IFN-λ4 is associated with increased risk and earlier occurrence of gastrointestinal, respiratory and malarial infections in Malian children

Abstract

Genetic polymorphisms within the IFNL3/IFNL4 genomic region encoding type III interferons have been strongly associated with impaired clearance of hepatitis C virus (HCV) infection. We hypothesized that this association might extend to the immune response to other pathogens as well. In a cohort of 914 Malian children enrolled at birth, we analyzed episodes of malaria, gastrointestinal and respiratory infections in relation to two genetic polymorphisms functionally affecting type III interferons -rs368234815 (IFN-λ4) and rs4803217 (IFN-λ3), using information for 30,626 clinic visits from birth through 1-5 years of follow-up. Compared to children with the rs368234815-TT/TT genotype (IFN-λ4-Null), each copy of the rs368234815-dG allele was associated with an earlier first episode of a gastrointestinal infection (p=0.004), malaria (p=0.044) or respiratory infection (p=0.045).The risk of ever experiencing an infection during the follow-up was also significantly increased with each copy of the rs368234815-dG allele -for gastrointestinal infections (OR=1.5, 95%CI (1.11-2.03), p=0.0079) and malaria (OR=1.32, 95%CI (1.04-1.68, p=0.022), but not respiratory infections (p=0.58). IFNL4-rs368234815 and IFNL3-rs4803217 were in moderate linkage disequilibrium in this population (r 2 =0.78). All the associations for rs4803217 were weaker and lost significance after adjusting for rs368234815, implicating IFN-λ4 and not IFN-λ3 as the primary cause of these associations.Thus, our results suggest the role of IFN-λ4 in several infections in young children.Recently, a genetic association was reported for IFNL4-rs12979860-T and rs368234815-dG alleles with impaired clearance of respiratory RNA viruses in nasal swabs of children from Rwanda (11). The observed effect was in the same direction as for clearance of HCV reported in many studies, suggesting that the negative impact of IFN-λ4 on clearance of RNA viruses is not limited by HCV but extends to respiratory RNA viruses. In our study, we observed an earlier occurrence of RI in children with rs368234815-dG allele, but the association with increased susceptibility to RI in these children did not reach statistical significance. This could be because respiratory symptoms recorded during clinic visits in our study were very common (were experienced by 97.7% of children during follow-up),

Monocytes differentiated into macrophages and dendritic cells in the presence of human IFN-λ3 or IFN-λ4 show distinct phenotypes

“…Genetic studies have shown that similar to its effect on HCV infections, the ΔG allele has a proviral effect in other respiratory viral infections and a similar risk phenotype in malaria infections. 25,26,27 The results shown here ascribe an overall Th2 phenotype to IFN-4, which may explain the above mentioned genetic association studies. We do note that our results from Figure 6B show an overall Th1 phenotype associated with IFN-4, whereas the results in Figure 9 show it to have a Th2 phenotype.…”

“…IFN-4 has been studied as an antiviral cytokine [1][2][3][4][5][6][7] ; however, the genetic association of the dinucleotide polymorphism rs368234815, which is responsible for IFN-4 expression, extends beyond viral infections, including several inflammatory disorders, [15][16][17][18][19][20][21][22] and even parasitic infections 27 and cancer. [28][29][30] Two SNPs are known to poten-tially regulate the expression of IFN-3 46,47 and it is not clear in many of the genetic associations which among IFN-3 and IFN-4 could be the causal factor.…”

“… 8 , 9 , 14 Inflammatory diseases, including asthma, 15 , 16 chronic obstructive pulmonary disease, 17 systemic lupus erythematosus, 18 nonalcoholic fatty liver disease, 19 liver fibrosis, 20 , 21 pulmonary fibrosis, 22 among others, are known to be influenced by the IFN- λ locus genetic polymorphisms. Moreover, a number of infectious diseases other than HCV infections have been associated with the IFN- λ locus genetic variants, 7 including cytomegalovirus infections, 23 the human immunodeficiency viruses, 24 respiratory viruses, 25 , 26 gastrointestinal viruses, 27 and even malarial infections. 27 In addition, some studies have also reported an association between the IFN- λ locusgenetic variants with cancers such as prostate cancer 28 , 29 and mucinous ovarian carcinoma.…”

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

“…carriers of IFNL4-dG allele) negatively affects the ability to protect against P. falciparum malaria during infancy in children living in a malaria holoendemic region of East Africa. These results are consistent with a longitudinal study of children in Mali, West Africa [28]. The underlying mechanism as to why the ability to express a type III interferon is not protective against a parasitic infection remains an important question for future studies.…”

“…The reason why the ancestral, IFNL4-dG allele, is still conserved in the African population and has not changed to the derived human-speci c allele, IFNL4-TT allele, remains unknown. Carriage of the IFNL4-dG allele is clearly not providing protection against HCV [4,[7][8][9], respiratory infections [11], gastrointestinal infections [28], human coronavirus, HCoV-229E or MERS-CoV [29], and now we have found similar results for P. falciparum malaria in children. Undoubtedly there are other selection pressures conserving this allele in this population.…”