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, it was 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. A cohort of 122 children from a malaria holoendemic region of Kenya was analysed. Episodes of clinical malaria and upper respiratory tract infections (URTIs) were determined using information collected from birth to 2 years of age. The dinucleotide frameshift variant IFNL4-rs368234815-dG/TT was genotyped using a TaqMan assay.

Results: In this cohort, 33% of the study participants had the dG/dG genotype, 45% had the dG/TT genotype, and 22% had TT/TT genotype. The number and time to first episode of clinical malaria and URTIs with respect to the IFNL4-rs368234815 allele was evaluated. It was 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: The results suggest that the ability to produce IFN-λ4 negatively affects host immune protection against P. falciparum malaria in Kenyan children.

Keywords: IFN-λ4; Innate Immunity; Malaria; Plasmodium falciparum; Type III Interferon.

Fig. 1

Sickle cell trait genotype and G6PD allelic determinant stratified by IFNL4 allele. The study subjects were divided into two groups based on presence or absence of an IFNL4-dG allele. Within each group, subjects were further stratified based on carriage of sickle cell trait (SCT) and Glucose-6-Phosphate (G6PD) deficiency. Most of the subjects, 67% for the IFNL4-dG allele group and 55% for the IFNL4-TT/TT genotype group had neither the G6PD deficiency allelic determinant nor were carriers of the sickle cell trait. On the contrary, only 3% of the subjects with the IFNL4-dG allele were both carriers of the sickle cell trait and G6PD deficiency allelic determinant, while the percentage of subjects that had both genes in the IFNL4-TT/TT genotype group was 1%

Fig. 2

Incidence of URTIs and time to first infection in children from the CHAP prospective cohort study. The study subjects were grouped based on presence of a IFNL4-dG allele, dG/dG and dG/TT genotypes (n = 95) and compared with children that did not carry a dG allele, TT/TT genotype (n = 27). a Histograms showing the distribution of URTIs in the study population during the first 2 years of life presented based on IFNL4-rs368234815 polymorphism. The mean number of URTIs and standard deviation (SD) is included. The rate of URTI’s was 11.80% lower for those that had the IFNL4- TT/TT genotype relative to those that had an IFNL4-dG allele after adjusting for the number of visits (95% CI −32.76%, 14.46%; p-value: 0.355). b Kaplan–Meier survival curve showing time to first URTIs based on IFNL4-rs368234815 polymorphism. No significant difference between IFNL4-rs368234815 genotype was found (p-value:0.512)

Fig. 3

Frequency and time to first Malaria episodes in relation to IFNL4-rs368234815 polymorphism. The 122 study subjects were grouped based on presence of a IFNL4-dG allele, dG/dG and dG/TT genotypes (n = 95) and compared with children that did not carry a dG allele, TT/TT genotype (n = 27). a Histograms showing the distribution of malaria episodes in the study population during the first 2 years of life presented based on IFNL4-rs368234815 polymorphism. The mean and standard deviation (SD) of malaria episodes is included. After accounting for the number of visits, cases of malaria were found to be 38.75% lower for those with the IFNL4- TT/TT genotype relative to those that had a IFNL4-dG allele (95% CI −66.70%, 10.14%; p-value: 0.111). b Kaplan–Meier survival curve showing time to first malaria episode based on IFNL4-rs368234815 polymorphism. Earlier timing of the first malaria infection was associated with IFNL4-dG allele (p-value: 0.019) as compared to children with the IFNL4-TT/TT genotype. c Forest plot showing the results of a Cox proportional hazard model that takes into consideration the effect of two genetic traits that are known to be associated with resistance to blood stage malaria infection, G6PDd and sickle cell, on time to first episode. Adjustments for gravidity and maternal malaria exposure did not improve model fit, so they were not included for Cox proportional hazards model. Hazard ratios are reported along with confidence intervals and p-values for IFNL4 (dG allele, dG/dG and dG/TT genotypes and TT allele, TT/TT genotype), G6PD alleles and sickle cell genotypes. A significant hazard ratio (p-value: 0.021) is observed for the IFNL4 genotype, indicating reduced malaria risk for those with the IFNL4-TT/TT genotype