Parasites represent a major selective force for interleukin genes and shape the genetic predisposition to autoimmune conditions

TLDR

Human genes have evolved under constant infectious pressure, and the hygiene hypothesis suggests that reduced parasite exposure in modern societies leads to immune imbalances that increase susceptibility to autoimmune and allergic diseases, a premise reinforced by prior polymorphism studies linking interleukin loci to such conditions. The study aims to demonstrate that helminth exposure has been a major selective force shaping the evolution of specific interleukin genes across human populations. The authors estimated pathogen richness in 52 human populations and analyzed 91 interleukin genes, then correlated GWAS‑identified risk alleles with micropathogen richness to assess selection pressures. They identified five interleukin genes under balancing selection and found that six inflammatory bowel or celiac disease risk alleles correlate with micropathogen richness, supporting the hygiene hypothesis for IBD and highlighting potential targets for helminth susceptibility.

Abstract

Many human genes have adapted to the constant threat of exposure to infectious agents; according to the "hygiene hypothesis," lack of exposure to parasites in modern settings results in immune imbalances, augmenting susceptibility to the development of autoimmune and allergic conditions. Here, by estimating the number of pathogen species/genera in a specific geographic location (pathogen richness) for 52 human populations and analyzing 91 interleukin (IL)/IL receptor genes (IL genes), we show that helminths have been a major selective force on a subset of these genes. A population genetics analysis revealed that five IL genes, including IL7R and IL18RAP, have been a target of balancing selection, a selection process that maintains genetic variability within a population. Previous identification of polymorphisms in some of these loci, and their association with autoimmune conditions, prompted us to investigate the relationship between adaptation and disease. By searching for variants in IL genes identified in genome-wide association studies, we verified that six risk alleles for inflammatory bowel (IBD) or celiac disease are significantly correlated with micropathogen richness. These data support the hygiene hypothesis for IBD and provide a large set of putative targets for susceptibility to helminth infections.