Elsevier

Clinics in Dermatology

Volume 25, Issue 3, May–June 2007, Pages 242-249
Clinics in Dermatology

Genetics of sarcoidosis

https://doi.org/10.1016/j.clindermatol.2007.03.001Get rights and content

Asbtract

The predisposition to sarcoidosis is genetically determined, and genetics appears also to account for the variability in clinical phenotype and behaviour. Many genetic loci have been investigated to date, mainly in case-control association studies. However, only a small number of human leukocyte antigen (HLA) alleles have been consistently associated with sarcoidosis susceptibility/phenotype. In this regard, the association between Löfgren's syndrome and the extended HLA-DRB1*0301/DQB1*0201 haplotype is probably the most extensively reproduced. Several, generally less convincing, associations have been also reported. Of these, the chemokine receptor and butyrophilin-like 2 (BTNL2) associations are most promising. However, two major limitations of genetic studies are that the understanding of the biological relevance of gene variations in the genome is still incomplete and that the reported associations need to be verified in populations of different ethnicities. Despite a number of intriguing hypotheses, what causes sarcoidosis remains obscure. Genetic studies and, importantly, functional analysis of candidate genes will provide insight into pathogenesis and disease risk. However, if, as many believe, sarcoidosis is a heterogeneous collection of disorders, a critical step will be to carefully refine the clinical phenotype, as genetic studies of complex diseases are more rewording if a very specific disease subset is addressed.

Introduction

Sarcoidosis is a systemic inflammatory disorder characterized by the accumulation of CD4+ T lymphocytes and macrophages along with the presence of noncaseating epithelioid granulomas in affected organs.1, 2 Despite intriguing hypotheses of an infectious or environmental etiology, what causes this disease remains obscure, but evidence of familial and ethnic clustering strongly suggests that a genetic predisposition exists.3 Sarcoidosis is not caused by defects in a single major gene or chemical pathway and instead is a complex (multifactorial) disease likely to result from the interaction of environmental factors and multiple genes—some with a major disease effect, but many with a relatively minor effect. Genetic factors are also likely to contribute to the wide variety of clinical presentation, progression, and prognosis observed in sarcoidosis. Rather than a single disorder, sarcoidosis seems to represent a family of diseases, including Löfgren syndrome, persistent/progressive lung disease, and granulomatous uveitis, each with potentially distinct genetic associations; berylliosis, in addition, could also be considered as a subset of the broad grouping of sarcoidosis and almost certainly had been historically.4, 5, 6, 7, 8, 9

Section snippets

Genetic analysis of complex diseases

The term complex disease indicates a disorder that is thought to have multiple genetic and environmental components. Whereas classical Mendelian diseases are generally caused by specific and relatively rare mutations, complex diseases result principally from genetic variations relatively common in the general population and, importantly, involving multiple genes, each contributing an effect of varying magnitude.

Several approaches are available to detect specific genetic associations in complex

Familial sarcoidosis and familial genetic studies

Familial clustering of disease has been reported in several sarcoidosis populations. It was first reported in 2 German sisters in 1923, and, since then, studies on various populations have identified 2.7% to 17% of index case patients as having another family member who is affected.10, 11, 12 ACCESS (A Case-Control Etiologic Study of Sarcoidosis) estimated sarcoidosis familial relative risk in 10,862 first-degree and 17,047 second-degree relatives of 706 case patients and control subjects who

Major histocompatibility complex genes

The human MHC is located on chromosome 6p21 and is composed of 3 classes: MHC classes I, II, and III. Major histocompatibility complex class I mainly includes the HLA-A, HLA-B, and HLA-C genes; MHC class II, the HLA-DR, HLA-DQ, and HLA-DP subclasses. The MHC class III region is located between classes I and II and contains genes encoding for tumor necrosis factor (TNF)-α, TNF-β, the complement proteins (C4A, C4B, C2, and Bf), enzymes involved in steroid synthesis (CYP21A and CYP21B), and heat

Conclusions

In the literature on sarcoidosis genetics, case-control association studies have often reported conflicting results because of sampling methodology (e.g., population stratification, small sample size, and patient misclassification) and, probably, transethnic differences in disease mechanisms. In contrast, there has emerged a striking consistency in the HLA associations that have been reproduced across populations of different ethnicities. Tighter phenotype definition, larger cohorts of

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