© 2003 American Thoracic Society
The Gene for Acute Sarcoidosis?Boston University School of Medicine Boston, Massachusetts A rheumatologist might order a test for human leukocyte antigen (HLA)-B27 in a patient with sacroiliitis to assess whether there is genetic predisposition to ankylosing spondylitis. In this issue of the Journal (pp. 1162–1166), Spagnolo and colleagues (1) report the association of a genetic trait with an acute form of sarcoidosis (Lofgren's syndrome). Should pulmonologists now consider genetic testing in the evaluation of sarcoidosis? Certain granulomatous responses have been shown to reflect genetic traits. Chronic beryllium disease occurs in only 5% of exposed workers, but 95% of those patients who develop lung disease in response to beryllium carry a specific HLA DPB1 allele (2). Crohn's disease and Blau's syndrome (an autosomal dominant sarcoid-like illness in children) are both characterized by granuloma formation and an association with polymorphisms of the CARD15 gene on chromosome 16 (3). This gene appears to be involved in host recognition of bacterial peptidoglycans and thus may be critical to a balanced host response to intracellular bacterial invasion. Similar attempts to identify susceptibility genes in sarcoidosis have been relatively unrewarding, presumably reflecting the complex genetics of the disease. Sarcoidosis is characterized by broad variability in disease presentation and outcome, ranging from acute uncomplicated disease to chronic multi-system organ dysfunction (4). This creates difficulties in determining prognosis for individual patients. Genetic susceptibility to both the inciting antigen(s) and to the subsequent nature and intensity of the granulomatous response could account for much of the variation in sarcoid disease phenotype. A recent emphasis has been placed on finding genetic traits that modify disease severity and course rather than disease susceptibility.
Acute sarcoidosis frequently presents as Lofgren's syndrome (4, 5). A biopsy is usually not required in this syndrome, since the constellation of erythema nodosum, anterior uveitis, arthralgia, and bilateral hilar lymphadenopathy is due to sarcoidosis in over 95% of cases in the Northeastern United States. If Lofgren's syndrome is diagnosed, the likelihood of spontaneous remission in 12–24 months exceeds 95%. These data would suggest little need for genetic markers of diagnosis or disease outcome. Nevertheless, acute sarcoidosis can present without Lofgren's syndrome, and some patients with Lofgren's syndrome develop chronic disease. For these reasons, genetic markers suggestive of acute sarcoidosis may be clinically useful. Three major genetic associations with Lofgren's syndrome have been reported. Several studies have shown that an activating polymorphism of the tumor necrosis factor-
Is CCR-2 an appropriate gene to study in sarcoidosis? Candidate genes may be identified by genome-wide screens using linkage analysis or by a functional approach, where a specific gene is chosen based on its likely contribution to disease pathogenesis. Both approaches support the choice of CCR-2 as a candidate gene in sarcoidosis. A recent study, reporting a genome-wide search for genes predisposing to sarcoidosis, involved 63 families with two or more siblings diagnosed with sarcoidosis (8). This study confirmed a prominent association of sarcoidosis with the major histocompatibility locus on chromosome 6 (the site of HLA class II and TNF Is there evidence that the CCR-2 haplotype reported by Spagnolo and coworkers is likely to be relevant to the Lofgren's syndrome phenotype? At present, this is impossible to answer. Like many polymorphism association studies, the functional consequences, if any, of the reported CCR-2 polymorphisms are unknown. It is possible that through linkage disequilibrium these polymorphisms are inherited in conjunction with another genetically linked polymorphism of greater impact. The strength of these genetic associations must also be placed in perspective. Approximately 80% of patients with Lofgren's syndrome express the reported alleles compared with 40% of the control population. In contrast, HLA B27 is present in 5–8% of the general population but in over 90% of patients with ankylosing spondylitis (11). The high prevalence of these alleles in the normal population emphasizes the fact that individual polymorphisms are unlikely to provide significant information alone. Indeed, it is probable that several genetic "hits" in combination are required to confer disease susceptibility and phenotype. It is increasingly evident that specific disease states and clinical manifestations are caused by inherited variations in gene expression and function. The expanding number of genetic association studies in sarcoidosis, such as that reported by Spagnolo and coworkers (1), are providing exciting insights into disease pathogenesis. We must now place an emphasis on showing that these genetic associations are reproducible in sarcoid cohorts (other than the 137 Dutch white patients studied in this article), and in understanding their functional consequences. Should a pulmonologist consider genetic testing in sarcoidosis? The answer remains no, but perhaps the time is approaching where the use of genetic analysis in complex diseases like sarcoidosis will be practical and clinically relevant. FOOTNOTES Conflict of Interest Statement: A.W.O. and J.S.B. have no declared conflict of interest. REFERENCES
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