Sarcoidosis is an inflammatory disease defined by the formation of tiny cellular collections called granulomas, which most often affect the lungs and lymph nodes. The precise cause remains unknown, but evidence points to a combination of genetic and environmental factors. In genetically susceptible individuals, the immune system may overreact to triggers like bacteria or viruses, leading to the inflammation that forms granulomas.
Understanding Familial Risk
The appearance of sarcoidosis in multiple members of the same family suggests a genetic component. This pattern, known as familial clustering, indicates that having a close relative with sarcoidosis increases an individual’s chances of developing it. While not a traditional hereditary disease passed through a single gene, genetics play a part in susceptibility. A person with a parent, sibling, or child who has sarcoidosis has a higher likelihood of being diagnosed.
Research quantifies this increased risk. A large study found that having at least one first-degree relative with sarcoidosis is associated with an approximately 3.7-fold increase in risk. The risk climbs to about 4.7 times the average if a person has two or more first-degree relatives with the condition.
A higher relative risk does not mean that developing sarcoidosis is inevitable for family members, as the vast majority of people with a family history will not develop it themselves. This is because genetic makeup is a contributing factor, but not the sole determinant, in the development of the disease.
Key Genes in Sarcoidosis
Genetic research has identified several genes that influence a person’s susceptibility, with much of the focus on the Human Leukocyte Antigen (HLA) region on chromosome 6. These genes produce proteins that help the immune system differentiate between the body’s own cells and foreign invaders.
Specific variations within the HLA gene family, particularly in a gene called HLA-DRB1, are strongly associated with sarcoidosis. Certain alleles of HLA-DRB1 have been linked to an increased risk in various populations. These genetic variants appear to modify the immune response, making it more prone to the overreaction that leads to granuloma formation.
Another gene located near the HLA region, Butyrophilin-like 2 (BTNL2), has also been identified as a potential risk factor. A specific polymorphism within the BTNL2 gene has been suggested to predispose individuals to sarcoidosis by influencing T-cell activation. The close proximity of BTNL2 to HLA-DRB1 has made it challenging for researchers to determine if its effect is independent or linked to the HLA genes.
Gene-Environment Interaction
Not everyone with a genetic predisposition develops sarcoidosis, which points to the involvement of other factors. Researchers believe the disease arises from an interplay between genetic makeup and environmental triggers. This concept suggests both a genetic susceptibility and an environmental encounter are necessary for the disease to manifest.
While no single trigger has been proven to cause sarcoidosis, research has highlighted several potential candidates. These include airborne substances such as occupational dusts, molds, and insecticides. Some studies have also explored links to infectious agents, including specific types of bacteria or viruses, as potential initiators.
The interaction can be quite specific. For instance, some research suggests that exposure to insecticides or mold might increase risk primarily in individuals carrying particular HLA-DRB1 variants. This demonstrates how an exposure that is harmless to one person could provoke granuloma formation in someone with a different genetic profile.
Genetic Testing and Counseling
Currently, there is no single genetic test available to diagnose sarcoidosis or to predict whether someone will develop it. Because the disease involves multiple genes that only confer a predisposition, genetic testing is not used for routine diagnosis or screening in the general population.
Genetic testing for variants like those in HLA-DRB1 is primarily a tool for research, helping scientists better understand the disease’s mechanisms. While some specific HLA types are associated with certain disease courses, such as a higher likelihood of the condition resolving on its own, this information is not yet consistently used to guide clinical practice.
A genetic counselor can be a resource for families with multiple affected members. These professionals help individuals understand familial risk and interpret statistics in a personal context. They can clarify the limitations of genetic science regarding sarcoidosis and explain why a predictive test is not yet feasible. As research continues, this knowledge may one day lead to better risk assessment tools or personalized therapies.