This mutation is also associated with higher-than-normal levels of TGF-β1, an anti-inflammatory molecule, a finding that requires more study, its researchers noted.
The study, “The rs3761548 FOXP3 variant is associated with multiple sclerosis and transforming growth factor β1 levels in female patients,” was published in the journal Inflammation Research.
MS is caused by a combination of genetic and environmental factors. Mutations in about 200 genes, most of them related to the immune response, have been associated with an increased risk of developing MS.
Some of these mutations are located in the FOXP3 gene, which is key for the development and proper function of immune Tregs. Tregs are a subset of immune T-cells that regulate other T-cells, stopping them from attacking the body’s own tissues while maintaining an adequate immune response against harmful intruders.
A variation of a single nucleotide (the building blocks of DNA) in a specific region of the FOXP3 gene — called the rs3761548 polymorphism — has been linked to lower levels of FOXP3, and a greater risk of MS among people in Iran. This mutation was reported to be in one or both copies of the FOXP3 gene.
No such association, however, was found for the Polish population.
“It is well known that ethnicity influences the presence of variants in various genes, which may cause controversial results in different populations, that is why is important to survey this association in different ethnicities,” the researchers wrote.
They have now confirmed a statistically significant link between this FOXP3 mutation and a heightened risk of developing MS in women in Brazil.
They analyzed the genetic and clinical data of 170 MS patients (121 women and 49 men) in a remission phase (no relapse episodes within the three months prior to study enrollment), and 182 age- and gender-matched healthy people in southern Brazil.
Patients’ disability was assessed through the Expanded Disability Status Scale (EDSS), while disability progression was measured by the Multiple Sclerosis Severity Score (MSSS) — with scores above five being classified as a faster progression.
Patients had a median age of 32 at diagnosis, and had the disease for a median of six years. A total of 146 had relapsing-remitting MS, 19 had secondary progressive MS, and five had primary progressive MS.
Results showed that a significantly higher proportion of women with MS carried this FOXP3 mutation than did healthy women, and the mutation’s presence doubled the risk of MS.
This association was also found for all genetic models: the co-dominant model (where the increasing number of mutated gene copies, from zero to two, increase the mutation’s effect), the dominant model (where one mutated copy is sufficient to cause disease), and the recessive model (where the mutation’s effect — MS — takes place only when the mutation is present in both gene copies).
These associations, only found for women, remained significant after adjusting data for age, ethnicity, body mass index (BMI), and smoking habits.
However, the presence of this mutation was not linked to greater MS disability or faster disease progression among MS patients of either gender.
“These data suggest that [this FOXP3 mutation] may be associated with the quantitative or functional alteration of Treg cells, which could be one of the factors involved in susceptibility to MS in females,” the researchers wrote.
They also found that MS patients had significantly higher levels of TGF-β1 and IL-10 — two anti-inflammatory molecules — than did healthy people. Women with MS carrying the FOXP3 mutation also showed higher levels of TGF-β1 than those without it.
Researchers hypothesized that raised levels of TGF-β1 and IL-10 may reflect the body’s anti-inflammatory response as it tries to counteract the inflammatory processes associated with MS.
They emphasized that future studies are needed to better understand the complex interaction between FOXP3 mutations, TGF-β1 levels, and MS development.