Elsevier

Clinics in Chest Medicine

Volume 18, Issue 4, 1 December 1997, Pages 707-717
Clinics in Chest Medicine

GENETICS OF SARCOIDOSIS

https://doi.org/10.1016/S0272-5231(05)70414-7Get rights and content

Nearly all diseases can be thought of as occurring in response to an interaction between environmental and genetic factors. For sarcoidosis, although the environmental factors remain unknown, evidence exists to support a genetic predisposition. Sarcoidosis incidence varies among different ethnic groups,8, 18, 57 for example. It is three times more common in the Irish living in London than in native Londoners, and eight times more common in natives of Martinique living in France than the indigenous French population.30 In the United States, African-Americans are 457 to 1753 times more commonly affected with sarcoidosis than whites. Although environmental risk factors may vary by race, it is likely that the racial variation in sarcoidosis incidence, in part, is attributable to genetic factors.

The strongest support for a hereditary susceptibility to sarcoidosis comes from observing familial clustering of the disease. Families with two or more members affected with sarcoidosis are more common than expected from the low incidence of sarcoidosis in the population.23, 57, 58 And when sarcoidosis has been observed in twins, monozygotic twins are two to four times more concordant for disease than dizygotic twins.58

Although much work remains to be done to define the genetic epidemiology of sarcoidosis, this article reviews what is currently known and summarizes the methods that can be used to study the role of hereditary risk factors in 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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    Address reprint requests to Michael C. Iannuzzi, MD Pulmonary and Critical Care Medicine Henry Ford Health System 2799 West Grand Blvd. Detroit, MI 48202

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