Pathogenic Interleukin-10 Receptor Alpha Variants in Humans — Balancing Natural Selection and Clinical Implications

AbstractBalancing natural selection is a process by which genetic variants arise in populations that are beneficial to heterozygous carriers, but pathogenic when homozygous. We systematically investigated the prevalence, structural, and functional consequences of pathogenicIL10RA variants that are associated with monogenic inflammatory bowel disease. We identify 36 non-synonymous and non-sense variants in theIL10RA gene. Since the majority of theseIL10RA variants have not been functionally characterized, we performed a systematic screening of their impact on STAT3 phosphorylation upon IL-10 stimulation. Based on the geographic accumulation of confirmed pathogenicIL10RA variants in East Asia and in Northeast China, the distribution of infectious disorders worldwide, and the functional evidence of IL-10 signaling in the pathogenesis, we identifySchistosoma japonicum infection as plausible selection pressure driving variation inIL10RA. Consistent with this is a partially augmented IL-10 response in peripheral blood mononuclear cells from heterozygous variant carriers. A parasite-driven heterozygote advantage through reduced IL-10 signaling has implications for health care utilization in regions with high allele frequencies and potentially indicates pathogen eradication strategies that target IL-10 signaling.Graphical abstract
Source: Journal of Clinical Immunology - Category: Allergy & Immunology Source Type: research