IFN-λ4 is associated with increased risk and earlier occurrence of several common infections in African children

Abstract

Genetic polymorphisms within the IFNL3/IFNL4 genomic region, which encodes type III interferons, have been strongly associated with clearance of hepatitis C virus. We hypothesized that type III interferons might be important for the immune response to other pathogens as well. In a cohort of 914 Malian children, we genotyped functional variants IFNL4-rs368234815, IFNL4-rs117648444, and IFNL3-rs4803217 and analyzed episodes of malaria, gastrointestinal, and respiratory infections recorded at 30,626 clinic visits from birth up to 5 years of age. Compared to children with the rs368234815-TT/TT genotype (IFN-λ4-Null), rs368234815-dG allele was most strongly associated with an earlier time-to-first episode of gastrointestinal infections (p = 0.003). The risk of experiencing an infection episode during the follow-up was also significantly increased with rs368234815-dG allele, with OR = 1.53, 95%CI (1.13-2.07), p = 0.005 for gastrointestinal infections and OR = 1.30, 95%CI (1.02-1.65), p = 0.033 for malaria. All the associations for the moderately linked rs4803217 (r² = 0.78 in this set) were weaker and lost significance after adjusting for rs368234815. We also analyzed all outcomes in relation to IFN-λ4-P70S groups. Our results implicate IFN-λ4 and not IFN-λ3 as the primary functional cause of genetic associations with increased overall risk and younger age at first clinical episodes but not with recurrence or intensity of several common pediatric infections.

Fig. 1. Time-to-first episode of infections in relation to IFNL4- rs368234815 polymorphism in 914 children from the Mali birth cohort study.

Malaria – positivity by blood smear test with/without additional clinical symptoms, includes both severe (SM) and non-severe malaria; GII—gastrointestinal infections; RI—respiratory infections. The plots are for Kaplan–Meyer analysis, P values are for Cox proportional hazards regression models with per-allele linear trends, for malaria—adjusting for HBB status. Padj—additionally adjusting for sex and paternal tribes.

Fig. 2. Time-to-first episode of infections in relation to IFN-λ4-P70S group status in 914 children from the Mali birth cohort study.

Malaria – positivity by blood smear test with/without additional clinical symptoms, includes both severe (SM) and non-severe malaria; GII – gastrointestinal infections; RI – respiratory infections. The plots are for Kaplan-Meyer analysis, P values are for Cox proportional hazards regression models with per-group linear trends, for malaria – adjusting for HBB status. Padj – additionally adjusting for sex and paternal tribes.