Genes that have been linked to the likelihood of developing sarcoidosis may not necessarily be associated with disease course, according to a study conducted in Portugal, which also points to other genes that may help to predict a patient’s outcome.
Susceptibility to, and clinical manifestations of, sarcoidosis are highly variable, possibly due to changes in different genes that affect several processes related to inflammation and the immune system.
The HLA (class I and II) genes were the first to be consistently associated with sarcoidosis, but other studies have identified changes in the coding sequence of certain other genes — changes that are called polymorphisms — as being associated with the development of sarcoidosis.
These genes are BTNL2 and ANXA11 and, together with the HLA genes, they encode proteins of the immune system and inflammatory pathways. Changes in these genes may, therefore, cause dysfunctional proteins that affect the regulation of these processes, leading to disease onset. But researchers are uncertain whether polymorphisms alone are responsible for sarcoidosis onset, or whether the disease might be caused by gene-gene interactions of these known polymorphisms.
Researchers obtained DNA from blood samples of 138 unrelated Portuguese sarcoidosis patients (mean age of 37.2 years) and looked for the presence of the known polymorphisms for the BTNL2 and ANXA11 genes (BTNL2 rs2076530 and ANXA11 rs1049550). The team also analyzed HLA class I/II genes.
After a follow-up period, 66 patients showed improvement (disappearance of symptoms and normalization of chest radiographs and lung function), whereas 72 (52 percent) developed chronic sarcoidosis (defined as disease that persisted after two years). Comparison of rs1049550 and rs2076530 polymorphism frequencies showed no significant differences among patients. One form of an HLA gene (HLA DRB1*03), however, was found in significant numbers of patients who experienced improvement, consistent with previous studies reporting that DRB1*03 is a marker of good prognosis in sarcoidosis patients.
Moreover, when potential interactions between the polymorphisms were explored, DRB1*03 remained the only significant factor for disease course, with no statistically significant interactions between the HLA genes and the two polymorphisms analyzed for BTNL2 and ANXA11.
“[T]he presence of HLA-DRB1*03 in a Portuguese population was an accurate marker of favorable disease course in patients with sarcoidosis, with no additional influence exerted by the susceptibility [polymorphisms] of BTNL2 and ANXA11 genes,” the researchers concluded.
These results indicate that genes thought to influence sarcoidosis susceptibility are not necessarily associated with its clinical course, whereas other genes may serve as good biomarkers for disease outcome.