene expression, we can help in the diagnosis and treatment of patients with the disease," he said.
