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Cincinnati, OH
Drs. Baughman and Lower are affiliated with the Department of Medicine, University of Cincinnati Medical Center.
Correspondence to: Robert P. Baughman, MD, FCCP, 1001 Holmes, Eden Ave, Cincinnati, OH 45267-0565; e-mail: bob.baughman{at}uc.edu
Sarcoidosis is a multiorgan disease in which some patients never require therapy and others receive long-term treatment. The prevalence of the disease varies throughout the world. The wide array of rates of disease and clinical outcomes appear related more to the host’s response than to the etiologic agent. Each of us possesses genetic polymorphisms that account for our uniqueness. These polymorphisms influence our risk for acquiring a particular disease, the manifestation of the disease, and the resolution of disease. Sarcoidosis is one of many diseases in which the study of polymorphisms may lead to greater insight regarding disease manifestations.
The genetic diversity of sarcoidosis has been observed for ethnic groups. There are major differences in disease manifestations for Japanese vs Scandinavians1 and for African Americans vs whites in the United States.2 However, investigators have experienced difficulty in attributing an ethnic group’s difference to a particular genetic polymorphism. Hence, many studies of sarcoidosis have compared sarcoidosis patients to race-matched and age-matched control subjects. The reported differences are then more likely due to the disease than to a coincidental relationship. Studies that have compared various ethnic groups have found that genetic patterns may lead to different patterns of the disease, depending on the ethnic group.3
Genetic studies often have been developed around candidate genes. Their products are particular proteins or groups of proteins that have biological importance in the disease. However, finding an association does not always mean that the gene product is the cause for the disease. The gene may be linked to another gene that is the true disease modifier. Also, a variable response may not change the risk for the disease, but it may alter the outcome of the disease once it occurs.
The granuloma, which is the hallmark of sarcoidosis, is initiated by the complex of the antigen-presenting cell, usually a macrophage, and the T lymphocyte. The release of cytokines associated with a T helper type 1 cell response leads to granuloma formation. Candidate genes include the major histocompatibility complex (MHC) area, especially the human leukocyte antigen (HLA). Studies in familial and matched control studies have indicated that some HLA patterns are associated with an increased risk for sarcoidosis.4 5 6
The angiotensin-converting enzyme (ACE) is elevated in 60 to 80% of patients with active sarcoidosis. Studies have suggested that ACE polymorphisms can lead to different serum ACE levels.7 Some groups,7 8 but not all groups,9 10 have found that ACE polymorphisms are associated with an increased risk for acquiring the disease. In a study by Maliarik et al,8 the deletion of a nontranslated portion of the ACE gene was associated with an increased risk for sarcoidosis in African Americans but not in whites. The importance of the enzyme in sarcoidosis remains unclear, since ACE inhibitors have never been shown to modify the disease. The variability seen with ACE polymorphisms may be explained by a linked neighboring gene.
Tumor necrosis factor (TNF)-
has been shown to be secreted in increased amounts in patients with active sarcoidosis. Studies11
have demonstrated that patients with chronic disease who are unresponsive to therapy with prednisone have persistent TNF release. Therapy to block TNF, such as thalidomide12
or anti-TNF antibodies,13
has proved to be useful. Studies of polymorphisms of TNF have been promising.14
15
The TNF gene is closely associated with the MHC genome area.16
The association between sarcoidosis presentation and TNF polymorphisms could be related to MHC changes or vice versa.
In this issue of CHEST (see page 1520), Morohashi and colleagues report on another candidate gene, vascular endothelial growth factor (VEGF). This is a logical protein to study, since it is part of the mononuclear cell response during the formation of a granuloma. The investigators chose to study single nuclear polymorphisms of the VEGF gene in a homogenous population of Japanese subjects. One polymorphism (the T allele at position +813) was associated with a decreased risk for sarcoidosis. Previously, this particular polymorphism was associated with lower VEGF plasma levels in healthy control subjects.17 Because reduced VEGF release inhibits the monocyte inflammatory response, one could argue that this is a biologically plausible reason for protection from sarcoidosis.
It has been previously reported18 that cigarette smokers have lower levels of VEGF in their lungs. Epidemiologic studies19 20 have found that sarcoidosis patients are less likely to be cigarette smokers. One hypothesis for this relationship is that cigarette smoking may be protective, since it down-regulates VEGF. We are not recommending cigarette smoking to prevent sarcoidosis, but the modification of VEGF may be a new therapeutic target that was identified by this genetic study.
The authors also tried to examine the potential impact of VEGF polymorphisms on disease presentation. They noted a relationship between changes at -627 and the FEV1/FVC ratio. Airway obstruction is not a major condition of most patients with sarcoidosis, and the relationship reported here was clinically insignificant. This study failed to identify a relationship between specific VEGF polymorphisms and organ involvement in sarcoidosis. However, this study further illustrates one of the dilemmas encountered when only one ethnic group is analyzed.
The study by Morohashi et al of 103 sarcoidosis patients included 71 patients with ocular disease and only 7 with skin disease. In a study of American sarcoidosis patients in which specific definitions of organ involvement were developed and applied to all the patients studied,21 the incidence of ocular and skin disease ranged between 10% and 20% for both organs.2 In the American study, there was more ocular and skin disease in the African American vs the white population,2 but the amount of eye disease was significantly less than that seen in Japan.
Most sarcoidosis patients experience a self-limited course, while others have chronic disease.22 Chronic disease is attributed to various factors, including host response to the disease. Studies of genetic polymorphisms may provide useful prognostic information as well. Certain HLA polymorphisms23 have yielded prognostic information. ACE polymorphisms have provided useful prognostic information in one study of Scandinavian subjects,24 but not in subjects from another ethnic group.9
These conflicting results may be attributed to a lack of standard classification for chronic disease. Everyone agrees that the sarcoidosis patient with normal findings on a physical examination and from laboratory tests who is receiving no therapy has disease resolution. However, universal agreement is more difficult for the classification of the asymptomatic patient with persistent changes on chest roentgenograms who has not received therapy for > 2 years.
As we continue to acquire the genetic profile of patients with sarcoidosis, it will be imperative to refine our clinical phenotype of these patients. Some of the variation reported in different studies may be due to different classification schemes. In the future, one hopes that investigators will agree on a standard evaluation of organ involvement and disease severity. Studies of genetic polymorphisms may prove to be useful in the prediction of the risk for disease, organ involvement, response to specific therapy, and chronicity of disease. Genetic profiling must be studied in various ethnic groups to determine its applicability. As various research groups are acquiring DNA banks for studies on new candidate genes, it is imperative that clinical information is acquired and reported in a standard fashion so that the genotype can be matched with the phenotype.
References
This article has been cited by other articles:
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  S. Rothkrantz-Kos, M. P. van Dieijen-Visser, P. G.H. Mulder, and M. Drent Potential Usefulness of Inflammatory Markers to Monitor Respiratory Functional Impairment in Sarcoidosis Clin. Chem., September 1, 2003; 49(9): 1510 - 1517. [Abstract] [Full Text] [PDF]
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