Maureen D. Mayes, MD, MPH Professor of Medicine - Division of Rheumatology
University of Texas – Houston Medical School
Presented at the Scleroderma Society AGM 31 st July 2004
It has been clear for many years that scleroderma affects women more than men (approximately 4:1 ratio of women to men), and that adults are more often affected than children. However, it has only recently become clear that there are more cases in the United States (higher prevalence and incidence) than in the UK, Europe, Scandinavia or Japan. In addition, the Choctaw Native American group has a higher prevalence than the U.S. population in general.
The Choctaw tribe originated in the Southeastern part of the U.S. and were relocated to the West (Oklahoma) in the early to mid 1800's. In 1990 Dr. Howard, a rheumatologist trained at the University of Texas, was assigned to the Indian Health Service Clinic on the Choctaw reservation. It was there that he observed a ‘surprising' number of scleroderma cases, a disease that was supposed to be rare. This observation led to a formal collaboration with researchers at the University of Texas to calculate the prevalence of scleroderma among the Choctaw and to try to identify the reason that there were almost three times the expected number of cases in this group. As the story unfolded, the affected individuals, who were not known to be closely related, were all descended from a single ‘founder‘ family, suggesting that there was a genetic component to their susceptibility.
This led to a search for the genes that could be responsible. Thus far, several genes and gene regions have been identified as possibly associated with the disease. This research is still ongoing, and as usual with early research, there are more questions than answers. Can we generalize these findings to the general non-native American scleroderma population, or is this a peculiar situation in this closed and relatively inbred group that has no relevance to other scleroderma patients?
One of the questions that naturally comes to mind is the simple query: ‘Does scleroderma run in families?' Up until about 6 years ago, the answer would have been a categorical ‘no.' Most scleroderma patients have never heard of the disease prior to their own diagnosis, and have no affected family members. However, when this question was addressed in a scientific way, the answer was surprising. It is true that 98% of scleroderma patients have no affected family members, but 2% actually do have a first degree relative (parent, sibling or child) who also have scleroderma. This study was done looking at a group of patients in the states of Michigan and Texas, who were of European, African-American, or Hispanic ancestry. This relatively small proportion of multicase families is actually far greater than one would expect. This also explains why the impression of most physicians, including most rheumatologists, and most patients, were reluctant to consider that there may be a genetic component.
Another way of examining genetic versus ‘environmental' influences is to study twins to see if identical twins (sharing all genes) are more likely to have the same disease than non-identical or fraternal twins, who are no more closely related than usual siblings. In a disease with a strong genetic component there will be a higher concordance for disease among the identical twin pairs than among the fraternal twins. Diseases which result from a single-gene defect that is inherited, eg: cystic fibrosis, the concordance is 100% . For complex genetic diseases, requiring multiple genes as well as an interaction with the environment, eg: scleroderma, the disease concordance rate will be higher in the identical twin pairs than the control group of the fraternal twins, but there will still be a statistically significant difference between the two groups.
Well, since scleroderma is relatively rare, and twinning occurs only in 1/200 to 1/500 births, you can appreciate the difficulty in doing this study. However, it has been done. Drs. Wright and Feghali at the University of Pittsburgh, with help from the Scleroderma Foundation Newsletter in the U.S., managed over several years to collect samples from 42 twin pairs with scleroderma, 24 of whom were identical and 18 of whom were fraternal. And the disease concordance rate? Well, the concordance was the same between the two groups – approximately 5%. At first glance, this seemed to disprove the concept of a genetic basis. However, what was striking in this study, was the finding that the concordance rate for positive ANA's (antinuclear antibodies) was 95% among the identical twins and only 60% among the fraternal twins. This would suggest that there is a genetic predisposition to getting scleroderma, but that it takes another event to actually ‘trigger' the disease.
There is much conjecture but little hard evidence regarding the nature of this external or environmental trigger. It is tempting to speculate that this is a virus or a bacterial infection that interacts with particular genes resulting in a chronic auto-immune disease. According to this theory, the infection might be a common one but only causes scleroderma in those with the ‘right' or perhaps ‘wrong' combination of genes. Several studies have investigated exposures to environmental agents, like silica dust (miners and sandblasters), dry cleaning chemicals, and other substances, as possible triggers. Thus far, the only convincing evidence has been for silica dust exposure. However, out of the more than 2,000 scleroderma patients I have seen, only one has had this exposure. That leaves 1,999 cases with no identifiable cause.
As principal investigator for the Scleroderma Family Registry and DNA Repository, my colleagues and I continue to search for these genes and these triggers. We are currently performing genetic analyses of 500 scleroderma patients and 1200 unaffected family members and unrelated controls, looking at several promising genes and gene regions. The results of this analysis are not yet known. I am confident that we can solve this mystery, and, by identifying the responsible genes, figure out what the likely triggers are. We all look forward to the day when scleroderma will be understood, uninteresting, and curable.