Systemic sclerosis (SSc) is an autoimmune condition with an incidence of 10–19 new cases/million/year (1). The cause of SSc has not been identified, but environmental factors have been implicated in some cases. Studies examining the relative contribution of inherited (genetic) factors and/or environmental factors in the pathogenesis of SSc have been few and inconclusive. In a recent report on familial SSc in 3 US cohorts, the disease occurred in 0.4% of siblings of SSc patients (2).
The classic approach for assessing the role of genetic versus environmental factors in disease pathogenesis is the study of twins. Monozygotic (MZ) twins provide a unique study opportunity, since they share an identical genetic background. The study of such twins allows us not only to control for genotype, but also to control for age, family background/history, and, to some extent, environmental exposures and socioeconomic variables.
Thus far, publications on twins with SSc have been limited to case reports, describing a total of 10 twin pairs. One report described a pair of 5-year-old twins concordant for SSc (3) and 2 other reports each described one pair of adult twins concordant for SSc (4, 5). An additional disease-concordant twin pair was recently reported in Belgium (6). Dubois et al described a twin pair in which one twin had SSc and the other had possible systemic lupus erythematosus (SLE) (7). Dustoor et al reported a twin pair discordant for SSc (8). Cook et al described a twin pair in which one twin had SSc and the other twin had possible SSc sine scleroderma (9). A 1995 study by McHugh et al included 3 MZ twin pairs discordant for SSc (10). Neither antinuclear antibodies (ANAs) nor SSc-associated autoantibodies were detected in the “healthy” twin siblings of these 3 SSc patients (10).
Twin studies in several other autoimmune diseases have been published, with widely varying concordance rates. For rheumatoid arthritis (RA), frequency of twin concordance has ranged from 12.3% to 21% in MZ twins and from 0% to 3.6% in DZ twins (11–14). In SLE, concordance has ranged from 10% to 69% in MZ twins and from 0% to 2% in DZ twins (14–17). In these studies, the overall higher concordance rate in the MZ twins as compared with the DZ twins suggests that a genetic component plays an important role in disease development.
To determine the relative contribution of inheritance to the development of SSc, we have undertaken a study of MZ and DZ twins concordant or discordant for SSc.
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We have evaluated 42 twin pairs with one or both members having SSc. The estimated frequency of twinning in the US population is 10 of every 1,000 births (39). Based on the reported prevalence of SSc in the US of between 4 and 253 per million (40) and a national population of 275 million, we estimate the prevalence of twin pairs concordant or discordant for SSc in the US to be 11–696.
The majority of our study participants were female, as expected in SSc. It has been reported that MZ twinning is more common in females than in males (41), with 3 of every 10 female/female pairs being MZ twins and 7 of every 10 being DZ twins (42). Of the DZ twins, it is expected that nearly half will be same-sex twins and half will be opposite-sex twins. In contrast to the above-noted DZ:MZ twinning rate of 2:1 (43), we recruited a greater number of MZ twins as compared with DZ twins (DZ:MZ ratio 0.75:1). A similar ratio has been observed by others who have examined twin disease concordance for various autoimmune conditions (13), which may reflect recruitment bias, particularly when participants are ascertained via a volunteer-based approach (43) or through public advertising and/or patient support organizations (14). Another possibility is that genomic imprinting and/or X-inactivation may occur in MZ twinning in females, e.g., the Wiedemann-Beckwith syndrome (44).
The concordance rate for a disease in MZ twins reflects the contribution of inherited genetic factors to disease development. The overall concordance rate for SSc in our study was low (4.7%) in comparison with the rates of SLE and RA observed in twins (14). This is especially true considering that we identified twins through advertisement rather than through random sampling from a population-based twin registry. The latter approach usually favors recruitment of disease-concordant twins. Thus, factors other than inheritance must play a role in the development of SSc. The concordance rate for DZ twins was similar to that for MZ twins, also suggesting that the triggers for SSc are probably environmental agents or acquired genetic alterations rather than inherited genetic factors.
These findings are consistent with the currently accepted paradigm that inherited factors prime an individual for autoimmunity, which may develop if acquired genetic or environmental factors provide the costimulation necessary for expression of the autoimmune phenotype. With heritability being expressed as 2(rMZ − rDZ), where “r” is the correlation (45), heritability for SSc in our twin cohort would be 0.008, a very low value. One pair of MZ twins was concordant for SSc, but the twins were diagnosed with different SSc variants. This is consistent with the findings of MacGregor et al, who reported a lack of similarity of clinical features in MZ twins concordant for RA (46).
