Gene-environment interactions in sarcoidosis: challenge and opportunity
Introduction
Sarcoidosis is a systemic inflammatory syndrome of unknown etiology characterized by accumulation of immune effector cells in affected organs.1 Noncaseating granulomas are the pathologic hallmark of the disease, and the clinical course is extremely heterogeneous. There are accumulating parallel data suggesting important roles for both genetic susceptibility (reviewed by du Bois2) and specific transmissible environmental agents (reviewed by Crouser3) (Table 1). A variety of investigators have reported important susceptibility and protective roles for genes mediating immune responses, especially for the human leukocyte antigen (HLA) genes located on chromosome 6p.4., 5., 6. The HLA genes govern the expression of the type II major histocompatibility complex on antigen-presenting cells, which mediates antigen-specific responses to exogenous agents by presenting the relevant antigen to a cognate T-cell antigen receptor that is expressed on the surface of T cells. These observations fit well with the current concepts of disease pathogenesis, reserving a central role for activation of antigen-specific oligoclonal CD4+ T cells by major histocompatibility complex class II–restricted antigen-presenting cells, which then amplify immune mechanisms that lead to granuloma formation. At the same time, epidemiologic and experimental observations suggest a causative role for several environmental exposures, likely in the form of respirable particles. These 2 avenues of investigation, genetic and environmental, support the general hypothesis that development of sarcoidosis depends on an appropriate exposure in a genetically susceptible host (Fig. 1). Bridging the 2 approaches is a challenge for sarcoidosis research.
It is clear that there is not one set of genetic susceptibility markers that is sufficient to explain all sarcoidosis cases. In this regard, numerous attempts to define disease susceptibility genes, usually by candidate gene approaches, although more recently using haplotype analysis, have yielded results that are poorly reproducible.7 More recently, 2 whole genome scans have yielded differing results, possibly because 2 different populations were studied.8., 9. Recent successful genetic analyses have relied on defining very clear phenotypes, such as Lofgren syndrome, to demonstrate reproducibility between populations.10., 11. These findings illuminate the need for assiduous clinical phenotyping, careful study design, and circumspection when extrapolating results between groups. Likewise, the influence of variable environmental exposures on the results of most genetic studies has not been tested.
Several exposures have been suggested to mediate disease risk, but there has been poor reproducibility of the findings, leading to the hypothesis that a range of agents may mediate sarcoidosis and that epidemiologic risk factors may vary between disparate populations. It is possible that the correct term is “sarcoidoses,” connoting a set of stereotyped immune responses to various agents that may display phenotypic differences and for which various pathogenetic mechanisms might obtain. Therefore, dissecting the interactions between genetic polymorphisms and environmental exposures will likely be highly relevant to advancing understanding of pathogenesis. Several considerations, however, present obstacles to these lines of investigation.
Section snippets
General considerations
Progress in genetic epidemiology and genotyping technology has yielded tremendous advances in recent years. Useful information on disease pathogenesis, genetic susceptibility profiling, and pharmacogenomics have been derived from these endeavors. In contrast, although it is widely recognized that many human diseases are influenced by both genes and environment, the study of gene-environment interactions is in its infancy. Many susceptibility genes do not have a substantial primary etiologic
Study designs
As a general principle, exposure can be assessed using cohort, case-control, or family-based designs. The strengths and weaknesses of these approaches for sarcoidosis are summarized in Table 3. Population cohort studies have the advantages of minimizing selection bias and ascertainment bias, and avoiding recall error when assessing exposures. In the case of uncommon diseases, however, with variable age of onset and unclear disease latency, cohort studies are problematic.25 To be effective in
Evidence for main effects
Observational data suggesting familial clustering and ethnic susceptibility for sarcoidosis led early investigators to hypothesize that there might be a genetic predisposition to sarcoidosis. The inheritance pattern in familial sarcoidosis is complex, suggesting polygenic susceptibility.42 More recently, genetic studies of sarcoidosis have demonstrated that specific gene polymorphisms are involved in both susceptibility to and phenotypic determination of the disease.43 Until recently, however,
Conclusions
The study of gene-environment interaction in sarcoidosis is nascent but holds the promise of dramatically improving our understanding of sarcoidosis. A number of benefits can be envisioned. Specific pathophysiologic mechanisms will be illuminated, including some that are not obvious until one considers the interaction of genes and environment. Specific combinations of genetic susceptibility markers may be linked to individual antigens, allowing better disease characterization and risk
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2015, Respiratory MedicineCitation Excerpt :Subsequently, the digested antigen circulates via the lymphatic and vascular systems, affecting the extrathoracic lymph nodes, liver, and spleen [16]. Amplification of the Th1 response, modified not only by genetic predisposing factors but also probably by certain environmental conditions, plays a central role in both disease development and remission by removing the antigenic stimulus [12,17–23]. When considering the first observation this study makes, a similar distribution of organ involvement in subgroups differentiated by age has been found in previous studies.
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2014, Atlas of the Oral and Maxillofacial Surgery Clinics of North AmericaCitation Excerpt :The human leucocyte antigen (HLA) gene has been implicated in both sarcoidosis and in Heerfordt syndrome but specifically the HLA-DRB1*04 allele seems protective for sarcoidosis, but increases the risk for ocular manifestations.9 Despite significant research the exact cause has remained elusive and further genetic and immunologic studies are required.8,11–13 In patients with sarcoidosis, usually fever, followed by uveitis, parotid gland swelling, and then facial nerve palsy are classic for Heerfordt syndrome (Figs. 9 and 10).1–5
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