Krause-Kyora Ben, da Silva Nicolas Antonio, Kaplan Elif, Kolbe Daniel, Wohlers Inken, Busch Hauke, Ellinghaus David, Caliebe Amke, Sezgin Efe, Nebel Almut, Schreiber Stefan
Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
Institute of Clinical Molecular Biology, Kiel University, Kiel, Germany.
EBioMedicine. 2025 Mar;113:105591. doi: 10.1016/j.ebiom.2025.105591. Epub 2025 Feb 8.
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.
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.
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.
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.
German Research Foundation (EXC 2167 390884018 and EXC 2150 390870439).
白细胞介素23受体（IL23R）基因中的次效变体rs11209026-A为欧洲人预防免疫相关疾病，尤其是炎症性肠病（IBD）提供了显著保护。如今，A等位基因在欧洲的平均出现频率为5%。
本研究包含来自欧洲的251个跨越14000多年的古代基因组。在这些样本中，研究重点是对rs11209026-A及其单倍型进行混合信息分析和选择扫描。
在安纳托利亚农民（AF）中发现rs11209026-A的频率较高（18%）。AF后来将该等位基因引入古代欧洲基因库。随后的基因混合导致其频率下降，并在欧洲形成了当前从西南到东北的等位基因频率梯度。rs11209026-A的地理分布可能影响IBD发病率梯度，该病在北欧和东欧发病率最高。
鉴于新石器时代从狩猎采集到农业的巨大变化，AF可能面临来自促炎性生活方式和饮食的选择压力。因此，保护性A等位基因可能通过减轻肠道炎症和微生物群失调而提高了生存率。该变体的适应性进化功能可能有助于现代IL-23中和疗法对慢性炎症性疾病的高效性和低副作用。
德国研究基金会（卓越集群2167 390884018和卓越集群2150 390870439）。
