GENETICS OF SARCOIDOSIS
Section snippets
FAMILIAL AGGREGATION IN SARCOIDOSIS
Familial sarcoidosis was first noted in Germany in 1923 by Martenstein, who reported two affected sisters.39 Although several cases were then noted across Europe, familial sarcoidosis was not reported in the United States until 1947, when Robinson and Hahn reported two sets of brothers.55 The British Thoracic and Tuberculosis Association (BTTA), which conducted a survey of its members, reported 59 families with a total of 121 cases of sarcoidosis.58
Since the BTTA report, over 400 kindreds have
RISK IN FAMILIES
Increased disease risk in relatives of sarcoidosis patients can be attributable to shared environment and genes. If polygenic inheritance is the major reason for the increased risk, then, according to quantitative genetics theory, the risk of disease to family members should vary on a continuum. If different etiologic subsets of disease exist, such as one with a greater genetic or one with a greater environmental component, then one might expect heterogeneity in risk among families. We tested
DISEASE TRANSMISSION IN FAMILIES
Segregation analysis provides an analytic method to test different models of disease inheritance in families, including both genetic and nongenetic models of inheritance, and to determine which best explains the disease distribution in families. Although an adequate fit to a genetic model does not prove that a disease is under genetic control, it does offer strong statistical support for a major gene effect.
Breast cancer and diabetes offer two examples in which segregation analysis helped
PERSON-TO-PERSON TRANSMISSION OF SARCOIDOSIS—ISLE OF MAN STUDIES
An epidemiologic investigation using a cluster analysis on the Isle of Man found a time–space association with sarcoidosis incidence.25, 47 The authors concluded that the major causative factor in sarcoidosis is communicable. A few points regarding the Isle of Man study should be considered, however: First, there was a lack of spouse pairs among the 49 patient–patient contacts identified and, more notably, nine pairs of patients were blood related. There also was a greater-than-expected
HUMAN LEUKOCYTE ANTIGEN ASSOCIATIONS
Because the pathophysiology of sarcoidosis likely involves antigen recognition, processing, and presentation, investigators have searched for associations with HLA-related genes9, 21, 28, 35, 36, 37, 40, 44, 45, 46, 65, 73 (Table 3). Although no consistent association has been found, the most common allele found associated with sarcoidosis has been HLA-B8,9, 37, 40, 46, 65 with relative risks between 2.18 and 4.39. The only HLA study of African-Americans showed no significant association
THE GENETICS OF OTHER GRANULOMATOUS DISEASES
Familial clustering of leprosy and tuberculosis in endemic areas, the apparent influence of ethnic factors on the incidence of mycobacterial infection and survival, and twin studies support that resistance to mycobacterial infections is genetically controlled.60, 61, 63 Leprosy also provides an example of individual differences in granulomatous response to a common stimulus that is likely under genetic control.
Three separate segregation analyses have given evidence for genetic susceptibility to
GENETIC EPIDEMIOLOGIC APPROACH TO SARCOIDOSIS
Does sarcoidosis have a genetic cause? To address that question, study populations should be large enough to stratify patients according to phenotype and, preferably, large enough to identify families with multiple affected members. Genetic studies in the United States should also focus on African-Americans, who are more commonly53, 57 and severely17, 29, 78 affected and who are more likely to have a positive family history.23 We next briefly review the methods that can be used to study the
CANDIDATE GENES FOR SARCOIDOSIS
The next step after identifying a candidate gene is to describe its function as it relates to the disease process. Although it is entirely possible that one or more putative sarcoidosis susceptibility genes are presently unknown, it is also possible, given the large number of functional genes already identified, that the sarcoidosis susceptibility gene or genes are known, but their relationship to the sarcoidosis disease process has not been described. If one considers the pathophysiology of
DISEASE PHENOTYPING
In our discussion of breast cancer and diabetes, we noted that stratifying patients according to phenotype yields results that would have been missed otherwise. We also noted that for leprosy, the genetic mechanism found depended upon how the phenotype was defined. Because sarcoidosis is a clinically heterogeneous disorder, considering how patients should be phenotyped will likely be important for genetic analysis. The supposition is that genetic heterogeneity may underlie the varied different
SUMMARY
Hereditary susceptibility to sarcoidosis is suggested by ethnic preponderance, familial clustering, and multigenerational involvement. The genetics of sarcoidosis cannot be adequately addressed in small samples of patients; a large-scale study with stratification for patient phenotypic differences is necessary.2, 3, 12 A study that uses both genetic marker and environmental data would be able to control for and examine different causative mechanisms. Until such a well-designed, comprehensive
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Cited by (42)
Human leukocyte antigen-A, -B, and -DRB1 alleles and sarcoidosis in Chinese Han subjects
2011, Human ImmunologyCitation Excerpt :Studies on African Americans have reported that HLA-DQB1 and not HLA-DRB1 plays an important role in sarcoidosis susceptibility [11]; HLA-DQB1*0201 and HLA-DQB1*0602 especially exhibited stronger associations with sarcoidosis [12]. Adding to the complexity, varying HLA associations have also been reported in sarcoidosis patients in different ethnic groups [13]. In this study, we examined the HLA-A, -B, and -DRB1 alleles in patients with sarcoidosis in an attempt to investigate the association between the polymorphism of HLA genes and sarcoidosis in Chinese Han subjects.
Familial sarcoidosis in Taiwan
2007, Journal of the Formosan Medical AssociationGenetics of sarcoidosis
2007, Clinics in DermatologyCitation Excerpt :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.
Human leukocyte antigens A and B in Turkish patients with sarcoidosis
2004, Archivos de BronconeumologiaImmunopathology of the noninfectious posterior and intermediate uveitides
2001, Survey of OphthalmologyClinical insights and basic science correlates in sarcoidosis
2001, American Journal of the Medical SciencesCitation Excerpt :It is often stated that concordance for sarcoidosis status is higher among monozygotic than dizygotic twins, but this is based upon the relative number of case reports of twins with sarcoidosis in the literature rather than upon large population-based surveys.63,64,66,67 A number of authors have suggested that some of the clusters of sarcoidosis cases that have been invoked in support of an infectious etiology may in whole or in part reflect familial clustering of the disease.63 For example, in the Isle of Man studies, very few new cases of sarcoidosis developed among the spouses of patients with the disease.
Address reprint requests to Michael C. Iannuzzi, MD Pulmonary and Critical Care Medicine Henry Ford Health System 2799 West Grand Blvd. Detroit, MI 48202