A Scleroderma
Twin Tale
By Carol Feghali, Ph.D., Research Assistant Professor of
Medicine, University of Pittsburgh (originally published in
"Scleroderma Voice," 2003 #3)
Editor's note: This is a long article. You can skip
directly to the sections that interest you, by clicking on
these links:
Systemic sclerosis (SSc) is a disease of unknown cause. Several
studies suggest the role of environmental factors as “triggers”
of SSc.
Multiple cases of SSc within the same family are rare, yet
SSc does occur in siblings of SSc patients more frequently
than in the average population.
To determine the role that environmental and inherited genetic
factors play in the development of SSc, Carol Feghali-Bostwick,
Ph.D.; Timothy M. Wright, M.D.; and Thomas A. Medsger, Jr.,
M.D., began the first study of SSc in fraternal and identical
twins in which one or both twins have SSc.
Why Study Twins?
The study of twins is the “gold standard” for
determining whether a disease is due to shared genes or shared
environmental factors.
The logic behind the approach is that if inheritance is important
in the development of a disease, then one would expect identical
twins to develop the disease, because they inherit the same
sets of genes from their parents.
If only one twin of an identical twin pair develops the disease,
then the disease is not due to inherited genes and is more
likely due to environmental factors and/or genetic changes
that occur through life.
When both twins have the disease, the twins are said to be
“concordant” for the disease. When only one twin
has the disease, the twins are “discordant.”
For a disease to result from inherited genes, a larger proportion
of identical twins should be concordant for the disease compared
to fraternal twins.
The Genetic Rationale for Studying
Twins
Twin studies are based on the fact that identical (monozygotic,
from the Greek: mono = one; zygote = fertilized egg) twins
come from a single fertilized egg and share 100% of their
inherited genes while fraternal (dizygotic; di = two, zygote
= fertilized egg) twins come from two separate fertilized
eggs.
Fraternal twins are not more similar to one another than
they are to any brothers and sisters, and they share on average
50% of their inherited genes.
Therefore a purely genetic disease would result in 100% concordance
in identical twins and lower concordance in fraternal twins,
whereas a purely environmental disease would result in similar
concordance rates in identical and fraternal twins.
A disease that is due to a combination of both genetic and
environmental factors would have a concordance of less than
100% in identical twins and a higher concordance in identical
twins than in fraternal twins.
Previous Studies of Similar Diseases
Previous studies of other connective-tissue diseases, such
as systemic lupus erythematosus (SLE) and rheumatoid arthritis
(RA), suggest that inherited genes play a role in disease
development, but inheritance is not the only factor involved.
Concordance for SLE and RA in these studies was higher in
identical twins compared to fraternal twins, but did not reach
100%. This suggests that a combination of inherited genes
and environmental factors is needed for these diseases to
develop.
Similar findings have been reported for several other autoimmune
and/or connective tissue diseases.
How We Recruited Study Participants
We recruited twins via announcements in the Scleroderma Foundation’s
publication The Beacon and the United Scleroderma Foundation’s
publication Scleroderma Spectrum.
We also publicized the study at various support group meetings
nationwide, and by announcement to more than 3,000 rheumatologists
in the U.S. who are members of the American College of Rheumatology.
Description of Study Participants
A total of 42 twins pairs completed the study. Of these,
24 pairs of twins were identical, and 18 pairs were fraternal.
Women were the majority of the group, reflecting the higher
incidence of SSc in women.
Of 42 twin pairs, 38 pairs were Caucasian, 3 were African-American,
and 1 was Hispanic; 36 were female/female twin pairs, 2 were
male/male pairs, and 4 were female/male pairs in which the
patient with SSc was female (Table 1).
The ages of the twins ranged from 28 to 69 years. The average
age of the identical twins was 47.9 years and the average
age of the fraternal twins was 48.5 years.
The SSc patients’ disease duration ranged from 1 to
35 years, with the average duration from the onset of SSc
symptoms being 11.1 years in identical twins and 12. 9 years
in fraternal twins.
Study Procedures
All twins completing the study provided a blood sample. The
sample was used to determine the presence of autoantibodies
in each study participant.
Autoantibodies are antibodies produced by the cells of the
immune system against self or normal components of our cells
such as proteins.
An autoantibody test was considered positive if antibody
was detected when one part of the patient’s blood was
mixed with 40 parts of buffer—that is, if autoantibodies
were detected in a 1:40 dilution of the serum.
DNA was prepared from the white blood cells and used in DNA
“fingerprint” analysis. This assay is routinely
used in paternity testing, and also used by researchers to
confirm whether twins are identical or fraternal.
As shown in Figure 1, concordance for the presence
of autoantibodies was higher (95%) in identical twins compared
to fraternal twins (60%). Similar autoantibodies have been
detected by other investigators in approximately 25% of first
degree relatives of patients with SSc. This suggests that
inherited genes may play a role in the development of autoantibodies
even in the absence of SSc by predisposing the immune system
of individuals with similar genetic make-up to produce antibodies
against self proteins.
Of the 42 pairs of twins, SSc occurred in both twins only
twice, in one fraternal and one identical pair (Table 2).
In the fraternal twin pair, both twins had the limited cutaneous
or CREST form of SSc, and in the identical twin pair, one
twin had limited cutaneous SSc and one had diffuse cutaneous
SSc.
As shown in Figure 2, concordance for SSc was 4.2%
in identical twins and 5.6% in fraternal twins.
Overall concordance for SSc in all twins was 4.7%. A similar
concordance rate in identical and fraternal twins suggests
that inherited genes alone are not sufficient for the development
of SSc and that environmental factors are involved.
The concordance rate for SSc in this twin study was lower
than the concordance rate reported by other researchers for
connective tissue diseases such as SLE and RA.
In addition, in SSc the concordance rate is similar in identical
and fraternal twins, whereas in SLE and RA the concordance
rate is higher in identical compared to fraternal twins.
Summary of Our Findings
The results of our study have been published in the July
2003 issue of Arthritis & Rheumatism, the official
journal of the American College of Rheumatology (ACR).
Our findings suggest that:
1) autoantibodies are detected in the circulation of the
majority of healthy twins if the affected twin has SSc;
2) identical twins are more likely to have autoantibodies
in their blood compared to fraternal twins, suggesting that
inherited genes may be responsible for the ability of an individual
to make antibodies against components of their own cells;
3) concordance for SSc in identical twins is not 100%, indicating
that inheritance is not solely responsible for the development
of SSc and that environmental factors or genetic changes occurring
at some point in life are likely to be important triggers
of SSc.
Our results also suggest that a certain inherited genetic
background can predispose individuals to develop SSc, and
that SSc may develop when genetically susceptible individuals
are exposed to certain factors or a sequence of events that
can then trigger the disease.
Our Work Continues with Phase Two
at the University of Pittsburgh
About 50% of the twins have completed the second part of
our study by providing skin biopsies for the culture of skin
cells known as fibroblasts.
These cells are responsible for the excessive production
of collagen and other matrix proteins, and thus the skin thickening
seen in SSc patients.
Studies involving this second phase of our research are ongoing
at the University of Pittsburgh.
We Need You!
If you or your twin have scleroderma, we invite you to participate
in our study.
Please contact the study coordinator, Jennifer Jablon, at
1-800-603-8960.
Acknowledgments
This study was made possible through funding from the Scleroderma
Foundation, the Arthritis Foundation, and the National Institutes
of Health (NIH) to Dr. C.A. Feghali-Bostwick; from the R.P.
Bryant Foundation to Dr. T.M. Wright; and from the Scleroderma
Research Fund to Drs. T.M. Wright and T.A. Medsger, Jr. |
