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
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Maureen
Mayes, M.D., M.P.H. |
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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