IFNL3 Gene Variant Linked to High Risk of PF in Scleroderma Patients, Study Finds

Joana Carvalho, PhD avatar

by Joana Carvalho, PhD |

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IFNL3 gene variant

A recently discovered variant of the IFNL3 gene increases the risk of pulmonary fibrosis (PF) in people with scleroderma, a study reveals.

In contrast, no such link was found between this variant and worsened skin fibrosis in these patients.

Findings also revealed markedly increased serum levels of the IFNL3 protein in people with scleroderma and PF, suggesting a potential treatment target for both disorders, the scientists said.

Led by researchers at Westmead Hospital at the University of Sydney in Australia, the study, “IFNL3 genotype is associated with pulmonary fibrosis in patients with systemic sclerosis,” was published in the journal Scientific Reports.

Scleroderma, also known as systemic sclerosis (SSc), is characterized by the accumulation of scar tissue (fibrosis) in the skin and internal organs such as the kidneys and lungs.

PF is the leading cause of serious complications among people living with scleroderma. With the availability and development of new treatments for different forms of PF, including that associated with scleroderma, figuring out who is at high risk is key for early intervention and clinical improvement, according to the scientists.

“Genetic variants that might contribute to more severe fibrosis and/or progression could [be used to as risk predictors], as they do not fluctuate over the course of disease and are not time-dependent,” they wrote.

Recent studies found that a genetic variant in the IFNL3 gene (rs12979860) is associated with fibrosis in different liver diseases. This gene provides instructions for making interferon-lambda 3 (IFNL3), a protein with antiviral, antitumor, and immunomodulatory activity. Its receptors can be found in epithelial tissues, including the lungs and liver.

“Thus, it is plausible that genetic variants in the IFNL3 locus could also affect PF risk,” the researchers wrote.

To explore whether this genetic variant could also be associated with PF and an aggravation of skin fibrosis in scleroderma, the investigators performed genetic tests in 733 Caucasian patients with this disease (mean age 59 years, 86% women). All patients participated in the Australian Scleroderma Cohort Study, a multicenter prospective study designed to evaluate risk factors for clinically important outcomes in scleroderma.

A total of 180 patients (24.5%) had PF, and 155 (21.1%) had diffuse scleroderma.

In addition, the team also measured serum levels of IFNL3 in a subgroup of 200 patients.

Results showed the rs12979860 variant was more frequent among those with scleroderma and PF (29%) than in those who did not have PF (21%). Statistical analyses demonstrated this variant was linked to an increased risk of PF, even after accounting for potential differences in age, gender, baseline disease duration, and skin thickness (a marker of disease severity).

In contrast, no associations were found between the variant and an aggravation of skin fibrosis within one year.

Serum IFNL3 protein levels were 10 times higher among scleroderma patients with PF than in those without this disease. Importantly, the researchers noted, this difference remained significant after adjusting for genetic differences in the variant and use of immunosuppressive agents.

Subsequent analysis in a mouse model of PF revealed that, similar to the results in patients, RNA levels of Ifnl3 (generated in protein production) were higher than in control animals.

“In conclusion, IFNL3 serum levels and the genetic variant known to be associated with liver fibrosis are similarly linked to PF, but not to worsening of skin fibrosis in SSc. These data highlight both common fibrosis pathways operating between organs, as well as differential effects within the same disease,” the scientists wrote.

Future studies should focus on better understanding the association between IFNL3 and fibrosis. If confirmed, IFNL3 may be explored as a potential therapeutic target for these disorders, they added.