In our twin cohort, ANA positivity in index cases and their “healthy” twin siblings was more frequent among the MZ twins than among the DZ twins, suggesting that inherited genetic background is important for the development of autoantibodies but that development of these antibodies and the presence of the underlying genetic background are themselves not sufficient for disease occurrence. Positivity for ANAs was found in 40% of “healthy” DZ twins. ANAs have been detected in the sera of healthy individuals, with frequencies varying from 4% in young individuals to 18% in the elderly (47). In a 1997 study conducted by 15 laboratories worldwide using HEp-2 cells as substrate, 31.7% of healthy individuals between the ages of 20 and 60 years were found to be ANA positive at a titer of ≥1:40 (48). Therefore, the concordance of ANA positivity in our SSc twin pairs cannot be explained by the expected rate of positivity for ANAs in the normal population. In a Finnish cohort study, the presence of ANAs was examined in 76 MZ and 86 DZ twin pairs, and concordance for ANAs was rare (49). In studies examining the presence of ANAs in first-degree relatives of SSc patients, ANAs were detected in 12–27% of blood relatives when HEp-2 cells were used as substrate in indirect immunofluorescence (50). Thus, our concordance rate for the presence of ANAs in DZ twins, and especially in MZ twins, is much higher than that previously reported for relatives (including siblings and progeny) of patients with SSc.
Six of the “healthy” twins participating in our study had Raynaud's phenomenon of several years' duration and did not have any detectable SSc-specific autoantibodies. This is consistent with a previous report suggesting that the longer a patient has Raynaud's phenomenon with no associated underlying condition, the less likely he or she is to develop a connective tissue disease such as SSc in the future (51). The occurrence of Raynaud's phenomenon in these twins may also be genetic in etiology, since familial Raynaud's disease is not uncommon (52) and may be unrelated to SSc. The frequency of Raynaud's phenomenon in “healthy” twins of SSc patients in our study was 14% (6 of 42). In a population-based study of Raynaud's phenomenon in Charleston, South Carolina, and Tarentaise, Savoie, France, the prevalence of Raynaud's phenomenon in females was 5.7% and 20.1%, respectively (53).
Our study was a cross-sectional analysis of disease concordance. Although it is possible that some discordant twins may become concordant over time, new twin pairs discordant for SSc may also be identified and concordance rates may not change significantly. For example, a 7.5-year longitudinal followup of twins with multiple sclerosis showed only a minor increase in concordance in MZ twins, from 25.9% to 30.8%, and in DZ twins, from 2.4% to 4.4% (54). In addition, concordant twins may be overrepresented relative to the total number of twins, due to the bias that a twin is more aware of a disease because his or her co-twin has the disease. As noted above, the volunteer-based method of ascertainment that we used is reported to lead to the overrepresentation of MZ twins and to the preferential recruitment of concordant twins (14).
Since no population-based twin study of SSc has been published, we cannot determine if concordance for SSc in twins is comparable with that in nontwin siblings. Familial SSc is rare. Only a few case reports of familial SSc are available (2, 5, 55), and no conclusions can be drawn from them regarding the role that genetic or environmental factors may play in disease development. The rarity of SSc in families suggests that SSc is more likely to develop following an environmental trigger in a genetically predisposed individual.
In summary, our results suggest that inherited genetic factors are not sufficient for the development of SSc, but that such factors may play a significant role in the susceptibility of individuals to produce autoantibodies. One or a combination of environmental factors and/or acquired genetic alterations may trigger SSc in genetically predisposed individuals. Such a “predisposing” background can partially explain the clustering of autoimmune diseases observed in some families. Different triggers may result in different autoimmune phenotypes, such as SSc, SLE, RA, or thyroiditis, in the context of an “autoimmune” genetic predisposition.
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The authors thank Stephen R. Wisniewski, PhD, Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, for his assistance with statistical analyses, Masataka Kuwana, MD, PhD, and Noreen Fertig, BS, for helpful discussion and suggestions, and Barbara Lipari for administrative assistance. We offer special thanks to physicians who referred twins to the study and to Mrs. Marie Coyle of the Scleroderma Foundation for assistance in the recruitment of participants.