"A Scleroderma Twin Tale"

By Carol Feghali, Ph.D., Research Assistant Professor of Medicine, University of Pittsburgh (originally published in "Scleroderma Voice," 2003 #3)

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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.

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