IFNL3 Genetic Variant Linked to PF, but not to Skin Fibrosis in Patients with Systemic Sclerosis, Study Finds

IFNL3 Genetic Variant Linked to PF, but not to Skin Fibrosis in Patients with Systemic Sclerosis, Study Finds

A genetic variant at the IFNL3 gene is linked to raised levels of IFN-lambda 3 in the blood and is associated with the presence of pulmonary fibrosis in patients with systemic sclerosis, but it does not represent a risk factor for worsening of skin fibrosis in these patients, a study reports.

The study, “IFNL3 genotype is associated with pulmonary fibrosis in patients with systemic sclerosis,” was published in the journal Scientific Reports.

Pulmonary fibrosis (PF), a form of interstitial lung disease that’s marked by progressive scarring of lung tissue, is a leading cause of disease and death in patients with systemic sclerosis, or scleroderma (SSc) — an autoimmune disease characterized by fibrosis in skin and internal organs, immune dysregulation, and blood vessel damage.

As new treatments are being developed, early identification of those at high risk of PF will help with timely interventions, and improve outcomes.

“Unfortunately, reliable predictors of who will develop PF among those with scleroderma are not available,” the researchers wrote.

However, finding genetic risk factors that predispose patients to more severe fibrosis could offer important biomarkers.

Recently, scientists found that a common genetic variant — called rs12979860 CC — located in the genome near the IFNL3 (interferon lambda 3) gene, is a strong predictor of fibrosis risk across multiple liver diseases.

IFNL3 gives instructions for the production of a signaling molecule (cytokine), called IFN-lambda 3, which is crucial for immune responses against viruses and tumors, and for the modulation of immune system activities.

In prior studies, IFN-lambda 3 was the cytokine found to mediate IFNL3 genetic risk of liver inflammation and fibrosis. Part of the team involved in the discovery believed this genetic variant could also be a risk factor for PF, and worsening skin fibrosis in people with SSc, based on the idea that fibrosis shares common mechanisms, regardless of the organs affected.

To determine if this was the case, researchers genetically tested 733 Caucasian patients with SSc, and looked for associations with PF and skin fibrosis.

Results showed that the IFNL3 variant rs12979860 CC, which was previously associated with liver fibrosis, was present at a significantly higher frequency in SSc patients with PF (29%) than those without PF (21%), regardless of age, gender, disease duration, and baseline severity of skin symptoms of SSc.

However, additional analysis showed no association between IFNL3 variants and the degree of skin fibrosis in patients within one year of study enrollment. This indicated that “the IFNL3 variant was not a risk factor for worsening of skin fibrosis,” the researchers wrote.

To further explore the potential role of IFNL3 variants, they measured the serum levels of IFN-lambda 3 in 200 of the SSc patients.

Consistent with what was reported for liver fibrosis in previous studies, blood levels of IFN-lambda 3 were higher — 10 times as high — among subjects with PF, compared with those unaffected by PF. Importantly, patient carriers of the risk variant rs12979860 CC had greater levels of IFN-lambda 3, compared with carriers of other genetic variants.

“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,” the researchers wrote. “These data highlight both common fibrosis pathways operating between organs, as well as differential effects within the same disease.”

“The functional mechanisms for the pro-fibrotic effects of IFNL3 will require further investigation and if confirmed, can be exploited as a potentially more effective therapeutic target,” they added.

Ana is a molecular biologist with a passion for discovery and communication. As a science writer she looks for connecting the public, in particular patient and healthcare communities, with clear and quality information about the latest medical advances. Ana holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in genetics, molecular biology, and infectious diseases
Total Posts: 110
Patrícia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.
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Ana is a molecular biologist with a passion for discovery and communication. As a science writer she looks for connecting the public, in particular patient and healthcare communities, with clear and quality information about the latest medical advances. Ana holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in genetics, molecular biology, and infectious diseases
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