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Aschenbrenner, D.* ; Ye, Z.* ; Zhou, Y.* ; Hu, W.* ; Brooks, I.* ; Williams, I.* ; Capitani, M.* ; Gartner, L.* ; Kotlarz, D.M. ; Snapper, S.B.* ; Klein, C.* ; Muise, A.M.* ; Marsden, B.D.* ; Huang, Y.* ; Uhlig, H.H.*

Pathogenic interleukin-10 receptor alpha variants in humans - balancing natural selection and clinical implications.

J. Clin. Immunol., DOI: 10.1007/s10875-022-01366-7 (2022)

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	Open Access Gold (Paid Option)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Il-10 ; Il10ra ; Inflammatory Bowel Disease ; Natural Selection

ISSN (print) / ISBN 0271-9142

e-ISSN 1573-2592

Journal Journal of Clinical Immunology

Publisher Springer

Publishing Place New York, NY

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Translational Genomics (ITG)