Because siblings share both a portion of their genome and some environmental exposures, it is logical to test the hypothesis that phenotypic expression of sarcoidosis between affected siblings should be more similar than between cases selected at random. The concordance of liver and ocular sarcoidosis between affected siblings supports, albeit weakly, this hypothesis, whereas the other organ systems and phenotypic parameters of sarcoidosis we examined failed to show concordance between siblings.
In addition, if sarcoidosis is a multigenetic disease associated with environmental exposure, then our inability to find close phenotypic similarities between siblings would not necessarily disprove a genetic basis for the disease. It may be that a specific combination of genes determines sarcoid phenotypes. In addition, it is possible that the genes responsible for the development of sarcoidosis are distinct from those that determine the phenotypic expression of the disease. Thus, while affected siblings may share disease predisposing genes, differences in genes and/or exposures important in the determination of sarcoidosis phenotypes may still exist between sibling pairs. The concept of multiple sarcoidosis susceptibility genes is supported by two studies’ that identified multiple linkage sites associated with sarcoidosis. It is also possible that few phenotypic similarities were seen in sibling pairs because environmental influences were different enough to override the genetic similarities. Because a genetic analysis of affected sibling pairs that included environmental histories was not performed in this study, these issues remain unresolved.
There are several potential limitations to our study. The principal investigators at all clinical centers were pulmonologists and were therefore more likely to recruit patients with pulmonary disease. We do not believe that our population was skewed in this regard, as it has been estimated that 90 to 95% of sarcoidosis patients have abnormal chest radiograph findings, and 96% (308 of 320 of our subjects) had pulmonary involvement.
Another potential limitation is that there were some inconsistencies in data collection. This was a retrospective multicenter study. The clinical data evaluated in this study were collected from medical record review that may have been incomplete. In addition, physicians caring for the sarcoidosis patients may have differed in their clinical evaluation, and this may have accounted for different frequencies of organ involvement across the clinical centers. However, we doubt that this potential bias significantly impacted our results, in that it is likely that clinically significant organ involvement was detected in most cases and the prevalence of organ involvement was within the range of that found in other studies of African-American sarcoidosis patients.