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

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-lambda 4-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 (r(2) = 0.78 in this set) were weaker and lost significance after adjusting for rs368234815. We also analyzed all outcomes in relation to IFN-lambda 4-P70S groups. Our results implicate IFN-lambda 4 and not IFN-lambda 3 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.

Automated summary

Genetic polymorphisms in the IFNL3/IFNL4 genomic region have been associated with hepatitis C virus clearance, and may also play a role in immune response to other pathogens. In a cohort of 914 Malian children, specific variants were found to be associated with earlier onset of gastrointestinal infections, with IFN-lambda 4 identified as the primary functional cause of increased overall risk and younger age at first clinical episodes of common pediatric infections.