Searching for Scleroderma
Genes
By Maureen Mayes,
M.D., M.P.H., Professor of Medicine, University of Texas Health
Science Center at Houston (originally published in "Scleroderma
Voice," 2002 #1)
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Maureen
Mayes, M.D., M.P.H. |
Five years ago, most
doctors thought genes did not play a significant role in scleroderma.
However, in the last
few years several things have happened to challenge that assumption.
Dr. Frank Arnett,
along with several other researchers in Houston, and my colleagues
and I in Detroit, took a closer look at our patients in Texas
and Michigan, focusing on family history.
The results were
surprising.
The
Growing Evidence for Genetic Involvement
A little over 1%
of scleroderma patients had a close relative (mother/father/brother/sister)
who also had scleroderma.
In addition, another
1 % had a family member with lupus or another autoimmune disease.
Although 1 % may
not sound like much, it is far more than what would be expected
in the general population, where scleroderma occurs in about
1 in 4,000 individuals.
At the same time,
several groups of researchers identified "gene regions"
(not specific genes) clearly associated with lupus. They have
not yet identified the precise genes that exist in these gene
regions but they are well on their way to doing so.
What has also become
clearer in the past few years is that there are many genes
involved, perhaps as many as 20 or more, and that not all
patients will have all genes. In addition, just having the
right combination of genes will not guarantee that someone
will get the disease, only that he or she is more likely to
get it. In addition, some genes may determine which internal
organs will become involved or which will be protected.
It seems quite probable,
although not yet proven, that some of the "lupus genes"
will also turn out to be "scleroderma genes," whereas
other genes will be specific for the particular disease.
The obvious next
question is, "What are these genes?" There are several
good candidates to be investigated, including genes that are
key to inflammation and immune function. Some of these genes
have already been studied and have not turned out to be associated.
As usual in research, we have far more questions than answers.
The information derived
from the Human Genome Project, as well as some recent advances
in genetic technology that allows us to search for thousands
of genes at a time (high throughput DNA analysis) presents
us with a terrific opportunity and a daunting challenge.
Where
Do We Go From Here?
Considering all of
the above, how do we move from where we are now, with "hunches"
about the role of genes in scleroderma, to where we want to
be: having solid data about specific genes?
The answer to this
question is straightforward but not easy.
To pursue these issues,
we need health histories and blood samples (to get DNA information)
from:
- Approximately 500 scleroderma cases and their family members-preferably
both parents, or at least one parent plus one or more siblings;
- Fifty to 100 childhood-onset cases (those starting before
the age of 16) with their parents and siblings;
- At least 100 "multiplex" families, that is,
families with more than one case of scleroderma, preferably
affecting siblings (brothers/sisters);
- Lots of healthy, non-blood-related controls (this is where
spouses come in); and
- A repository of these genetic samples so that investigators
from around the country can work on this problem, which
is clearly more than Dr. Arnett, Dr. Li Jin in Cincinnati,
and I can do by ourselves unless we get really lucky.
The
Scleroderma Family Registry and DNA Repository
Fortunately, the
National Institute of Arthritis and Musculoskeletal and Skin
Diseases (NIAMS), which is a branch of the National Institutes
of Health (NIH), agreed to fund this study and established
the "Scleroderma Family Registry and DNA Repository"
in September 2000.1 am leading this effort with Drs. Frank
Arnett and John Reveille at the University of Texas/Houston,
and Dr. Li Jin at the University of Cincinnati.
The purpose of the
Registry is to study possible genetic links with scleroderma.
As noted above, the key questions are the following:
- What genes are responsible for an
increased susceptibility to getting scleroderma?
- Are there specific genes that determine the severity of
disease or the pattern of organ involvement?
- Once we identify these genes, is it possible to interfere
with their activity and, thereby, improve the symptoms or
prevent progression of the disease?
To begin to answer
these questions, we need to determine which genes are more
commonly found in scleroderma patients than in people without
scleroderma.
The Scleroderma Family
Registry is designed to address these questions. The Repository
part of it involves "banking" DNA samples (as well
as serum samples) so that many other investigators can study
sclero derma genetics and accelerate this research effort.
The approach that
the Registry will use to do the genetic analysis involves
getting blood samples from three types of families: "singleton"
families, "multiplex" families, and "childhood-onset"
families.
Singleton
Families
The first type of
family that the Registry is interested in recruiting is one
in which there is only one case of scleroderma (99% of cases).
A very powerful genetic-analysis
technique involves studying the DNA from "trios"—that
is, a scleroderma patient and both parents.
When one parent is
unavailable, we can analyze DNA from sisters or brothers.
In this type of analysis,
we identify the genes that are selectively passed on to the
scleroderma patient. We plan to include about 500 scleroderma
patients and 1,000-1,500 family members in this part of the
study. It is essential for the analysis to include unaffected
family members. They are as important as the cases.
In addition to family
members, we need "control" samples from people who
are not blood relatives of cases and who have no autoimmune
diseases. The perfect group for control samples is spouses
of patients or spouses of their relatives. One reason they
are "perfect" is that they tend to be available
and willing to become involved in the study. (So this is one
situation in which your spouse gets to give a blood sample
when you go to the doctor.)
Multiplex
Families
Sometimes a family
will have several cases of scleroderma, plus lupus, plus other
autoim mune diseases. Although rare, these situations are
very important in helping us track down the responsible genes.
Because this is so
uncommon, we will need to do a nationwide search to identify
our target sample of 100 families. In this situation, we would
like to draw blood from all available family members. Healthy
family members are just as important to our study as those
with scleroderma, because we need to know which genes are
not associated with this disease. That is, we need to "subtract
out" unimportant genes found in the healthy relatives.
Other
Families
For some purposes,
it may be helpful to have samples from three generations (both
the parents and the grown children of the scleroderma case).
This will depend on the individual situation.
Childhood-Onset
Families
The systemic form
of scleroderma rarely occurs in childhood (younger than age
16). However, these childhood-onset cases may be telling us
something very important about the disease. These children
(some of whom are now adults) may have a "stronger"
genetic component than the adult cases, so they represent
an important part of our study.
We plan to collect
blood samples from 50 childhood-onset cases and their families.
Since this is a rare event, our nationwide search for multiplex
families will include a call for childhood-onset families.
To
Learn More About the Registry
The way to participate
in the Registry and become a "registrant" is to
call Marilyn Perry, the Registry Coordinator, at 800-736-6864.
Her complete contact information is:
Marilyn Perry
Coordinator, Scleroderma Family Registry and DNA Repository
6431 Fannin Street, MSB 5.243
Houston, Texas 77030
713-500-7196
800-736-6864
marilyn.perry@uth.tmc.edu
She will explain
the study further and send a consent form for you to sign
and return. Once we receive the signed consent form, we will
send you a kit that includes blood-drawing tubes, instructions,
and a return prepaid FedEx envelope for you to take to your
local doctor's office or lab. Part of the consent form is
a release of medical information that permits registry personnel
to review your medical records to verify the diagnosis, and
to determine some features of your particular type of scleroderma.
All information is
kept strictly confidential. It is not considered part of your
medical record, and will not be available to your insurance
company. This is true for all participants in the Registry:
patients, family members, and controls such as spouses or
friends. |
