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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.

SUBMITTER: Prokunina-Olsson L

PROVIDER: S-EPMC8042471 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundLate blight (caused by Phytophthora infestans) is a devastating potato disease that has been found to occur earlier in the season over the last decades in Fennoscandia. Up until now the reasons for this change have not been investigated. Possible explanations for this change are climate alterations, changes in potato production or changes in pathogen biology, such as increased fitness or changes in gene flow within P. infestans populations. The first incidence of late blight is of high economic importance since fungicidal applications should be typically applied two weeks before the first signs of late blight and are repeated on average once a week.MethodsWe use field observations of first incidence of late blight in experimental potato fields from five sites in Sweden and Finland covering a total of 30 years and investigate whether the earlier incidence of late blight can be related to the climate.ResultsWe linked the field data to meteorological data and found that the previous assumption, used in common late blight models, that the disease only develops at relative humidity levels above 90% had to be rejected. Rather than the typically assumed threshold relationship between late blight disease development and relative humidity we found a linear relationship. Our model furthermore showed two distinct responses of late blight to climate. At the beginning of the observation time (in Sweden until the early 90s and in Finland until the 2000s) the link between climate and first incidence was very weak. However, for the remainder of the time period the link was highly significant, indicating a change in the biological properties of the pathogen which could for example be a change in the dominating reproduction mode or a physiological change in the response of the pathogen to climate.ConclusionsThe study shows that models used in decision support systems need to be checked and re-parametrized regularly to be able to capture changes in pathogen biology. While this study was performed with data from Fennoscandia this new pathogen biology and late blight might spread to (or already be present at) other parts of the world as well. The strong link between climate and first incidence together with the presented model offers a tool to assess late blight incidence in future climates.

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

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