Early-life rotavirus infection susceptibility and later gastrointestinal cancer protection: Reverse antagonistic pleiotropy and potential vaccine benefits.

Rotavirus (RV) infection is a leading cause of gastroenteritis in children under five, often causing severe dehydration and hospitalization. The genetic factors influencing host susceptibility to severe RV infection remain poorly understood. We conducted whole-exome sequencing (WES) in children with severe RV infection and compared their profiles to those of healthy controls. Analyses identified seven candidate Single Nucleotide Polymorphisms (SNPs) across distinct genes, several of which are functionally linked to gastrointestinal cancer pathways. Transcriptomic data from acutely infected patients confirmed differential expression in at least two candidate genes. Polygenic risk score (PRS) analyses revealed a reduced risk of gastrointestinal cancer among RV-infected individuals. Supporting this, epigenomic and transcriptomic data from gastric cancer patients indicated that alterations in these genes may affect cancer progression. Extended haplotype homozygosity (EHH) analyses showed signatures of recent positive selection in top SNP/gene candidates. These findings support a model of reverse antagonistic pleiotropy, where genetic variants that increase early-life RV susceptibility may protect against gastrointestinal cancers in adulthood. This raises the hypothesis that RV vaccination, by replicating immunological and epigenetic effects of natural infection without early-life harm, could confer similar protective benefits. Overall, these results highlight the long-term impact of early-life viral exposures on host health and cancer risk.