Elsevier

Clinics in Dermatology

Volume 25, Issue 3, May–June 2007, Pages 267-275
Clinics in Dermatology

Gene-environment interactions in sarcoidosis: challenge and opportunity

https://doi.org/10.1016/j.clindermatol.2007.03.005Get rights and content

Abstract

Susceptibility to most human diseases is polygenic, with complex interactions between functional polymorphisms of single genes governing disease incidence, phenotype, or both. In this context, the contribution of any discrete gene is generally modest for a single individual, but may confer substantial attributable risk on a population level. Environmental exposure can modify the effects of a polymorphism, either by providing a necessary substrate for development of human disease or because the effects of a given exposure modulate the effects of the gene. In several diseases, genetic polymorphisms have been shown to be context dependent, ie, the effects of a genetic variant are realized only in the setting of a relevant exposure. Because sarcoidosis susceptibility is dependent on both genetic and environmental modifiers, the study of gene-environment interactions may yield important pathogenetic information and will likely be crucial for uncovering the range of genetic susceptibility loci. The complexity of these relationships implies, however, that investigations of gene-environment interactions will require the study of large cohorts with carefully defined exposures and similar clinical phenotypes. A general principle is that the study of gene-environment interactions requires a sample size at least severalfold greater than for either factor alone. To date, the presence of environmental modifiers has been demonstrated for one sarcoidosis susceptibility locus, HLA-DQB1, in African-American families. This article reviews general considerations obtaining for the study of gene-environment interactions in sarcoidosis. It also describes the limited current understanding of the role of environmental influences on sarcoidosis susceptibility genes.

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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