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

Mostafa Metwally ,Susan Lester,Lorenzo Beretta,Kathleen Tymms,Gene Siew Ngian ,Susanna Proudman,Pravin Hissaria,Nicholas Manolios,Jane Zochling,Gemma Strickland,Christopher Liddle,Khaled Thabet,Jenny Walker ,Janet Roddy,Jacob George,Mandana Nikpour,Joanne Sahhar,Wendy Stevens,Maureen Rischmueller,Ali Bayoumi,Olfat Shaker ,Mohammed Eslam

doi:10.1038/s41598-019-50709-9

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.

Highlights

Fibrosis across different organs and tissues is likely to share common pathophysiological mechanisms and pathways
We and others recently reported that single nucleotide polymorphisms (SNPs) in the interferon lambda (IFNL, a type III interferon) 3 region originally discovered through genome-wide association studies (GWAS) as a predictor of hepatitis C virus (HCV) clearance, are a strong predictor of the risk for fibrosis risk across multiple liver diseases[4,5,6]
The genotype distribution of IFNL3 rs12979860 conformed to Hardy-Weinberg equilibrium and the minor allele frequency (MAF) was 0.316, similar to that observed in a healthy Caucasian population from the 1000 genome project

Summary

Introduction

Fibrosis across different organs and tissues is likely to share common pathophysiological mechanisms and pathways. 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). Despite contributing up to 45% of deaths in the developed world, fibrotic diseases have largely been overlooked from the perspective of a shared phenotype[1] In this regard, organs such as lung, liver, skin, and kidney, while possessing unique tissue-specific fibrosis features, are likely to share common core and regulatory pathways. We evaluated whether there is a link between IFNL3 variants and the risk of skin and pulmonary fibrosis in a large cohort of Caucasian patients with SSc. Functionally, IFNλ-3 levels according to lung fibrosis were evaluated in human and mice

Methods

Results

Conclusion