Neolithic introgression of IL23R-related protection against chronic inflammatory bowel diseases in modern EuropeansResearch in context

Neolithic introgression of IL23R-related protection against chronic inflammatory bowel diseases in modern EuropeansResearch in context

Summary: Background: The hypomorphic variant rs11209026-A in the IL23R gene provides significant protection against immune-related diseases in Europeans, notably inflammatory bowel diseases (IBD). Today, the A-allele occurs with an average frequency of 5% in Europe. Methods: This study comprised 25...

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Main Authors: Ben Krause-Kyora, Nicolas Antonio da Silva, Elif Kaplan, Daniel Kolbe, Inken Wohlers, Hauke Busch, David Ellinghaus, Amke Caliebe, Efe Sezgin, Almut Nebel, Stefan Schreiber, Sabine Schade-Lindig, Joachim Wahl, Carola Berszin, Michael Francken, Irina Görner, Kerstin Schierhold, Joachim Pechtl, Gisela Grupe, Johannes Müller
Format: Article
Language:English
Published: Elsevier 2025-03-01
Series:EBioMedicine
Subjects:
IL23R
IL-23-signalling
Ancient genomics
Crohn's disease
Ulcerative colitis
Inflammatory bowel diseases
Online Access:http://www.sciencedirect.com/science/article/pii/S2352396425000350
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Summary:Summary: Background: The hypomorphic variant rs11209026-A in the IL23R gene provides significant protection against immune-related diseases in Europeans, notably inflammatory bowel diseases (IBD). Today, the A-allele occurs with an average frequency of 5% in Europe. Methods: This study comprised 251 ancient genomes from Europe spanning over 14,000 years. In these samples, the investigation focused on admixture-informed analyses and selection scans of rs11209026-A and its haplotypes. Findings: rs11209026-A was found at high frequencies in Anatolian Farmers (AF, 18%). AF later introduced the allele into the ancient European gene-pool. Subsequent admixture caused its frequency to decrease and formed the current southwest-to-northeast allele frequency cline in Europe. The geographic distribution of rs11209026-A may influence the gradient in IBD incidence rates that are highest in northern and eastern Europe. Interpretation: Given the dramatic changes from hunting and gathering to agriculture during the Neolithic, AF might have been exposed to selective pressures from a pro-inflammatory lifestyle and diet. Therefore, the protective A-allele may have increased survival by reducing intestinal inflammation and microbiome dysbiosis. The adaptively evolved function of the variant likely contributes to the high efficacy and low side-effects of modern IL-23 neutralisation therapies for chronic inflammatory diseases. Funding: German Research Foundation (EXC 2167 390884018 and EXC 2150 390870439).
ISSN:2352-3964

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