© 2004 American Thoracic Society
Clara Cell Protein in SarcoidosisAnother Job for the Respiratory Tract Protector?Pulmonary, Critical Care, and Sleep Medicine Mount Sinai Medical Center New York, New York Despite several attempts, including a well designed study involving over 700 cases and matched controls (ACCESS), the etiology of sarcoidosis remains unknown (1). The inciting agent responsible for sarcoidosis is likely airborne because the lungs are most commonly affected followed by the skin and eyes. The agent is also likely ubiquitous, as sarcoidosis has been found throughout the world. Because it is unlikely that one major cause for sarcoidosis exists, perhaps it is best to think of the disease not as sarcoidosis but sarcoidoses. It is genetic variation that likely explains why only some individuals develop granulomatous inflammation in response to the "sarcoidosis antigen" (2). That an inherited susceptibility to sarcoidosis exists is best supported by familial clustering (3, 4). While sarcoidosis in the United States is uncommon, ranging from 11 per 100,000 in Caucasians to 36 per 100,000 in African Americans (5), first- and second-degree relatives of sarcoidosis cases have a significantly higher risk (3). Because sarcoidosis susceptibility likely involves many genes, a genome-wide scan offers the most systematic and efficient approach to unraveling the genetics of sarcoidosis. So far, only one genome-wide search for sarcoidosis predisposing genes has been reported (6). On the basis of 225 microsatellite markers tested in 63 German families with affected siblings, linkage at the major histocompatibility complex was found with additional suggested linkage to markers on chromosome 1, 3, 9, and X. The U.S. Sarcoidosis Genetic Analysis Consortium is about to complete a linkage analysis of 360 African American families with affected siblings using a 300-microsatellite marker scan. While linkage is genome wide, association studies are limited to candidate genes or regions. The ideal candidate gene is functional, influences protein concentration, and, most importantly, influences responsiveness to environmental triggers. In this issue of the Journal (pp. 180–186), Ohchi and coworkers (7) report on an ideal candidate for sarcoidosis, the Clara cell 10-kD protein (CC10) gene located on chromosome 11q12–13.
Clara cells are increasingly recognized as major respiratory tract protectors. They serve as stem cells in bronchial epithelial repair, have high xenobiotic transformation capacity, and, through the Clara cell 10-kD protein, counterregulate inflammation (8). CC10 has been shown to inhibit interferon- The CC10 gene is comprised of three short exons separated by a long first and short second intron. The most studied CC10 polymorphism, and the one evaluated by Ohchi and colleagues (7), is an adenine-to-guanine substitution at position 38 (A38G) downstream from the transcription initiation site within the noncoding region of exon 1. The A/A genotype has functional consequences resulting in decreased CC10 levels (11). Ohchi and coworkers (7), using a case–control study design, found that the A allele was associated with sarcoidosis. Combining genotyping with bronchoalveolar lavage CC10 expression studies in patients significantly strengthens the findings in this study. Individuals with the A/A genotype had the lowest levels of CC10 in bronchoalveolar fluid. This was further supported by demonstrating that the A38G substitution influences promoter activity. In the population studied, the A allele association was driven by those patients with progressive disease, raising a caveat: if CC10 is associated with sarcoidosis, it appears to be associated with the progressive disease phenotype rather than with susceptibility. Chromosome 11, where CC10 resides, was not linked to sarcoidosis in the only genome scan reported so far (6), but the previous reported linkage analysis was likely underpowered to detect a locus with only a mild affect.
CC10 is an ideal candidate gene for sarcoidosis. It functions the way we might expect a disease gene to function. CC10 counterregulates inflammation and affects monocyte recruitment and phagocytosis. CC10 influences other central mediators such as tumor necrosis factor- Even when choosing an ideal candidate, case–control association studies may suffer from population stratification (one subgroup being genetically different from another). Ohchi and coworkers (7) studied a more homogeneous population, namely Japanese sarcoidosis patients and controls from the same region in Japan. Although this may minimize the problem of stratification, two subsequent steps are required. The A38G polymorphism should be tested in a different ethnic group. Failure to replicate this finding may not mean the present study is flawed because gene environment interactions may simply be different in the Japanese population studied. Replication, however, would go a long way to support the role of CC10 in sarcoidosis. Second, the CC10 association should be verified in a family-based study. In family-based association studies, alleles preferentially transmitted to the affected offspring are compared with those that are not (14); thus, the genetic background is controlled for and the problem of spurious associations minimized. Because sarcoidosis generally affects individuals in their fourth decade of life, parents are usually available (15). Ohchi and colleagues (7) provide evidence for an association of a CC10 gene polymorphism with disease progression. This case–control study has a large sample size, phenotyping based on at least three years of observation, small p's, a candidate gene that makes biological sense, and an allele that affects gene expression. Provided that these findings can be replicated and verified by family-based studies, this should provide important information about disease progression in sarcoidosis and gives another job to the Clara cell. FOOTNOTES Conflict of Interest Statement: M.C.I. has no declared conflict of interest. REFERENCES
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
, tumor necrosis factor-
, and interleukin-1 ß. Both the murine and human CC10 promoter regions contain sites where inflammatory mediators, such as tumor necrosis factor-