A G908R mutation in the NOD2 gene is an indicator of familial sarcoidosis, according to a French study. When present in combination with IL17RA, EPHA2, and KALRN gene variants, it influences disease progression, researchers reported.
Genetics plays an important role in the exaggerated immune response and formation of granulomas (clusters of cells that induce inflammation) observed in sarcoidosis.
The NOD2 protein is a key player in the body’s response to bacterial infections. It triggers an immune response that sends inflammatory cells to the site of injury or disease to clear the infection. Mutations in the NOD2 gene have been associated with inherited sarcoidosis, but no confirmed cases have been reported.
Now, a large French study on familial sarcoidosis called SARCFAM (NCT02829853) identified one patient with a specific mutation — G908R — in the NOD2 gene. This variant has also been reported to be associated with inflammation of the digestive tract, or Crohn’s disease.
The team searched for mutations in members of the patient’s family with clinical symptoms of sarcoidosis, and compared the results with family members not affected by sarcoidosis, and also with healthy individuals (controls).
A total of four family members with sarcoidosis, two unaffected family members, and four unrelated healthy controls were analyzed.
Using targeted exome sequencing — a technique that reads protein-coding DNA at a specified location in chromosomes — the researchers identified the G908R mutation in NOD2 in three of the four family members with sarcoidosis.
They also found the same variant in one of the two unaffected family members. None of the healthy controls had this mutation.
Since one of the unaffected family members also carried the NOD2 G908R variant, researchers searched for mutations in other regions of the chromosome that could differentiate the unaffected family members from those with sarcoidosis.
They used whole exome sequencing (WES), which provides information on the DNA that codes for proteins in the entire genome.
WES identified new mutations called single nucleotide polymorphisms, or SNPs, in three immune system-related genes: IL17RA, KALRN, and EPHA2. These variants were only found in family members with sarcoidosis.
NOD2 regulates the immune system through a protein called NF-kB, which in turn controls the levels of proinflammatory molecules like interleukin-8 (IL-8) and tumor necrosis factor-A (TNF-A).
To assess the influence of the NOD2 mutation on its ability to regulate the immune system, researchers evaluated the levels of the NF-kB protein, IL-8, and TNF-A in blood from the participants.
Results showed that NF-kB levels were lower in family members affected by sarcoidosis, compared to unaffected family members and healthy controls.
However, higher levels of IL-8 and TNF-A in family members with sarcoidosis were observed. The increased levels of IL-8 and TNF-A explain the chronic state of inflammation associated with the condition, the researchers suggested.
“For the first time in the literature, we described the presence of the NOD2 [G908R] variant in a case of familial sarcoidosis,” researchers wrote.
“Our finding further establishes that the NOD2 [G908R] variant in combination with variants for IL17RA, EPHA2, and KALRN genes could play a significant role in the development of sarcoidosis,” they added.