"The Role of Genetics in Scleroderma"
Is It in Your Genes or in Your Environment?

by Maureen Mayes, M.D., M.P.H., Professor of Medicine, University of Texas/Houston, (originally published in "Scleroderma Voice," 2004 #2)

In order to understand this question, it is first necessary to know the expected prevalence and incidence of scleroderma in the U.S.

The Prevalence and Incidence of Scleroderma

Working with a team of collaborators, I recently completed a study (published in 2003) that sought to identify every person with systemic scleroderma (SSc) in the Detroit area of Michigan. We did not include localized scleroderma, that is, we did not include cases of morphea or linear disease, because these cases were too difficult to identify with the resources we had available to us.

Based on 706 identified and verified cases, and assuming that the population in Southeast Michigan was representative of the country as a whole, we calculated the expected total number of cases in the U.S.

This study estimated that the prevalence (the total number of cases) of SSc was 250 per million U.S. adults, and the incidence (the number of new cases per year) in the U.S. was 20 per million U.S. adults.

This leads to a total number of SSc cases in the U.S. of about 70,000. It is clear that the study missed some patients, so this must be interpreted as a conservative estimate. Also, it did not include those with localized scleroderma.

Who Gets Scleroderma?

With this background information, we compared our prevalence figures to other reports to see if there is a difference among populations in terms of who gets scleroderma. Not surprisingly, 80% of our cases were women; systemic scleroderma usually started in adulthood and was rare in children; and SSc occurred more frequently in the U.S. than in Europe, Scandinavia, or Japan. There was a group, however, that had a higher incidence of scleroderma than we estimated, and that was the Choctaw Native Americans in Oklahoma. (This was reported in 1996.)

Why Is Scleroderma More Prevalent Among the Choctaws?

Although the total number of Choctaw cases was low, there were many more than would be expected using the Michigan prevalence figures. In fact, there was almost three times the expected number of cases among the Choctaw population.

In addition, the Choctaw cases shared many similar clinical features in that almost all had diffuse skin disease, pulmonary fibrosis, and the same serum autoantibodies.

Was there a genetic predisposition in these cases that made them more susceptible to scleroderma? Or was there something in the environment in the region that was triggering scleroderma?

The non-Choctaws in the region did not seem to have a lot of scleroderma, so the search focused on studying the genes in the cases versus the healthy Choctaws.

A genetic analysis called a “genome-wide scan” was done to see if there were certain gene regions that clustered in the cases more frequently than in the controls. This was found to be the case, and a total of 14 gene regions (encompassing hundreds of potentially relevant genes) were found to be associated with SSc.

Several “interesting” genes are included within these gene regions, and are now being studied as possible candidates for disease susceptibility in non-Choctaw scleroderma patients. Some are genes that control the formation of collagen (but not the actual collagen genes), some are genes that are involved with the immune system, and some are genes whose role is unknown.

Well, what about non-Choctaw cases—does scleroderma run in families? For most people, the answer is “no,” that is, 98.3% of scleroderma cases will not have a relative with scleroderma. However, the remaining 1.7% will have another family member affected, and this is much more than would be expected by chance alone.

Implications of the Choctaw Study

So, how important can a factor be if it only occurs less that 2% of the time? The answer is that this genetic feature may hold the key to understanding all or most of scleroderma cases.

What has become clear is that there is no single gene that causes scleroderma. It is likely that there are many genes, perhaps a dozen or more, that confer an increased risk of getting the disease.

It is also clear, that the answer will not be found in the genes alone. There must be a triggering event that “turns on” the genes that eventually result in disease expression. The nature of this triggering event is unknown; it could be a virus, a bacterial infection, an allergen, or a toxin. In fact, it may be different things in different people.

Much Work Still Remains

There is much research being done—and much more that needs to be done. In collaboration with other researchers, I am studying the genetic makeup of hundreds of scleroderma patients and thousands of their unaffected relatives to identify which genes are more frequently seen in the patients than in their healthy relatives.

A very important group to study are those few families (1.7% of all cases) that have a first-degree family member also affected with scleroderma.

From the genetic analysis point of view, the “best” type of family is one in which there are two siblings with scleroderma (involving brothers and/or sisters).

The Scleroderma Family Registry and DNA Repository

The Scleroderma Family Registry and DNA Repository is funded by NIH/NIAMS (National Institutes of Health/National Institute of Arthritis, Musculoskeletal, and Skin Diseases) to identify these susceptibility genes.

Participation in the Registry involves a phone interview and a one-time blood draw which can be performed at a local area doctor’s office or lab.

The Registry also has a sample repository for other investigators who are doing research in scleroderma but lack a sufficient number of samples to perform their studies.

The Registry phone number is 1-800-736-6864. Learn more at www.sclerodermaregistry.org.

We are actively recruiting multicase families or single-case families in which both parents are available for a blood sample. It is only through the participation of patients and family members like yourselves that this work can be done and the answer eventually found.

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