IFN-λ4 increases the risk of gastrointestinal infections and malaria in Malian children

Genetic polymorphisms within the IFNL3 / IFNL4 genomic region encoding type III interferons have been strongly associated with impaired clearance of hepatitis C virus (HCV) infection. We hypothesized that this association might extend to the immune response to other pathogens as well. In a cohort of 914 Malian children enrolled at birth, we analyzed episodes of malaria, gastrointestinal and respiratory infections in relation to two genetic polymorphisms functionally affecting type III interferons - rs368234815 (IFN-λ4) and rs4803217 (IFN-λ3), using information for 30,626 clinic visits from birth through 1-5 years of follow-up. Compared to children with the rs368234815-TT/TT genotype (IFN-λ4-Null), each copy of the rs368234815-dG allele was associated with an earlier first episode of a gastrointestinal infection (p=0.004), malaria (p=0.044) or respiratory infection (p=0.045). The risk of ever experiencing an infection during the follow-up was also significantly increased with each copy of the rs368234815-dG allele – for gastrointestinal infections (OR=1.5, 95%CI (1.11-2.03), p=0.0079) and malaria (OR=1.32, 95%CI (1.04-1.68, p=0.022), but not respiratory infections (p=0.58). IFNL4 -rs368234815 and IFNL3 -rs4803217 were in moderate linkage disequilibrium in this population (r 2 =0.78). All the associations for rs4803217 were weaker and lost significance after adjusting for rs368234815, implicating IFN-λ4 and not IFN-λ3 as the primary cause of these associations. Thus, our results suggest the role of IFN-λ4 in several infections in young children.