Evidence for a sex-dependent effect modification in the association between IFN-λ DNA polymorphisms and expression of IFN-λ and interferon-stimulated genes in human PBMCs

Abstract

Human interferon (IFN) lambda (IFNL, IFN-L or IFN-λ) locus has several functional genetic variants but their role in regulating in vivo gene expression, and whether they associate with antiviral states in healthy individuals, is not clear. In this study, we recruited ∼550 healthy individuals belonging to both sexes, genotyped them for several IFNL genetic variants and measured, by qPCR, the expression of IFNL2/3, IFNL4 and four IFN-stimulated genes (ISGs) (MX1, OAS1, ISG15 and RSAD2) from their peripheral blood mononuclear cells (PBMC) both before and after stimulation with a viral mimic, poly I: C. We also measured secreted levels of several cytokines including IFN-λ1 and IFN-λ3 in poly I:C stimulated PBMCs. We found that males secrete higher levels of IFN-λs than females. The IFNL3/4 genetic variants significantly associated with secreted levels of both IFN-λ1 and IFN-λ3 in opposite directions, only in males. While the IFNL3/4 variants significantly associated with ISG expression either in basal or poly I:C induced or in both states, the direction of effect was opposite for the two sexes, suggesting that sex was a strong effect modifier. We did not see this trend in the association of ISG expression with the IFNL1 polymorphism, rs7247086, whose association with ISG expression and secreted IFN-λ3 levels was seen in females but not in males. Further, expression of several genes was associated with the IFN-λ4 activity-modifying variant rs117648444. However, we neither saw any strong correlation between levels of IFN-λ1/3 and ISG expression, nor did we see any strong evidence of IFNL4 expression that could be responsible for the association between ISG expression and IFNL genetic variants. These results suggest that there are complex interactions involving gender, IFN-λs, IFN-λ genetic variants and antiviral states in humans.