IFN-λ4 Genetic Variants Influence Clinical Malaria Episodes in A Cohort of Kenyan Children

Abstract

Background: Interferon (IFN)- λ4, a type III IFN, production is controlled by a dinucleotide frameshift variant (rs368234815-dG/TT) within the first exon of the IFNL4 gene. Carriers of the IFNL4-dG allele but not the IFNL4-TT allele are able to produce the IFN-λ4 protein. Patients with hepatitis C virus that do not produce the IFN-λ4 protein have higher rates of viral clearance suggesting a potential inhibitory role of IFN-λ4 in liver-tropic infections.Methods: In this study, we investigated whether children infected with Plasmodium falciparum, which has a well-characterized liver stage infection, would be more susceptible to clinical malaria relative to their IFNL4- rs368234815 allele. We analyzed a cohort of 122 children from a malaria holoendemic region of Kenya. Episodes of clinical malaria and upper respiratory tract infections (URTIs) were determined using information collected from birth to two years of age. The dinucleotide frameshift variant IFNL4-rs368234815-dG/TT was genotyped using a TaqMan assay.Results: In this cohort, we found that 33% had the dG/dG genotype, 45 % had the dG/TT genotype, and 22% had TT/TT genotype. We evaluated the number and time to first episode of clinical malaria and URTIs with respect to the IFNL4-rs368234815 allele. We found that children that carried the IFNL4-rs368234815-dG allele had an increased number of clinical malaria episodes. In addition, there was a significant association between earlier age of first malaria infection with carriers of the IFNL4-dG allele (p-value: 0.021).Conclusion: Our results suggest that the ability to produce IFN-λ4 negatively affects host immune protection against P. falciparum malaria in Kenyan children.Classification: Immunology, Microbiology, Genetics