Analysis of Common Infections in Malian Children Under Five: IFNL4-dG Allele Is Associated with Higher Risk and Earlier Episodes of Gastrointestinal Infections

Background: Genetic polymorphisms within the IFNL3 / IFNL4 genomic region, which encodes type III interferons, have been strongly associated with impaired clearance of hepatitis C virus (HCV) infection. We hypothesized that type III interferons might be important for the immune response to other pathogens as well. Methods: In a cohort of 914 Malian children, we analyzed episodes of malaria, gastrointestinal and respiratory infections using information for 30,626 clinic visits from birth through 1-5 years of follow-up. Genetic polymorphisms IFNL4 -rs368234815 and IFNL3-rs4803217 that functionally affect type III interferons were genotyped with TaqMan assays. For both genetic variants and each infection, we evaluated time-to-first episode and calculated odds ratios (ORs) for the risk of an infection episode during follow-up. Results: 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=0.003) and respiratory infection (p=0.045). The risk of experiencing an infection episode during the follow-up was also significantly increased with each copy of the rs368234815-dG allele – for gastrointestinal infections (OR=1.53, 95%CI (1.13-2.07), p=0.005) and malaria (OR=1.30, 95%CI (1.02-1.65), p=0.033). IFNL4 -rs368234815 and IFNL3 -rs4803217 were in moderate linkage disequilibrium in this population (r2 =0.78), and 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. Interpretation: Our results provide support for the role of IFN-λ4 in common gastrointestinal infections, and possibly in other infections as well.Trial Registration: NCT01168271Funding Statement: The study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute (NCI), the Intramural Research Program, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, US Department of Health and Human Services.Declaration of Interests: L.P.-O. is a co-inventor on IFN-λ4-related patents issued to NCI/NIH, and receives royalties for monoclonal antibodies for IFN-λ4 detection. Other authors have no conflict of interest to declare.Ethics Approval Statement: The protocol and study procedures were approved by the institutional review board of the National Institute of Allergy and Infectious Diseases (NIAID) at the US National Institutes of Health (ClinicalTrials.gov ID NCT01168271), and the Ethics Committee of the Faculty of Medicine, Pharmacy and Dentistry at the University of Bamako, Mali.