FLI1 Gene Variant Linked to Increased Scleroderma Risk, Greater Skin Thickness in Study

Long stretches of DNA repeats in the FLI1 gene — which gives instructions for a protein that controls the activity of genes — are linked to an increased risk for scleroderma and with greater skin thickness in people with the disorder, a study suggests.

Titled “Association of functional (GA) n microsatellite polymorphism in the FLI1 gene with susceptibility to human systemic sclerosis,” the study was published in the journal Rheumatology.

Genome-wide association studies (GWAS) — an approach for finding genetic variations linked to a particular disease — have enabled researchers to pinpoint genes that may contribute to the risk of developing scleroderma. However, most such genes are not exclusively associated with scleroderma and the processes that lead to fibrosis (scarring) and blood vessel damage in these patients.

Studies with mouse models suggested that a deficiency in the activity of the FLI1 gene was a potential risk factor for scleroderma. Notably, people with this disorder have lower production of the FLI1 protein in skin lesions, indicating that it suppresses the overproduction of collagen that results in scarring. However, whether FLI1 is associated with scleroderma still requires more studies.

“We wanted to specifically go after FLI1 that has been shown to be produced to a lesser extent in the lesional skin of systemic sclerosis [scleroderma] patients. We thought that downregulation of FLI1 may be a trigger for systemic sclerosis,” Naoyuki Tsuchiya, professor at the University of Tsukuba, in Japan, and the study’s senior author, said in a press release.

The human FLI1 gene was previously shown to carry long stretches of repeated DNA sequences, called microsatellite repeat polymorphisms, composed of two nucleotides known as guanine (G) and adenine (A) — the building blocks of DNA.

“It is known that extended repeats of microsatellites result in reduced FLI1 expression,” Tsuchiya said. “We hypothesized that patients with systemic sclerosis may also have these extended DNA repeats in the FLI1 gene.”

Researchers at the University of Tsukuba and their collaborators analyzed the GA-microsatellite region of FLI1 in DNA samples from 639 Japanese patients with scleroderma and 851 healthy people (controls).

The team found that an FLI1 gene carrying 22 or more GA repeats — called long (L) alleles, or gene copies — was significantly linked with a greater susceptibility for scleroderma, compared with one carrying 21 or fewer GA repeats. The link was significant for both diffuse cutaneous and limited cutaneous disease.

“Our results show an association between GA repeats over 22 in the FLI1 gene and systemic sclerosis,” said Keita Yamashita, the study’s first author.

The clinical features of patients carrying FLI1 L alleles were examined next.

The FLI1 L alleles were found to be significantly enriched in patients with a modified Rodnan skin score (mRSS) over 10. The Rodnan score is a measure of skin thickness; higher mRSS scores are linked with increased thickness.

In addition, when compared with controls, people with scleroderma had lower levels of FLI1 messenger RNA (mRNA), the molecule generated from DNA that contains information to make the FLI1 protein. The healthy controls carrying FLI1 L alleles also had lower FLI1 mRNA levels compared with those carrying fewer GA repeats.

“Our results strongly support that FLI1 may be a genetic factor that could be directly related to the pathogenesis [disease processes] of human SSc [scleroderma] and could possibly partly account for the ‘missing heritability’ in [the disease],” the scientists wrote.

Overall, these findings “show how extended repeat alleles of FLI1 GA microsatellites may affect the expression of FLI1 and the development of systemic sclerosis,” Tsuchiya said. “Our results provide a novel insight into the pathogenesis of systemic sclerosis, as well as into the relevance of microsatellite polymorphisms in human diseases.”