Sarcoidosis: Do Our Genes Really Matter?

Roland M. du Bois, M.D.

Royal Brompton Hospital, London, UK

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As the mysteries of the human genome unfold, interest in the genetic predisposition to lung disease has increased. This interest ranges from monogenic diseases such as cystic fibrosis and -1 antitrypsin deficiency to the so-called "complex diseases" in which a number of genes are involved with a varying contribution from environmental triggers. These complex diseases include asthma and sarcoidosis.

Several studies have highlighted the variable prevalence, incidence, and severity of sarcoidosis in different races. The aggregation of sarcoidosis within families provides compelling evidence that a moderately strong genetic predisposition exists. Sarcoidosis is more likely to occur in first- and second- degree family members of individuals with sarcoidosis. This has been quantified in a study from Detroit in which 14% of patients with sarcoidosis had first- or second-degree family members with the disease (1). The relative risk of sarcoidosis (risk of disease affecting a first- or second-degree relative expressed as a ratio or population prevalence of disease) ranged from 36 to 73 in a study from London (2).

For the analysis of diseases that are likely to be polygenic, two main approaches can be taken. Candidate genes (genes that are known to be involved in the pathogenesis of disease) can be studied or chromosomal genomic screens can be used. These screens involve polymorphic markers, which identify regions of the genome in which tandem base repeats occur (microsatellites). These general approaches can be applied to populations of patients with disease by comparison with control populations or in families. The ideal approach would be to use family linkage data (in which markers are seen to track with members of the family who have disease, but not with those who do not) to generate regions of interest and then to test these in case control populations. Study design needs to be meticulous with well-matched populations of cases and controls, adequate numbers, appropriate statistics with correction for multiple comparison, and a choice of target genes that makes biologic sense (3).

Schürmann and coworkers (pp. 840-846) have applied these principles to study 63 German families in whom 138 patients were identified (4). The investigators used 225 microsatellite markers chosen to cover the whole genome. Higher resolution mapping was undertaken on the short arms of chromosomes 3 and 6 and the whole of chromosome 16. Nevertheless this was not a high-density screen and, as noted by Schürmann and coworkers, may not have sufficient resolution to identify all regions of interest. Detailed statistical analysis was performed, which included a linkage calculation program to perform multipoint nonparametric linkage that depends upon the identification of a series of polymorphic sites along a chromosome.

Linkage could be assigned for individual families, and also for all families taken together. This approach identified that the strongest linkage was found on the short arm of chromosome 6 involving six adjacent markers that cover a relatively large area of the genome (16 centimorgans [cM]). The greatest linkage score occurred in the major histocompatibility complex (MHC) class III region, which is located between the MHC class I and II regions that encode genes that initiate the immune response. This finding is interesting for several reasons. Sarcoidosis is an immune granulomatous disease; the first component of pathogenesis requires the identification of a class II/antigen complex by the T-cell antigen receptor on the CD4+ T cell (5). It makes biologic sense therefore for a prominent linkage peak to be found in this region. Other studies have confirmed this as a region of interest. Maliarik and coworkers identified an association in African-Americans with sarcoidosis with specific HLADPB1 alleles that contain either a valine at position 36 or an aspartate at position 55 (6). Foley and coworkers reported HLADRB1 allele frequencies in three ethnic populations (U.K., Polish, Czech Republic) (7) and compared these with three other large series in the literature (Scandinavian, Italian, Japanese) (8). There were a number of susceptibility alleles (HLADR12, 14, 15, 17) but, more strikingly, a shared "protection" allele (HLADRB1*01) in all six populations. Taken together, the study by Schürmann and coworkers and the case control studies in other ethnic populations support the concept of familial and sporadic disease having similar predispositions.

The study by Schürmann and coworkers found six other regions with more minor peaks of linkage on chromosomes 1, 3, 7, 9, and the x chromosome. The regions identified do contain candidate genes of interest but the distances between markers make detailed hypotheses highly speculative. Confirmation from candidate gene studies would add support to these hypotheses. In this regard, the chromosome 3 marker may be relevant. The chemokine receptors CCR2 and CCR5 are located on chromosome 3 (although 8 cM from the chromosome 3 marker). Their ligands attract monocytes and T cells to disease siteshighly relevant to the pathobiology of sarcoidosis. Petrek and coworkers have independently identified an association between polymorphisms in these genes with pulmonary sarcoidosis in Czech patients (11).

The findings of Schürmann and coworkers, supported by other studies, are clearly of interest. However, the authors do acknowledge that the average distance of almost 20 cM between markers is large. Further genome screens of other populations would be helpful with further fine mapping where appropriate. Combining this approach with a candidate gene approach for genes known to be in proximity to these markers will further enhance the mapping potential. It seems inevitable that a number of genetic loci, in addition to the MHC region loci, will be shown to be involved in disease predisposition, to explain the very high relative risk in sarcoidosis. The heterogeneity of familial risk emphasizes that there will be different relative contributions of environment and genome to disease risk, further emphasizing the complexity of the task. Studies such as that being undertaken in the United States (ACCESS) will hopefully suggest new disease triggers to allow more detailed molecular epidemiologic studies to be undertaken. At this time, however, the key triggers are unknown. As advances in technological methodology enhance throughput, and interest in this intriguing disease increases, it is hoped that progress in unraveling the complexity of the initiation of sarcoidosis will be more rapid than in previous decades.

	References

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