Genetics of sarcoidosis
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
References (80)
- et al.
Genetics of sarcoidosis
Clin Chest Med
(1997) - et al.
HLA-DRB1*1101: a significant risk factor for sarcoidosis in blacks and whites
Am J Hum Genet
(2003) - et al.
Familial sarcoidosis in Finland and Hokkaido, Japan—a comparative study
Respir Med
(1999) - et al.
The BTNL2 gene and sarcoidosis susceptibility in African Americans and whites
Am J Hum Genet
(2005) - et al.
HLA and sarcoidosis in the Japanese
Chest
(1989) - et al.
Severe pulmonary sarcoidosis is strongly associated with the haplotype HLA-DQB1*0602–DRB1*150101
Hum Immunol
(2005) Vitamin D, calcium, and sarcoidosis
Chest
(1996)- et al.
Genetic polymorphisms of the major histocompatibility complex–encoded antigen-processing genes TAP and LMP in sarcoidosis
Hum Immunol
(1996) - et al.
Tumour necrosis factor alpha promoter gene polymorphism in sarcoidosis
Cytokine
(1997) - et al.
The influence of T cell receptor and cytokine genes on sarcoidosis susceptibility in African Americans
Hum Immunol
(1999)
Sarcoidosis
N Engl J Med
Statement on sarcoidosis
Am J Respir Crit Care Med
The importance of sarcoidosis genotype to lung phenotype
Am J Respir Cell Mol Biol
The bilateral hilar lymphoma syndrome; a study of the relation to tuberculosis and sarcoidosis in 212 cases
Acta Med Scand
HLA-DPB1 glutamate 69: a genetic marker of beryllium disease
Science
Familial aggregation of sarcoidosis. A Case-Control Etiologic Study of Sarcoidosis (ACCESS)
Am J Respir Crit Care Med
Interstitial lung diseases: an epidemiological overview
Eur Respir J Suppl
Familial risk ratio of sarcoidosis in African-American sibs and parents
Am J Epidemiol
Epidemiology of familial sarcoidosis in the UK
Thorax
Familial sarcoidosis is linked to the major histocompatibility complex region
Am J Respir Crit Care Med
Results from a genome-wide search for predisposing genes in sarcoidosis
Am J Respir Crit Care Med
Sarcoidosis is associated with a truncating splice site mutation in BTNL2
Nat Genet
BTL-II: a polymorphic locus with homology to the butyrophilin gene family, located at the border of the major histocompatibility complex class II and class III regions in human and mouse
Immunogenetics
Genetics of susceptibility to human infectious disease
Nat Rev Gene
HLA and sarcoidosis: new pathogenetic insights
Sarcoidosis Vasc Diffuse Lung Dis
Sarcoidosis: genes and microbes—soil or seed?
Sarcoidosis Vasc Diffuse Lung Dis
Increased HLA-B7 antigen frequency in South Carolina blacks in association with sarcoidosis
Transplant Proc
Association of HLA B8 with spontaneous resolution in sarcoidosis
Thorax
HLA-B8 in sarcoidosis
Ann Allergy
HLA-B8/DR3 in sarcoidosis. Correlation to acute onset disease with arthritis
Tissue Antigens
HLA-B8 and erythema nodosum
Can Med Assoc J
HLA associations in sarcoidosis: a study of two ethnic groups
Thorax
Histologic findings in siblings with acute sarcoid arthritis: association with the B8, DR3 phenotype
J Rheumatol
Class II MHC antigen (HLA-DR3) predisposes to sarcoid arthritis
J Clin Lab Immunol
Human leukocyte antigen class I alleles and the disease course in sarcoidosis patients
Am J Respir Crit Care Med
HLA-DQB1*0201: a marker for good prognosis in British and Dutch patients with sarcoidosis
Am J Respir Cell Mol Biol
HLA class II genotyping of sarcoidosis patients in Hokkaido by PCR-RFLP
Jpn J Ophthalmol
HLA serological and class II genotyping in sarcoidosis patients in Japan
Jpn J Ophthalmol
Genetic aspects of sarcoidosis. Class II histocompatibility antigens and a family study
Arch Intern Med
TNF-alpha and HLA-DR genotyping as potential prognostic markers in pulmonary sarcoidosis
Eur Cytokine Netw
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