Journal Article

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

Capitani, Melania, Marsden, Brian D., Brooks, Isabel, Muise, Aleixo M., Kotlarz, Daniel, Zhou, Ying, Williams, Isabelle, Snapper, Scott B., Uhlig, Holm H., Ye, Ziqing, Klein, Christoph, Gartner, Lisa, Huang, Ying, Aschenbrenner, Dominik, Hu, Wenhui

2023

Overview

Balancing 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 pathogenic IL10RA variants that are associated with monogenic inflammatory bowel disease. We identify 36 non-synonymous and non-sense variants in the IL10RA gene. Since the majority of these IL10RA 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 pathogenic IL10RA 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 identify Schistosoma japonicum infection as plausible selection pressure driving variation in IL10RA . 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

• Publisher: Springer US,Springer Nature B.V
• Subject: alleles / Biomedical and Life Sciences / Biomedical research / Biomedicine / China / Crohn's disease / Cytokines / Evolution & development / Gastroenterology / Gene frequency / Genetic diversity / Health risk assessment / health services / heterozygosity / Heterozygote advantage / HIV / homozygosity / Hospitals / Human immunodeficiency virus / Humans / Immunology / Infections / Infectious Diseases / Inflammatory bowel disease / Inflammatory bowel diseases / Interleukin 10 / Interleukin-10 - genetics / Interleukin-10 Receptor alpha Subunit - genetics / Internal Medicine / Leukocytes, Mononuclear / Medical Microbiology / Natural selection / Original / Original Article / pathogenesis / Pathogens / Pediatrics / Peripheral blood mononuclear cells / Phosphorylation / Population / Population genetics / Receptors, Interleukin-10 - genetics / Schistosoma japonicum / selection pressure / Selection, Genetic / Stat3 protein / Structure-function relationships / Tuberculosis / White people