IFNL3 genotype is associated with pulmonary fibrosis in patients with systemic sclerosis

Abstract

Fibrosis across different organs and tissues is likely to share common pathophysiological mechanisms and pathways. Recently, a polymorphism (rs12979860) near the interferon lambda gene (IFNL3) was shown to be associated with fibrosis in liver across multiple disease etiologies. We determined whether this variant is a risk factor for pulmonary fibrosis (PF) and worsening cutaneous fibrosis in systemic sclerosis (SSc). Caucasian patients with SSc (n = 733) were genotyped to test for association with the presence of PF and worsening of skin fibrosis. Serum IFN-λ3 levels from 200 SSc cases were evaluated. An association of the IFNL3 polymorphism with PF was demonstrated (OR: 1.66 (95% CI: 1.142–2.416, p = 0.008). The IFNL3 variant was not a risk factor for worsening of skin fibrosis. Functionally, IFN-λ3 serum levels were higher among subjects with PF compared to those unaffected (P < 0.0001). 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.

Monocytes differentiated into macrophages and dendritic cells in the presence of human IFN-λ3 or IFN-λ4 show distinct phenotypes

“…IFN-4 has been studied as an antiviral cytokine [1][2][3][4][5][6][7] ; however, the genetic association of the dinucleotide polymorphism rs368234815, which is responsible for IFN-4 expression, extends beyond viral infections, including several inflammatory disorders, [15][16][17][18][19][20][21][22] and even parasitic infections 27 and cancer. [28][29][30] Two SNPs are known to poten-tially regulate the expression of IFN-3 46,47 and it is not clear in many of the genetic associations which among IFN-3 and IFN-4 could be the causal factor.…”

Interferon lambda in inflammation and autoimmune rheumatic diseases

“…Concentrations of IFNλs are highest in patients with SSc who have muscle involvement and correlate positively with concentrations of IFNγ, suggesting that IFNλs might interact with other cytokine networks to amplify pathogenicity in SSc. Notably, the rs12979860 variant of IFNL3 is associated with an increased risk of pulmonary fibrosis in SSc 97 , whereas no associations have been reported between this variant and skin fibrosis. Serum IFNλ3 concentrations are also higher in patients with SSc who have pulmonary fibrosis than in those patients with SSc who do not develop this complication, and Ifnl3 transcripts are increased in lung tissue in a mouse model of pulmonary fibrosis 97 .…”

Similarities between the effect of SARS-CoV-2 and HCV on the cellular level, and the possible role of ion channels in COVID19 progression: a review of potential targets for diagnosis and treatment

“…The levels of IFNL3 – a subset of the IFN-λ class of cytokines – in the blood can be a potential diagnostic marker for SARS-CoV-2. INFL3 is known to be a hallmark of the clearance of HCV infection and a predictor for the risk of developing fibrosis of the liver due to different hepatic diseases such chronic liver fibrosis and CF [ 42 ]. At the onset, IFNL3 possesses anti-tumorigenic and immune-modulatory effects and is primarily triggered by viral infections [ 43 ].…”

“…Importantly, the relationship between IFNL3 polymorphisms and circulating IFNL3 levels is dependent on the type of disease [ 43 ]. For instance, the levels of IFNL3 in serum have been found to be high in subjects with pulmonary fibrosis, resulting in the conclusion that this may be linked to both liver fibrosis and pulmonary fibrosis [ 42 ].…”